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Glucagon and Glucagon‐like Peptide Production and Degradation

Timothy J. Kieffer, Mehboob A. Hussain, Joel F. Habener

10.1002/cphy.cp070208

Source: Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism

Originally published: 2001

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 History
1.1 Glucagon
1.2 Glucagon‐like Peptides
2 The Glucagon Superfamily of Peptide Hormones
3 Tissue Distribution of Proglucagon Expression
3.1 Pancreas
3.2 Intestine
3.3 Brain
4 Proglucagon Biosynthesis
4.1 Organization and Structure of the Proglucagon Gene
4.2 Regulation of Glucagon Gene Expression
4.3 Posttranslational Processing of Proglucagon
4.4 Chemistry and Structure
5 Regulation of Glucagon Secretion
5.1 Overview
5.2 Intracellular Signals
5.3 Nutrients
5.4 Endocrine/Paracrine
5.5 Neural
5.6 Pulsatility
6 Regulation of Glucagon‐like Peptide‐1 Secretion
6.1 Overview
6.2 Intracellular Signals
6.3 Nutrients
6.4 Endocrine
6.5 Neural
7 Metabolism and Degradation
7.1 Overview
7.2 Renal Clearance
7.3 Hepatic Clearance
7.4 Degradation in the Circulation
7.5 Biologically Active Fragments
8 Physiological Actions
8.1 Glucagon
8.2 Glucagon‐like Peptide‐1
8.3 Glucagon‐like Peptide‐2
9 Mechanisms of Action
9.1 Glucagon
9.2 Glucagon‐like Peptide‐1
9.3 Glucagon‐like Peptide‐2
10 Human Disease
10.1 Glucagon
10.2 Glucagon‐like Peptide‐1
10.3 Glucagon‐like Peptide‐2
Figure 1. Figure 1.

Demonstration of the incretin concept. Blood glucose (left) and insulin (right) responses following either intravenous or intrajejunal glucose infusion in normal subjects. Although plasma glucose levels following intravenous glucose infusion were greater than those following intrajejunal glucose infusion, the latter generated a larger insulin response. Based on these results, McIntyre et al. 559 suggested that a humoral substance was released from the jejunum during glucose absorption, acting in concert with glucose to stimulate insulin release from pancreatic β cells.

[From McIntyre et al. 559 with permission.]
Figure 2. Figure 2.

The enteroinsular axis. Following ingestion of nutrients, hormonal secretion from different cell types of the pancreatic islets may be modified by endocrine transmission, neurotransmission, and direct substrate stimulation. A, α; B, β; D, δ; PP, pancreatic polypeptide; FA, fatty acid; AA, amino acid; CHO, carbohydrate.

[From Creutzfeldt 144.]
Figure 3. Figure 3.

Amino acid sequences of the members of the superfamily of glucagon‐related peptides, including human glucagon, human glucagon‐like peptide (GLP), human glucose‐dependent insulinotropic polypeptide (GIP), exendins (Heloderma horridum), human secretin, human peptide histidine methionine (PHM), helospectins (H. horridum), helodermin (H. suspectum), human pituitary adenylate cyclase–activating polypeptide (PACAP), human PACAP‐related peptide (PRP), human growth hormone–releasing factor (GRF), and human vasoactive intestinal polypeptide (VIP). Residues identical to those of glucagon in the same position are shaded. Standard single‐letter abbreviations are used for amino acids.
Figure 4. Figure 4.

Amino acid sequences of proglucagon from seven mammalian species (Genbank accession numbers in parentheses). Major proglucagon products are indicated by bars. GRPP, glicentin‐related pancreatic peptide; IP‐1 and IP‐2, intervening peptides; GLP‐1 and GLP‐2, glucagon‐like peptides. Shaded residues are completely conserved between the seven species. Standard single‐letter abbreviations are used for amino acids.
Figure 5. Figure 5.

Amino acid sequences of vertebrate glucagons. Classes are indicated and residues identical to those of human glucagon in the same position are shaded. Standard single‐letter abbreviations are used for amino acids.
Figure 6. Figure 6.

Amino acid sequences of vertebrate glucagon‐like peptide‐1 (GLP‐1). Classes are indicated, and residues identical to those of human GLP‐1 in the same position are shaded. Standard single‐letter abbreviations are used for amino acids.
Figure 7. Figure 7.

Proposed developmental pathway of the endocrine pancreas in the mouse, showing interruptions of development in response to disruptions of the transcription factor genes IDX‐1, Isl‐1, Pax‐4, and Pax‐6. Knockouts of IDX‐1 and Isl‐1 result in early failure of the development of epithelial cells derived from the endodermal stem cell. IDX‐1 is a key factor in the very early development of all pancreatic epithelial cells, whereas Isl‐1 is required for the development of the dorsal mesenchyme; its failure leads to a specific arrest of development of the epithelial cells of the dorsal pancreas. Mice die at embryonic age 9.5 days. Pax‐4 prevents development of the β and δ cells and shunts development to the α cell lineage. The Pax‐6 knockout does the opposite: α cells do not develop, but some development occurs in β and δ cells. GLU, glucagon; INS, insulin; SOM somatostatin; PP, pancreatic polypeptide. Days of embryonic development (E10, E12, E17) and postnatal days (P1, P21) are indicated on the left.

[From Habener and Stoffers 315 with permission.]
Figure 8. Figure 8.

Glucagon‐like peptide‐1‐immunoreactive cells in human rectal mucosa. Cells occur in all regions of the crypts, with a predominance in the basal region (above). They reach the lumen via slender apical processes (below). Bars = 25 μm.

[From Eissele 204 with permission.]
Figure 9. Figure 9.

The proglucagon gene and encoded mRNA. The gene consists of six exons (E1–E6) and five introns (IA–IE). Alternative splicing of exons E4 and E5 occurs in salmonid fishes but not in mammals. The exons encode functional domains of the preproglucagon. S, signal peptide; N, amino‐terminal sequence of proglucagon; Glue, glucagon; GLP, glucagon‐like peptide; IP, intervening peptide. Pairs of basic residues that serve as posttranslational sites of processing of the preproglucagon encoded by the mRNA are shown. M, methionine encoded by AUG codon that initiates translation; Q, glutamine; H, histidine; K, lysine; R, arginine; UN‐TX, untranslated regions of mRNA.

[From Mojsov et al. 577 with permission.]
Figure 10. Figure 10.

DNA control elements and interactive transacting protein factors in the 2300 bp promoter of the rat glucagon gene. ISEs, intestine‐specific enhancers [includes the glucagon upstream enhancer 419]; CAP, CREB‐associated protein; CBS, CAP‐binding site; CREB, cAMP‐response element–binding protein; CRE, cAMP‐response element; IRBP, insulin‐responsive‐binding protein; X, unknown protein; CES, CCAAT/enhancer‐binding protein enhancer site; PKC, protein kinase HNF‐3, hepatic nuclear factor‐3; ETS, ubiquitous developmental transcription factors; IEF1, insulin enhancer factor‐1; BEBP, B element–binding protein (βTF1‐like); Brn4, Brain‐4; Pax6, paired homeodomain protein‐6; Cdx2, caudal‐related homeobox‐2; G1, G2, G3, G4, major α cell/islet enhancers; TATA, TATA box; TRX, transcription.

[From Habener 312 with permission.]
Figure 11. Figure 11.

Immunohistochemistry of adult rat pancreas with antisera against IDX‐1 (top) and Brain‐4 (bottom). Expression of IDX‐1 occurs in the insulin‐producing β cells located in the center of the islet, whereas Brain‐4 expression occurs in the glucagon‐producing cells located in the periphery of the islet.

[From Hussain et al. 388 with permisison.]
Figure 12. Figure 12.

Alternative posttranslational processing of proglucagon in pancreas, intestine, and brain. Enzymatic cleavage at specific pairs of basic residues in proglucagon produces numerous multifunctional peptide hormones involved in nutrient metabolism. K, lysine; R, arginine. The major bioactive hormones derived from proglucagon are glucagon in the pancreatic α cells and glucagon‐like peptide‐1 (GLP‐1; two isoforms, 7–37 and 7–36 NH2) and GLP‐2 in the intestinal L cells and brain. Numbers on proglucagon denote amino acid positions. GRPP, glicentin‐related pancreatic peptide; Gluc, glucagon; IP‐1 and IP‐2, intervening peptides; MPF, major proglucagon fragment. Isoform GLP‐1(7–36) is α‐amidated on the carboxy‐terminal arginine residue.

[From Mojsov et al. 577 with permission.]
Figure 13. Figure 13.

Effects of small changes in glucose concentration, within the physiological range, on secretion of insulin and glucagon by isolated perfused canine pancreas.

[From Unger and Orci 885 with permission.]
Figure 14. Figure 14.

Comparison of effects of graded glucose concentrations on glucagon (squares) and insulin (circles) release from perfused rat pancreas in the presence (filled symbols) or absence (open symbols) of 5 ng/ml glucose‐dependent insulinotropic polypeptide (GIP).

[From Pederson and Brown 661 with permission].
Figure 15. Figure 15.

Arginine‐induced glucagon release in isolated perfused pancreas.

[From Assan et al. 35 with permission.]
Figure 16. Figure 16.

Three autonomic inputs to the islet. 1 Preganglionic sympathetic nerves travel in the spinal cord and innervate the celiac ganglia, which supply the postganglionic sympathetic fibers that innervate the pancreas. These nerves release norepinepherine (NE) and, in some species, galanin (GAL). 2 Preganglionic parasympathetic nerves travel in the vagus and innervate intrapancreatic parasympathetic ganglia, which send postganglionic parasympathetic fibers to the islet and exocrine tissue. These nerves release acetylcholine (ACh) and vasoactive intestinal peptide (VIP). 3 Preganglionic sympathetic nerves from the spinal cord innervate the adrenal medulla and stimulate release of the sympathetic neurohormone epinephrine (EPI), which reaches the islet via the arterial circulation. Each of these three autonomic inputs to the pancreas is activated by hypoglycemic stress. These redundant autonomic pathways can be blocked at the ganglionic level either by a nicotinic antagonist like hexamethonium (HEX), by surgical disruption (X) of the preganglionic parasympathetic nerves traveling in the vagus (VAGX) and preganglionic sympathetic nerves traveling in the spinal cord (CORDX), or by lesioning the autonomic control centers in the ventromedial hypothalamus (VMHX). The islet effect of norepinephrine and acetylcholine, but not of neuropeptides such as galanin or vasoactive intestinal peptide, can be blocked by adrenergic and muscarinic antagonists.

[From Taborsky et al. 839 with permission.]
Figure 17. Figure 17.

Plasma immunoreactive glucagon concentrations before and during insulin plus variable‐rate glucose infusion, producing hypoglycemia of 2.5 mmol/1 in seven women during saline infusion (CONT) and in the same women during ganglionic blockade with trimethaphan (TRIM).

[From Havel and Ahren 328 with permission.]
Figure 18. Figure 18.

Pulsatile glucagon and insulin secretion. Plasma concentrations of glucose, insulin, and glucagon and the molar insulin: glucagon ratio (I/G) obtained every 2 min through a venous catheter in a fasted, unanesthetized monkey.

[From Goodner et al. 289 with permission.]
Figure 19. Figure 19.

Secretory responses of glucagon‐like peptide‐1 (GLP‐1) isopeptides [GLP‐1(7–37) and GLP‐1(7–36)amide to a meal in six nondiabetic subjects. Radioimmunoassays are relatively specific for detection of the differences in the COOH termini of the two isopeptides. Approximately 80% of the total GLP‐1 consists of the GLP‐1(7–36)amide.

[From Ørskov et al. 642 with permission.]
Figure 20. Figure 20.

A: Effects of different concentrations of synthetic glucagon‐like peptide‐1(7–37) [GLP‐1(7–37)] and glucagon on insulin secretion from perfused rat pancreas. Background perfusate contains 6.6 mM glucose. B: Glucose dependence of effect of 10‐9 M GLP‐1(7–37) on insulin secretion from isolated perfused rat pancreas. Insulin responses at 2.8 and 6.6 mM glucose determined by scale at left; those at 16.7 mM determined by scale at right.

[From Weir et al. 930 with permission.]
Figure 21. Figure 21.

Proposed ion channels and signal‐transduction pathways in a pancreatic β cell involved in the mechanisms of insulin secretion in response to glucose and glucagon‐like peptide‐1 (GLP‐1). The key elements of the model are the requirement of dual inputs of the glucose‐glycolysis signaling pathway and the GLP‐1 receptor‐mediated cAMP protein kinase A (PKA) pathways to effect closure of ATP‐sensitive potassium channels (K‐ATP). Closure of these channels results in a rise in the resting potential (depolarization) of the β cell, leading to opening of voltage‐sensitive calcium channels (Ca‐VS). Influx of Ca2+ through the open end of the voltage‐sensitive Ca channel triggers vesicular insulin secretion by exocytosis. Repolarization of the β cell is achieved by opening of calcium‐sensitive potassium channels (K‐Ca). It is believed that the GLP‐1 receptor is coupled to a stimulatory G protein (Gs) and a calcium‐calmodulin‐sensitive adenylate cyclase.

[From Holz and Habener 376 with permission.]
Figure 22. Figure 22.

Insulinotropic actions of glucagon‐like peptide‐1 (GLP‐1) on β cells mediated by activation of the cAMP signaling pathway. Binding of GLP‐1 to its receptor (Re) activates adenylate cyclase (Ac), resulting in formation of cAMP. Binding of cAMP to the regulatory (R) subunit of protein kinase A (PKA) results in release of the active catalytic (C) subunit. The active kinase then phosphorylates and, therefore, activates the nuclear transcriptional activator cAMP‐response element–binding protein (CREB) bound to the cAMP‐response element (CRE) located in the promoter of the insulin gene. This cascade of signaling results in stimulation of transcription of the insulin gene and increased insulin biosynthesis to replete stores of insulin secreted in response to nutrients (glucose) and incretins (GLP‐1, glucose‐dependent insulinotropic polypeptide).

[From Habener 311 with permission.]
Figure 23. Figure 23.

Reduced incretin effect in subjects with type 2 diabetes. Levels of plasma insulin (top) and plasma C peptide (bottom) after an oral glucose load (filled symbols) and during isoglycemic intravenous glucose infusion (open symbols) in metabolically healthy subjects (left) and NIDDM patients (right). The incretin effect of augmentation of insulin and C‐peptide stimulation by an oral glucose load compared to an equivalent amount of glucose infused intravenously is blunted in NIDDM subjects. IR = immunoreactive.

[From Nauck et al. 593 with permission.]
Figure 24. Figure 24.

Glucagon‐like peptide‐1(7–37) [(GLP‐1(7–37)] administered to diabetic subjects stimulates insulin secretion and lowers blood glucose levels in response to meals. Infusions of GLP‐1 (filled symbols; 5 ng · kg · min‐1) and saline (open symbols) in five non‐insulin‐dependent diabetic subjects were concurrent with ingestion of a standard test meal. *P < 0.05 GLP‐1(7–37) versus placebo.

[From Nathan et al. 592 with permission.]


Figure 1.

Demonstration of the incretin concept. Blood glucose (left) and insulin (right) responses following either intravenous or intrajejunal glucose infusion in normal subjects. Although plasma glucose levels following intravenous glucose infusion were greater than those following intrajejunal glucose infusion, the latter generated a larger insulin response. Based on these results, McIntyre et al. 559 suggested that a humoral substance was released from the jejunum during glucose absorption, acting in concert with glucose to stimulate insulin release from pancreatic β cells.

[From McIntyre et al. 559 with permission.]


Figure 2.

The enteroinsular axis. Following ingestion of nutrients, hormonal secretion from different cell types of the pancreatic islets may be modified by endocrine transmission, neurotransmission, and direct substrate stimulation. A, α; B, β; D, δ; PP, pancreatic polypeptide; FA, fatty acid; AA, amino acid; CHO, carbohydrate.

[From Creutzfeldt 144.]


Figure 3.

Amino acid sequences of the members of the superfamily of glucagon‐related peptides, including human glucagon, human glucagon‐like peptide (GLP), human glucose‐dependent insulinotropic polypeptide (GIP), exendins (Heloderma horridum), human secretin, human peptide histidine methionine (PHM), helospectins (H. horridum), helodermin (H. suspectum), human pituitary adenylate cyclase–activating polypeptide (PACAP), human PACAP‐related peptide (PRP), human growth hormone–releasing factor (GRF), and human vasoactive intestinal polypeptide (VIP). Residues identical to those of glucagon in the same position are shaded. Standard single‐letter abbreviations are used for amino acids.



Figure 4.

Amino acid sequences of proglucagon from seven mammalian species (Genbank accession numbers in parentheses). Major proglucagon products are indicated by bars. GRPP, glicentin‐related pancreatic peptide; IP‐1 and IP‐2, intervening peptides; GLP‐1 and GLP‐2, glucagon‐like peptides. Shaded residues are completely conserved between the seven species. Standard single‐letter abbreviations are used for amino acids.



Figure 5.

Amino acid sequences of vertebrate glucagons. Classes are indicated and residues identical to those of human glucagon in the same position are shaded. Standard single‐letter abbreviations are used for amino acids.



Figure 6.

Amino acid sequences of vertebrate glucagon‐like peptide‐1 (GLP‐1). Classes are indicated, and residues identical to those of human GLP‐1 in the same position are shaded. Standard single‐letter abbreviations are used for amino acids.



Figure 7.

Proposed developmental pathway of the endocrine pancreas in the mouse, showing interruptions of development in response to disruptions of the transcription factor genes IDX‐1, Isl‐1, Pax‐4, and Pax‐6. Knockouts of IDX‐1 and Isl‐1 result in early failure of the development of epithelial cells derived from the endodermal stem cell. IDX‐1 is a key factor in the very early development of all pancreatic epithelial cells, whereas Isl‐1 is required for the development of the dorsal mesenchyme; its failure leads to a specific arrest of development of the epithelial cells of the dorsal pancreas. Mice die at embryonic age 9.5 days. Pax‐4 prevents development of the β and δ cells and shunts development to the α cell lineage. The Pax‐6 knockout does the opposite: α cells do not develop, but some development occurs in β and δ cells. GLU, glucagon; INS, insulin; SOM somatostatin; PP, pancreatic polypeptide. Days of embryonic development (E10, E12, E17) and postnatal days (P1, P21) are indicated on the left.

[From Habener and Stoffers 315 with permission.]


Figure 8.

Glucagon‐like peptide‐1‐immunoreactive cells in human rectal mucosa. Cells occur in all regions of the crypts, with a predominance in the basal region (above). They reach the lumen via slender apical processes (below). Bars = 25 μm.

[From Eissele 204 with permission.]


Figure 9.

The proglucagon gene and encoded mRNA. The gene consists of six exons (E1–E6) and five introns (IA–IE). Alternative splicing of exons E4 and E5 occurs in salmonid fishes but not in mammals. The exons encode functional domains of the preproglucagon. S, signal peptide; N, amino‐terminal sequence of proglucagon; Glue, glucagon; GLP, glucagon‐like peptide; IP, intervening peptide. Pairs of basic residues that serve as posttranslational sites of processing of the preproglucagon encoded by the mRNA are shown. M, methionine encoded by AUG codon that initiates translation; Q, glutamine; H, histidine; K, lysine; R, arginine; UN‐TX, untranslated regions of mRNA.

[From Mojsov et al. 577 with permission.]


Figure 10.

DNA control elements and interactive transacting protein factors in the 2300 bp promoter of the rat glucagon gene. ISEs, intestine‐specific enhancers [includes the glucagon upstream enhancer 419]; CAP, CREB‐associated protein; CBS, CAP‐binding site; CREB, cAMP‐response element–binding protein; CRE, cAMP‐response element; IRBP, insulin‐responsive‐binding protein; X, unknown protein; CES, CCAAT/enhancer‐binding protein enhancer site; PKC, protein kinase HNF‐3, hepatic nuclear factor‐3; ETS, ubiquitous developmental transcription factors; IEF1, insulin enhancer factor‐1; BEBP, B element–binding protein (βTF1‐like); Brn4, Brain‐4; Pax6, paired homeodomain protein‐6; Cdx2, caudal‐related homeobox‐2; G1, G2, G3, G4, major α cell/islet enhancers; TATA, TATA box; TRX, transcription.

[From Habener 312 with permission.]


Figure 11.

Immunohistochemistry of adult rat pancreas with antisera against IDX‐1 (top) and Brain‐4 (bottom). Expression of IDX‐1 occurs in the insulin‐producing β cells located in the center of the islet, whereas Brain‐4 expression occurs in the glucagon‐producing cells located in the periphery of the islet.

[From Hussain et al. 388 with permisison.]


Figure 12.

Alternative posttranslational processing of proglucagon in pancreas, intestine, and brain. Enzymatic cleavage at specific pairs of basic residues in proglucagon produces numerous multifunctional peptide hormones involved in nutrient metabolism. K, lysine; R, arginine. The major bioactive hormones derived from proglucagon are glucagon in the pancreatic α cells and glucagon‐like peptide‐1 (GLP‐1; two isoforms, 7–37 and 7–36 NH2) and GLP‐2 in the intestinal L cells and brain. Numbers on proglucagon denote amino acid positions. GRPP, glicentin‐related pancreatic peptide; Gluc, glucagon; IP‐1 and IP‐2, intervening peptides; MPF, major proglucagon fragment. Isoform GLP‐1(7–36) is α‐amidated on the carboxy‐terminal arginine residue.

[From Mojsov et al. 577 with permission.]


Figure 13.

Effects of small changes in glucose concentration, within the physiological range, on secretion of insulin and glucagon by isolated perfused canine pancreas.

[From Unger and Orci 885 with permission.]


Figure 14.

Comparison of effects of graded glucose concentrations on glucagon (squares) and insulin (circles) release from perfused rat pancreas in the presence (filled symbols) or absence (open symbols) of 5 ng/ml glucose‐dependent insulinotropic polypeptide (GIP).

[From Pederson and Brown 661 with permission].


Figure 15.

Arginine‐induced glucagon release in isolated perfused pancreas.

[From Assan et al. 35 with permission.]


Figure 16.

Three autonomic inputs to the islet. 1 Preganglionic sympathetic nerves travel in the spinal cord and innervate the celiac ganglia, which supply the postganglionic sympathetic fibers that innervate the pancreas. These nerves release norepinepherine (NE) and, in some species, galanin (GAL). 2 Preganglionic parasympathetic nerves travel in the vagus and innervate intrapancreatic parasympathetic ganglia, which send postganglionic parasympathetic fibers to the islet and exocrine tissue. These nerves release acetylcholine (ACh) and vasoactive intestinal peptide (VIP). 3 Preganglionic sympathetic nerves from the spinal cord innervate the adrenal medulla and stimulate release of the sympathetic neurohormone epinephrine (EPI), which reaches the islet via the arterial circulation. Each of these three autonomic inputs to the pancreas is activated by hypoglycemic stress. These redundant autonomic pathways can be blocked at the ganglionic level either by a nicotinic antagonist like hexamethonium (HEX), by surgical disruption (X) of the preganglionic parasympathetic nerves traveling in the vagus (VAGX) and preganglionic sympathetic nerves traveling in the spinal cord (CORDX), or by lesioning the autonomic control centers in the ventromedial hypothalamus (VMHX). The islet effect of norepinephrine and acetylcholine, but not of neuropeptides such as galanin or vasoactive intestinal peptide, can be blocked by adrenergic and muscarinic antagonists.

[From Taborsky et al. 839 with permission.]


Figure 17.

Plasma immunoreactive glucagon concentrations before and during insulin plus variable‐rate glucose infusion, producing hypoglycemia of 2.5 mmol/1 in seven women during saline infusion (CONT) and in the same women during ganglionic blockade with trimethaphan (TRIM).

[From Havel and Ahren 328 with permission.]


Figure 18.

Pulsatile glucagon and insulin secretion. Plasma concentrations of glucose, insulin, and glucagon and the molar insulin: glucagon ratio (I/G) obtained every 2 min through a venous catheter in a fasted, unanesthetized monkey.

[From Goodner et al. 289 with permission.]


Figure 19.

Secretory responses of glucagon‐like peptide‐1 (GLP‐1) isopeptides [GLP‐1(7–37) and GLP‐1(7–36)amide to a meal in six nondiabetic subjects. Radioimmunoassays are relatively specific for detection of the differences in the COOH termini of the two isopeptides. Approximately 80% of the total GLP‐1 consists of the GLP‐1(7–36)amide.

[From Ørskov et al. 642 with permission.]


Figure 20.

A: Effects of different concentrations of synthetic glucagon‐like peptide‐1(7–37) [GLP‐1(7–37)] and glucagon on insulin secretion from perfused rat pancreas. Background perfusate contains 6.6 mM glucose. B: Glucose dependence of effect of 10‐9 M GLP‐1(7–37) on insulin secretion from isolated perfused rat pancreas. Insulin responses at 2.8 and 6.6 mM glucose determined by scale at left; those at 16.7 mM determined by scale at right.

[From Weir et al. 930 with permission.]


Figure 21.

Proposed ion channels and signal‐transduction pathways in a pancreatic β cell involved in the mechanisms of insulin secretion in response to glucose and glucagon‐like peptide‐1 (GLP‐1). The key elements of the model are the requirement of dual inputs of the glucose‐glycolysis signaling pathway and the GLP‐1 receptor‐mediated cAMP protein kinase A (PKA) pathways to effect closure of ATP‐sensitive potassium channels (K‐ATP). Closure of these channels results in a rise in the resting potential (depolarization) of the β cell, leading to opening of voltage‐sensitive calcium channels (Ca‐VS). Influx of Ca2+ through the open end of the voltage‐sensitive Ca channel triggers vesicular insulin secretion by exocytosis. Repolarization of the β cell is achieved by opening of calcium‐sensitive potassium channels (K‐Ca). It is believed that the GLP‐1 receptor is coupled to a stimulatory G protein (Gs) and a calcium‐calmodulin‐sensitive adenylate cyclase.

[From Holz and Habener 376 with permission.]


Figure 22.

Insulinotropic actions of glucagon‐like peptide‐1 (GLP‐1) on β cells mediated by activation of the cAMP signaling pathway. Binding of GLP‐1 to its receptor (Re) activates adenylate cyclase (Ac), resulting in formation of cAMP. Binding of cAMP to the regulatory (R) subunit of protein kinase A (PKA) results in release of the active catalytic (C) subunit. The active kinase then phosphorylates and, therefore, activates the nuclear transcriptional activator cAMP‐response element–binding protein (CREB) bound to the cAMP‐response element (CRE) located in the promoter of the insulin gene. This cascade of signaling results in stimulation of transcription of the insulin gene and increased insulin biosynthesis to replete stores of insulin secreted in response to nutrients (glucose) and incretins (GLP‐1, glucose‐dependent insulinotropic polypeptide).

[From Habener 311 with permission.]


Figure 23.

Reduced incretin effect in subjects with type 2 diabetes. Levels of plasma insulin (top) and plasma C peptide (bottom) after an oral glucose load (filled symbols) and during isoglycemic intravenous glucose infusion (open symbols) in metabolically healthy subjects (left) and NIDDM patients (right). The incretin effect of augmentation of insulin and C‐peptide stimulation by an oral glucose load compared to an equivalent amount of glucose infused intravenously is blunted in NIDDM subjects. IR = immunoreactive.

[From Nauck et al. 593 with permission.]


Figure 24.

Glucagon‐like peptide‐1(7–37) [(GLP‐1(7–37)] administered to diabetic subjects stimulates insulin secretion and lowers blood glucose levels in response to meals. Infusions of GLP‐1 (filled symbols; 5 ng · kg · min‐1) and saline (open symbols) in five non‐insulin‐dependent diabetic subjects were concurrent with ingestion of a standard test meal. *P < 0.05 GLP‐1(7–37) versus placebo.

[From Nathan et al. 592 with permission.]
References
 1. Abello, J., F., Ye, A. Bosshard, C. Bernard, J.‐C. Cuber, and J.‐A. Chayvialle. Stimulation of glucagon‐like peptide‐1 secretion by muscarinic agonist in a murine intestinal endocrine cell line. Endocrinology 134: 2011–2017, 1994.
 2. Abrahamsen, E., and E. Nishimura. Regulation of glucagon and glucagon‐like peptide‐1 receptor messenger ribonucleic acid expression in cultured rat pancreatic islets by glucose, cyclic adenosine 3′,5′‐monophosphate, and glucocorticoids. Endocrinology 136: 1572–1578, 1995.
 3. Abrahamsen, N., K., Lundgren, and E. Nishimura. Regulation of glucagon receptor mRNA in cultured primary rat hepatocytes by glucose and cAMP. J. Biol. Chem. 270: 15853–15857, 1995.
 4. Ackerman, G. A., J., Yang, and K. W. Wolken. Differential surface and internalization of glucagon by peripheral leukocytes. J. Histochem. Cytochem. 31: 433–440, 1983.
 5. Adelhorst, K., B. B., Hedgegard, L. B. Knudsen, and O. Kirk. Structure–activity studies of glucagon‐like peptide‐1. J. Biol. Chem. 269: 6275–6278, 1994.
 6. Adrian, R. E., S. R., Bloom, K. Hermansen, and J. Iversen. Pancreatic polypeptide, glucagon and insulin secretion from the isolated perfused canine pancreas. Diabetologia 14: 413–417, 1978.
 7. Adrian, T. E., G. H., Ballantyne, W. E. Longo, A. J. Bichik, S. Graham, M. D. Bason, R. P. Tierney, and I. M. Modlin. Deoxycholate is an important releaser of peptide YY and enteroglucagon from the human colon. Gut 34: 1219–1224, 1993.
 8. Adrian, T. E., S. R., Bloom, H. S. Besterman, A. J. Barnes, J. V. C. Cook, R. C. G. Russell, and R. G. Faber. Mechanisms of pancreatic polypeptide release in man. Lancet 1: 161–163, 1977.
 9. Aguilar‐Parada, E., A. M., Eisentraut, and R. H. Unger. Effects of starvation on plasma pancreatic glucagon in normal man. Diabetes 18: 717–723, 1969.
 10. Ahlgren, U., S. L., Pfaff, T. M. Jessell, T. Edlund, and H. Edlund. Independent requirement for ISL1 in formation of pancreatic mesenchyme and islet cells. Nature 385: 257–260, 1997.
 11. Ahren, B., G., Bottcher, S. Kowalyk, B. E. Dunning, F. Sundler, and G. J. Taborsky, Jr.. Galanin is co‐localized with noradrenaline and neuropeptide Y in dog pancreas and celiac ganglion. Cell Tissue Res. 261: 49–58, 1990.
 12. Ahren, B., R., Hakanson, L. I. K. Sjolund, and F. Sundler. GIP‐like immunoreactivity in glucagon cells. Interactions between GIP and glucagon on insulin release. Acta Physiol. Scand. 112: 233–242, 1981.
 13. Ahren, B., H., Larsson, and J. J. Holst. Effects of glucagon‐like peptide‐1 on islet function and insulin sensitivity in noninsulin‐dependent diabetes mellitus. J. Clin. Endocrinol. Metab. 82: 473–478, 1997.
 14. Ahren, B., G. J. Taborsky, Jr., and D., Porte. Neuropeptidergic versus cholinergic and adrenergic regulation of islet hormone secretion. Diabetologia 29: 827–836, 1986.
 15. Akpan, J. O., M. C., Hurley, and W. E. Lands. Insulin and glucagon secretion in essentially fatty acid deficient rats. Acta Diabetol. Lat. 18: 147–156, 1981.
 16. Alberti, K. G., N. J., Christensen, S. E. Christensen, A. P. Hansen, J. Iversen, K. Lundbaek, K. Seyer‐Hansen, and H. Orskov. Inhibition of insulin secretion by somatostatin. Lancet 2: 1299–1301, 1973.
 17. Alford, F. P., S. R., Bloom, and J. D. N. Nabarro. Glucagon metabolism in man. Studies on the metabolic clearance rate and the plasma acute disappearance time of glucagon in normal and diabetic subjects. J. Clin. Endocrinol. Metab. 43: 830–838, 1976.
 18. Alford, F. P., F. J., Dudley, D. J. Chisholm, and D. M. Findlay. Effect of portasystemic venous shunt surgery on hyperglucagonemia in cirrhosis: paired studies of the pre‐ and post‐shunt subjects. Gut 20: 817–824, 1979.
 19. Al‐Mukhar, M. Y. T., G. R., Sagor, M. A. Ghatei, S. R. Bloom, and N. A. Wright. The role of pancreatico‐biliary secretions in intestinal adaptation after resection, and its relationship to plasma enteroglucagon. Br. J. Surg. 70: 398–400, 1983.
 20. Alpert, S., D., Hanahan, and G. Teitelman. Hybrid insulin genes reveal a developmental lineage for pancreatic endocrine cells and imply relationship with neurons. Cell 53: 295–308, 1988.
 21. Amatruda, J. M., and J. N. Livingston. The search for glucagon antagonists. In: Glucagon III, edited by P. J. Lefèbvre. Heidelberg: Springer‐Verlag, 1996, p. 133–148.
 22. Amiel, S. A., H. R., Archibald, G. Chusney, A. J. K. Williams, and E. A. M. Gale. Ketone infusion lowers hormonal responses to hypoglycaemia: evidence for acute cerebral utilization of a non‐glucose fuel. Clin. Sci. (Colch.) 81: 189–194, 1991.
 23. Amir, S.. Central glucagon‐induced hyperglycemia is mediated by combined activation of the adrenal medulla and sympathetic nerve endings. Physiol. Behav. 37: 563–566, 1986.
 24. Andersen, D. K. K., D., Elahi, and J. C. Brown. Oral glucose augmentation of insulin secretion: interactions of gastric inhibitory polypeptide with ambient glucose and insulin levels. J. Clin. Invest. 62: 152–161, 1978.
 25. Andreasen, J. J., C., Ørskov, and J. J. Holst. Secretion of glucagon‐like peptide‐1 and reactive hypoglycemia after partial gastrectomy. Digestion 55: 221–228, 1994.
 26. Andrew, A.. An experimental investigation into the possible neural crest origin of pancreatic APUD (islet) cells J. Embryol. Exp. Morphol. 35: 577–593, 1976.
 27. Andrews, S. S., S. A., Lopez, and W. G. Blackard. Effects of lipids on glucagon secretion in man. Metabolism 24: 35–44, 1975.
 28. Arnould, Y., R., Bellens, J. R. M. Franckson, and V. Conrad. Insulin response and glucose‐C14 disappearance rate during the glucose tolerance test in the unanethetized dog. Metabolism 12: 1122–1131, 1963.
 29. Aronson, N. N., Jr., and A. J., Barret. The specificity of cathepsin B. Hydrolysis of glucagon at the C‐terminus by a peptidyldipeptidase mechanism. Biochem. J. 171: 759–765, 1978.
 30. Ashby, J. P., and R. N. Speake. Insulin and glucagon secretion from isolated islets of Langerhans. The effects of calcium ionophores. Biochem. J. 150: 88–96, 1975.
 31. Asplin, C. M., T. L., Paquette, and J. P. Palmer. In vivo inhibition of glucagon secretion by paracrine beta cell activity in man. J. Clin. Invest. 68: 314–318, 1981.
 32. Asplin, C. M., P. K., Raghu, D. J. Koerker, and J. P. Palmer. Glucose counterregulation during recovery from neuroglucopenia: which mechanism is important? Metabolism 34: 15–18, 1985.
 33. Asplin, C. M., P. L., Werner, J. B. Halter, P. M. Hollander, and J. P. Palmer. Autonomic nervous system control of glucagon secretion during neuroglucopenia. Endocrinology 112: 1585–1589, 1983.
 34. Assan, R.. In vivo metabolism of glucagon. In: Glucagon: Molecular Physiology, Clinical and Therapeutic Implications, edited by P. J. Lefèbvre and R. H. Unger. New York: Pergamon, 1972, p. 45.
 35. Assan, R., J. R., Attali, G. Ballerio, J. Boillot, and J. R. Girard. Glucagon secretion induced by natural and artificial amino acids in the perfused rat pancreas. Diabetes 26: 300–307, 1977.
 36. Assan, R., J., Boillot, J. R. Attali, E. Soufflet, and G. Ballerio. Diphasic glucagon release induced by arginine in the perfused rat pancreas. Nature (New Biol.) 239: 125–126, 1972.
 37. Assan, R., S., Efendic, R. Luft, and E. Cerasi. Dose‐kinetics of pancreatic glucagon responses to arginine and glucose in subjects with normal and impaired pancreatic B cell function. Diabetologia 21: 452–459, 1981.
 38. Assan, R., M., Marre, and M. Gormley. The amino acid–induced secretion of glucagon. In: Handbook of Experimental Pharmacology, edited by P. J. Lefèbvre. Berlin: Springer‐Verlag, 1983, p. 19–42.
 39. Assan, R., G., Rosselin, and J. Dolais. The effects of perfusion and amino acid ingestion in glucagonemia. J. Annu. Diabetol. Hotel Dieu 7: 25–41, 1967.
 40. Assan, R., G., Tchobroutsky, and M. Derot. Glucagon radioimmunoassay: technical problems and recent data. Horm. Metab. Res. 3 (Suppl. 3): 82–90, 1971.
 41. Attali, J. R., J., Boillot, J. R. Girard, and R. Assan. Glucagon secretion and glucose metabolism in the pancreas. J. Annu. Diabetol. Hotel Dieu 259–267, 1979.
 42. Authier, F., and B. Desbuquois. Degradation of glucagon in isolated liver endosomes. ATP‐dependence and partial characterization of degradation products. Biochem. J. 280: 211–218, 1991.
 43. Authier, F., M., Janicot, F. Lederer, and B. Desbuquois. Fate of injected glucagon taken up by rat liver in vivo. Degradation of internalized ligand in the endosomal compartment. Biochem. J. 272: 703–712, 1990.
 44. Baldissera, F. G. A., J. J., Holst, S. Knuhtsen, L. Hilstedt, and O. V. Nielsen. Oxyntomodulin (glicentin 33–69) pharmacokinetics, binding to liver cell membranes, effects on isolated perfused pig pancreas, and secretion from isolated perfused small bowel. Regul. Pept. 21: 151–166, 1988.
 45. Balks, H. J., J. J., Holst, V. Z. Mühlen, and G. Brabant. Rapid oscillations in plasma glucagon‐like peptide‐1 (GLP‐1) in humans: cholinergic control of GLP‐1 secretion via muscarinic receptors. J. Clin. Endocrinol. Metab. 82: 786–790, 1997.
 46. Banting, F. G., and C. H. Best. The internal secretion of the pancreas. J. Lab. Clin. Med. 7: 25–41, 1921.
 47. Barazzone, P., P., Gorden, J.‐L. Carpentier, L. Orci, P. Freychet, and B. Canivet. Binding, internalization, and lsyosomal association of 125I‐glucagon in isolated rat hepatocytes. J. Clin. Invest. 66: 1081–1093, 1980.
 48. Barber, D. L., A. M., Cacace, D. T. Raucci, and M. B. Ganz. Fatty acids stereospecifically stimulate neurotensin release and increase [Ca2+]i in enteric endocrine cells. Am. J. Physiol. 261 (Gastrointest. Liver Physiol. 24): G497–G503, 1991.
 49. Barber, D. L., M., Gregor, and A. H. Soll. Somatostatin and muscarinic inhibition of canine enteric endocrine cells: cellular mechanisms. Am. J. Physiol. 253 (Gastrointest Liver Physiol. 6): G684–G689, 1987.
 50. Barden, N., J. P., Cote, M. Lavoie, and A. Dupont. Secretion of somatostatin by rat islets of Langerhans and gastric mucosa and a role for pancreatic somatostatin in the regulation of glucagon release. Metabolism 27: 1215–1218, 1978.
 51. Barden, N., M., Lavoie, A. Dupont, J. Cote, and J. P. Cote. Stimulation of glucagon release by addition of anti‐somatostatin serum to islets of Langerhans in vitro. Endocrinology 101: 635–638, 1977.
 52. Barseghian, G., and R. Levine. Effect of corticosterone on insulin and glucagon secretion by the isolated perfused rat pancreas. Endocrinology 106: 547–552, 1980.
 53. Barseghian, G., R., Levine, and P. Epps. Direct effect of Cortisol and cortisone on insulin and glucagon secretion. Endocrinology 111: 1648–1651, 1982.
 54. Bastl, C., F. O., Finkelstein, R. Sherwin, R. Hendler, P. Felig, and J. P. Hayslett. Renal extraction of glucagon in rats with normal and reduced renal function. Am. J. Physiol. 233: (Renal Fluid Electrolyte Physiol. 2): F67–F71, 1977.
 55. Baum, J., B. E. Simons, Jr., R. H. Unger and L. L. Madison. Localization of glucagon in the alpha cells in the pancreatic islet by immunofluorescent techniques. Diabetes 11: 371–374, 1962.
 56. Bayliss, W. M., and E. H. Starling. Mechanism of pancreatic secretion. J. Physiol. (Lond.) 28: 235–334, 1902.
 57. Bell, G. I.. The glucagon superfamily: precursor structure and gene organization. Peptides 7 (Suppl. 1): 27–36, 1986.
 58. Bell, G. I., R., Sanchez‐Pescador, P. J. Layboum, and R. C. Najarian. Exon duplication and divergence in the human preproglucagon gene. Nature 304: 368–371, 1983.
 59. Bell, G. I., R. F., Santerre, and G. T. Mullenbach. Hamster proglucagon contains the sequence of glucagon and two related peptides. Nature 302: 716–718, 1983.
 60. Benson, J., D., Johnson, J. Palmer, P. Werner, and J. Ensinck. Glucagon and catecholamine secretion during hypoglycemia in normal and diabetic man. J. Clin. Endocrinol. Metab. 44: 459–464, 1977.
 61. Berts, A., A., Ball, E. Gylfe, and B. Hellman. Suppression of Ca2+ oscillations in glucagon‐producing alpha 2‐cells by insulin/glucose and amino acids. Biochim. Biophys. Acta 1310: 212–216, 1996.
 62. Berts, A., E., Gylfe, and B. Hellman. Ca2+ oscillations in pancreatic islet cells secreting glucagon and somatostatin. Biochem. Biophys. Res. Commun. 208: 644–649, 1995.
 63. Berts, A., E., Gylfe, and B. Hellman. Cytoplasmic Ca2+ in glucagon‐producing pancreatic alpha‐cells exposed to carbachol and agents affecting Na+ fluxes. Endocrine 6: 79–83, 1997.
 64. Besterman, H. S., S. R., Bloom, and D. L. Sarson. Gut hormone profile in coeliac disease. Lancet i: 785–788, 1975.
 65. Beylot, M., S., Picard, and S. Chambrier. Effect of physiological concentrations of insulin and glucagon on the relationship between nonesterified fatty acids availability and ketone body production in humans. Metabolism 40: 1138, 1991.
 66. Bhathena, S., J., Louie, G. P. Schechter, R. S. Redman, L. Wahl, and L. Recant. Identification of human mononuclear leukocytes bearing receptors for somatostatin and glucagon. Diabetes 30: 127–131, 1981.
 67. Biggers, D., S., Myers, D. Neal, R. Stinson, N. Cooper, J. Jaspan, P. Williams, A. Cherrington, and A. Frizzel. Role of the brain in counterregulation of insulin‐induced hypoglycemia in dogs. Diabetes 38: 7–16, 1989.
 68. Bilbrey, G. L., G. R., Faloona, M. G. White, and J. P. Knochel. Hyperglucagonemia of renal failure. J. Clin. Invest. 53: 841–847, 1974.
 69. Bishop, A. E., J. M., Polak, I. C. Green, M. G. Bryant, and S. R. Bloom. The location of VIP in the pancreas of man and rat. Diabetologia 18: 73–78, 1980.
 70. Bjaaland, T., C. S., Hii, P. M. Jones, and S. L. Howell. Role of protein kinase C in arginine‐induced glucagon secretion from isolated rat islets of Langerhans. J. Mol. Endocrinol. 1: 105–110, 1988.
 71. Bjaaland, T., P. M., Jones, and S. L. Howell. Role of intracellular mediators in glucagon secretion: studies using intact and electrically permeabilized rat islets of Langerhans. J. Mol. Endocrinol. 1: 171–178, 1988.
 72. Blache, P., A., Kervran, M. Dufour, J. Martinez, D. Le‐Nguyen, S. Lotersztajn, C. Pavoine, F. Pecker, and D. Bataille. Glucagon‐(19–29), a Ca2+ pump inhibitory peptide, is processed from glucagon in the rat liver plasma membrane by a thiol endopeptidase. J. Biol. Chem. 265: 21514–21519, 1990.
 73. Blache, P., A., Kervran, J. Laur, A. Aumelas, D. Le‐Nguyen, J. Martinez, and D. Bataille. Antisera against preproglucagon fragments obtained by a “thiol‐maleoyl” coupling method. Coll. INSERM Libbey Eurotext 174: 519–522, 1989.
 74. Blache, P., A., Kervran, D. Le‐Nguyen, M. Dufour, A. Cohen‐Solal, W. Duckworth, and D. Bataille. Endopeptidase from rat liver membranes, which generates miniglucagon from glucagon. J. Biol. Chem. 268: 21748–21753, 1993.
 75. Blackard, W. G., N. C., Nelson, and S. S. Andrews. Portal and peripheral vein immunoreactive glucagon concentrations after arginine or glucose infusions. Diabetes 23: 199–202, 1974.
 76. Blackmore, P. F., S., Mojsov, J. H. Exton, and J. F. Habener. Absence of insulinotropic glucagon‐like peptide‐I(7–37) receptors on isolated rat liver hepatocytes. FEBS Lett. 283: 7–10, 1991.
 77. Blecher, M., and S. Goldstein. Hormone receptors. VI. On the nature of the binding of glucagon and insulin to human circulating mononuclear leukocytes. Mol. Cell. Endocrinol. 8: 301–315, 1977.
 78. Bloom, S., N., Vaughan, and R. Russell. Vagal control of glucagon release in man. Lancet 2: 546–549, 1974.
 79. Bloom, S. R.. GIP in diabetes [abstract], Diabetologia 11: 334, 1976.
 80. Bloom, S. R.. An enteroglucagon tumour. Gut 13: 520–523, 1972.
 81. Bloom, S. R., and A. V. Edwards. The release of pancreatic glucagon and inhibition of insulin in response to stimulation of the sympathetic innervation. J. Physiol. (Land.) 253: 157–173, 1975.
 82. Bloom, S. R., and A. V. Edwards. Certain pharmacological characteristics of the release of pancreatic glucagon in response to stimulation of the splanchnic nerves. J. Physiol. (Lond.) 280: 25–35, 1978.
 83. Bloom, S. R., and A. V. Edwards. Endocrine responses to exogenous bombesin and gastrin releasing peptide in conscious calves. J. Physiol. (Lond.) 344: 37–48, 1983.
 84. Bloom, S. R., A. V., Edwards, and R. N. Hardy. The role of the autonomic nervous system in the control of glucagon, insulin, and pancreatic polypeptide release from the pancreas. J. Physiol. (Lond.) 280: 9–23, 1978.
 85. Bloom, S. R., A. V., Edwards, and N. J. A. Vaughan. The role of the sympathetic innervation in the control of plasma glucagon concentration in the calf. J. Physiol. (Lond.) 233: 457–466, 1973.
 86. Bloom, S. R., A. V., Edwards, and N. J. A. Vaughan. The role of the autonomic innervation in the control of glucagon release during hypoglycemia in the calf. J. Physiol. (Lond.) 236: 611–623, 1974.
 87. Bloom, S. R., and J. M. Polak. The hormonal pattern of intestinal adaptation. A major role for enteroglucagon. Scand. J. Gastroenterol. 74: 93–103, 1982.
 88. Bloomgarden, Z. T., J. E., Liljenquist, A. D. Cherrington, and D. Rabinowitz. Persistent stimulatory effect of glucagon on glucose production despite downregulation. J. Clin. Endocrinol. Metab. 47: 1152–1155, 1978.
 89. Blundell, T. L.. The conformation of glucagon. In: Glucagon I, edited by P. J. Lefèbvre. New York: Springer‐Verlag, 1983, p. 37–56.
 90. Bode, H., D., Yule, H. Fehmann, B. Göke, and J. Williams. Spontaneous calcium oscillations in clonal endocrine pancreatic glucagon‐secreting cells. Biochem. Biophys. Res. Commun. 205: 435–440, 1994.
 91. Bonner‐Weir, S., and I. Orci. New perspectives on the microvasculature of the islets of Langerhans in the rat. Diabetes 31: 83–89, 1982.
 92. Borg, M. A., R. S., Sherwin, W. P. Borg, W. V. Tamborlane, and G. I. Shulman. Local ventromedial hypothalamus glucose perfusion blocks counterregulation during systemic hypoglycemia in awake rats. J. Clin. Invest. 99: 361–365, 1997.
 93. Borg, W., M., During, R. Sherwin, M. Borg, M. Brines, and G. Shulman. Ventromedial hypothalamic lesions in rats suppress counterregulatory responses to hypoglycemia. J. Clin. Invest. 93: 1677–1682, 1994.
 94. Bottger, I., R., Dobbs, G. R. Faloona, and R. H. Unger. The effects of triglyceride absorption upon glucagon, insulin and gut glucagon‐like immunoreactivity. J. Clin. Invest. 52: 2532–2541, 1973.
 95. Braaten, J. T., G. R., Faloona, and R. H. Unger. The effect of insulin on the alpha‐cell response to hyperglycemia in long‐standing alloxan diabetes. J. Clin. Invest. 53: 1017–1021, 1974.
 96. Braun, W., G., Wider, K. H. Lee, and K. Wuthrich. Conformation of glucagon in a lipid‐water interphase by 1H nuclear magnetic resonance. J. Mol. Biol. 169: 921–948, 1983.
 97. Bregman, M. D., D., Trivedi, and V. J. Hruby. Glucagon amino groups. Evaluation of modifications leading to antagonism and agonism J. Biol. Chem. 255: 11725–11731, 1980.
 98. Bromer, W. W., and W. Chance. Zinc glucagon depression of blood amino acids in rabbits. Diabetes 18: 748–754, 1969.
 99. Bromer, W. W., L. G., Sinn, A. Staub, O. K. Behrens, E. R. Diller, and H. L. Bird. The amino acid sequence of glucagon 1. Amino acid composition and terminal amino acid analyses. J. Am. Chem. Soc. 79: 2794–2798, 1957.
 100. Brown, J. C., J. R., Dryburgh, S. A. Ross, and J. Dupré. Identification and actions of gastric inhibitory polypeptide. Recent Prog. norm. Res. 31: 487–532, 1975.
 101. Brown, J. C., V., Mutt, and R. A. Pederson. Further purification of a polypeptide demonstrating enterogastrone activity. J. Physiol. (Lond.) 209: 57–64, 1970.
 102. Brown, J. C., and R. A. Pederson. A multiparameter study of the action of preparations containing cholecystokinin‐pankreozymin. Scand. J. Gastroenterol. 5: 537–541, 1970.
 103. Brown, J. C., and R. A. Pederson. GI hormones and insulin secretion. In: 5th Int. Congr. Endocrinol. Hamburg. Amsterdam: Excerpta Med. Year. GI hormones and insulin section. Endocrinology. Proceedings of the Fifth International Congress of Endocrinology. (James VHT, ed) Excerpta Medica, Amsterdam 1976; vol 2: 568–570.
 104. Brubaker, P.. Control of glucagon‐like immunoreactive peptide secretion from fetal rat intestinal cultures. Endocrinology 123: 220–226, 1988.
 105. Brubaker, P. L.. Regulation of intestinal proglucagon‐derived peptide secretion by intestinal regulatory peptides. Endocrinology 128: 3175–3182, 1991.
 106. Brubaker, P. L., A., Crivici, A. Izzo, P. Ehrlich, C.‐H. Tsai, and D. J. Drucker. Circulating and tissue forms of the intestinal growth factor, glucagon‐like peptide‐2. Endocrinology 138: 4837–4843, 1997.
 107. Brubaker, P. L., A., Izzao, M. Hill, and D. J. Drucker. Intestinal function in mice with small bowel growth induced by glucagon‐like peptide‐2. Am. J. Physiol. 272 (Endocrinol. Metab. 35): E1050–E1058, 1997.
 108. Brubaker, P. L., Y. C., Lee, and D. J. Drucker. Alterations in proglucagon processing and inhibition of proglucagon gene expression in transgenic mice which contain a chimeric proglucagon‐SV40 T antigen gene. J. Biol. Chem. 267: 20728–20733, 1992.
 109. Brubaker, P. L., D. C. Y., So, and D. J. Drucker. Tissue‐specific differences in the levels of proglucagon‐derived peptides in streptozotocin‐induced diabetes. Endocrinology 124: 3003–3009, 1989.
 110. Brubaker, P. L., and M. Vranic. Fetal rat intestinal cells in monolayer culture: a new in vitro system to study the glucagon‐like immunoreactive peptides. Endocrinology 120: 1976–1985, 1987.
 111. Brunicardi, F. C., R. M., Kleinman, G. Ohning, K. Lloyd, R. Gengerich, H. Wong, and J. Walsh. The inhibitory role of intraislet somatostatin on glucagon secretion in the isolated perfused human pancreas. Transplant. Proc. 26: 3451–3452, 1994.
 112. Brunicardi, F. C., J., Stagner, S. Bonner‐Weir, H. Wayland, R. Kleinman, E. Livingston, P. Guth, M. Menger, R. McCuskey, M. Intaglietta, A. Charles, S. Ashley, A. Cheung, E. Ipp, S. Gilman, T. Howard, and E. Passaro, Jr.. Microcirculation of the islets of Langerhans: Long Beach Veterans Administration Regional Medical Education Center Symposium. Diabetes 45: 385–392, 1996.
 113. Bruzzone, R., G., Tamburrano, A. Lala, M. Mauceri, B. Annibale, C. Severi, L. DeMagistris, F. Leonetti, and G. DelleFave. Effect of bombesin on plasma insulin, pancreatic glucagon, and gut glucagon in man. J. Clin. Endocrinol. Metab. 56: 643–647, 1983.
 114. Bryant, M. G., S. R., Bloom, and J. M. Polak. Measurement of gut hormonal peptides in biopsies from human stomach and proximal intestine. Gut 24: 114–119, 1983.
 115. Buchan, A. M. J., D. L., Barber, M. Gregor, and A. H. Soll. Morphologic and physiologic studies of canine ileal enteroglucgon‐containing cells in short‐term culture. Gastroenterology 93: 791–800, 1987.
 116. Buchanan, K. D., and W. A. Mawhinney. Glucagon release from isolated pancreas in streptozotocin‐treated rats. Diabetes 22: 797–800, 1973.
 117. Buchanan, K. D., and W. A. Mawhinney. Insulin control of glucagon release from insulin‐deficient rat islets. Diabetes 22: 801–803, 1973.
 118. Buchanan, K. D., J. E., Vance, K. Dinstl, and R. H. Williams. Effect of blood glucose on glucagon secretion in anesthetized dogs. Diabetes 18: 11–18, 1969.
 119. Buchs, A., F., Marki, and U. Keller. Effect of somatostatin and two of its analogues on basal and arginine‐stimulated insulin and glucagon secretion in the dog. Regul. Pept. 4: 117–126, 1982.
 120. Buggy, J. J., J. N., Livingston, D. U. Rabin, and H. Yoo‐Warren. Glucagon‐like peptide receptor chimeras reveal domains that determine specificity of glucagon binding. J. Biol. Chem. 270: 7474–7478, 1995.
 121. Bullock, B. P., R. S., Heller, and J. F. Habener. Tissue distribution of messenger ribonucleic acid encoding the rat glucagon‐like peptide‐1 receptor. Endocrinology 137: 2968–2978, 1996.
 122. Bunnett, N. W.. Release and breakdown: postsecretory processing of peptides. Am. Rev. Respir. Dis. 136: s27–s34, 1987.
 123. Burcelin, P., J., Li, and M. J. Charron. Cloning and sequencing the murine glucagon receptor‐encoding gene. Gene 164: 305–310, 1995.
 124. Burman, K. D., R. C., Smallridge, L. Jones, E. A. Ramos, J. T. O'Brian, F. D. Wright, and L. Wartofsky. Glucagon kinetics in fasting: physiological elevations in serum 3′5′3′ triiodothyronine increases the metabolic clearance rate of glucagon. J. Clin. Endocrinol. Metab. 51: 1158–1165, 1980.
 125. Cahill, G. F., Jr., S. Zottu, and E. S. Earle. In vivo effects of glucagon on hepatic glycogen, phosphorylase and glucose‐6‐phosphatase. Endocrinology 60: 265–269, 1957.
 126. Campbell, R. M., and C. G. Scanes. Evolution of the growth hormone–releasing factor (GRF) family of peptides. Growth Regul. 2: 175–191, 1992.
 127. Campillo, J. E., A. S., Luyckx, and P. J. Lefèbvre. Effect of oleic and octanic acids on glucagon and insulin secretion in vitro. Horm. Metab. Res. 14: 499, 1982.
 128. Campillo, J. E., A. S., Luyckx, and P. J. Lefèbvre. Effect of oleic acid on arginine‐induced glucagon secretion by the isolated perfused rat pancreas. Acta Diabetol. Lat. 16: 287–293, 1979.
 129. Campos, R. V., Y. C., Lee, and D. J. Drucker. Divergent tissue‐specific and developmental expression of receptors for glucagon and glucagon‐like peptide‐1 in mouse. Endocrinology 134: 2156–2164, 1994.
 130. Cannon, W. B., M. A., Mcluer, and S. W. Bliss. Studies on the condition of activity of endocrine glands. XIII. A sympathetic and adrenal mechanism for mobilizing sugar in hypoglycemia. Am. J. Physiol 69: 46, 1924.
 131. Capella, C., E., Solcia, B. Frigerio, and R. Buffa. Endocrine cells of the human intestine. An ultrastructural study. In: Endocrine Gut and Pancreas, edited by T. Fufita. Amsterdam: Elsevier, 1975, p. 42–59.
 132. Carlson, M. G., W. L., Snead, and P. J. Campell. Regulation of free fatty acid metabolism by glucagon. J. Clin. Endocrinol. Metab. 77: 11–15, 1993.
 133. Carranza, M. C., M. A., Simon, A. Torres, B. Romero, and C. Calle. Identification of glucagon receptors in human adipocytes from a liposarcoma. J. Endocrinol. Invest. 16: 439–442, 1993.
 134. Carruthers, C., C. G., Unson, H. N. Kim, and T. Sakmar. Synthesis and expression of a gene for the rat glucagon receptor. Replacement of an aspartic acid in the extracellular domain prevents glucagon binding. J. Biol. Chem. 269: 29321–29328, 1994.
 135. Cheeseman, C. I.. Upregulation of SGLT‐1 transport activity in rat jejunum induced by GLP‐2 infusion in vivo. Am. J. Physiol. 273 (Regulatory Integrative Comp. Physiol. 42): R1965–R1971, 1997.
 136. Cheeseman, C. I., and R. Tsang. The effect of GIP and glucagon‐like peptides on intestinal basolateral membrane hexose transport. Am. J. Physiol. 271 (Gastrointest Liver Physiol. 34): G477–G482, 1996.
 137. Cherrington, A. D., W. W., Lacy, and J.‐L. Chiasson. Effect of glucagon on glucose production during insulin deficiency in the dog. J. Clin. Invest. 323: 68–77, 1978.
 138. Cherrington, A. D., and M. Vranic. Effect of arginine on glucose turnover and plasma free fatty acids in normal dogs. Diabetes 22: 537–543, 1973.
 139. Chideckel, E., J., Palmer, J. Koerker, M. Ensinck, M. Davidson, and C. Goodner. Somatostatin blockade of acute and chronic stimuli of the endocrine pancreas and the consequences of this blockade on glucose homeostasis. J. Clin. Invest. 55: 754–762, 1975.
 140. Chohe, P., and D. Saggerson. Increased sensitivity of adipocyte adenylate cyclase to glucagon in the fasted state. FEBS Lett. 146: 357–360, 1982.
 141. Chou, P. Y., and G. D. Fassmans. The conformation of glucagon: predictions and consequences. Biochemistry 14: 2536–2541, 1975.
 142. Christensen, N., S., Christensen, A. Hansen, and K. Lundbaek. The effect of somatostatin on plasma noradrenaline and plasma adrenaline concentrations during exercise and hypoglycemia. Metabolism 24: 1267–1272, 1975.
 143. Christensen, N. J., and J. Iversen. Release of large amounts of norepinephrine from the isolated perfused canine pancreas during glucose deprivation. Diabetologia 9: 396–399, 1973.
 144. Consoli, A., F., Kennedy, J. Miles, and J. Gerich. Determination of Krebs cycle metabolic carbon exchange in vivo and its use to estimate gluconeogenesis in man. J. Clin. Invest. 80: 1303–1310, 1987.
 145. Costa, M., and J. B. Furness. Neuronal peptides in the intestine. Br. Med. Bull. 38: 247–252, 1982.
 146. Creutzfeldt, W.. The incretin concept today. Diabetologia 16: 75–85, 1979.
 147. Creutzfeldt, W. O., N., Kleine, B. Willms, C. Orskov, J. J. Holst, and M. A. Nauck. Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon‐like peptide I(7–36) amide in type 1 diabetic patients. Diabetes Care 19: 580–586, 1996.
 148. Crockett, S. E., E. L., Mazzaferri, and S. Catland. Gastric inhibitory polypeptide (GIP) in maturity onset diabetes mellitus. Diabetes 25: 931–935, 1976.
 149. Crockford, P. M., D., Porte, F. C. Wood, and R. H. Williams. Effect of glucagon on serum insulin, plasma glucose, FFA in man. Metabolism 15: 114–122, 1966.
 150. Cronan, J. J., and S. Stein. Glucagon therapy of esophageal food impaction. Interventional radiology. Conn. Med. 44: 77–80, 1980.
 151. Cryer, P. E.. Glucose counterregulation in man. Diabetes 1981: 261–264, 1981.
 152. Cryer, P. E.. Banting lecture: Hypoglycemia: the limiting factor in the management of IDDM. Diabetes 43: 1378–1389, 1994.
 153. Curry, D. M., and G. H. Beaton. Glucagon administration in pregnant rats. Endocrinology 63: 252–256, 1958.
 154. D'Alessio, D. A., W. Y., Fujimoto, and J. W. Ensinck. Effects of glucagonlike peptide I‐(7–36) on release of insulin, glucagon, and somatostatin by rat pancreatic islet cell monolayer cultures. Diabetes 38: 1534–1538, 1989.
 155. D'Alessio, D. A., S. E., Kahn, C. R. Leusner, and J. W. Ensinck. Glucagon‐like peptide 1 enhances glucose tolerance both by stimulation of insulin release and by increasing insulin‐independent glucose disposal. J. Clin. Invest. 93: 2263–2266, 1994.
 156. D'Alessio, D. A., R. L., Prigeon, and J. W. Ensinck. Glucagon‐like peptide 1(7–37) NH2 enhances glucose tolerance both by stimulation of insulin release and by increasing insulin independent glucose disposal. J. Clin. Invest. 93: 2263–2266, 1992.
 157. D'Alessio, D. A., R. L., Prigeon, and J. W. Ensinck. Enteral enhancement of glucose disposition by both insulin‐dependent and insulin‐independent processes: a physiological role of glucagon‐like peptide I. Diabetes 44: 1433–1437, 1995.
 158. Daubresse, J. C., G., Lerson, G. Plomteux, G. Rorive, A. S. Luyckx, and P. J. Lefèbvre. Lipids and lipoproteins in chronic uremia. A study of the influence of regular hemodialysis. Eur. J. Clin. Invest. 6: 159–166, 1976.
 159. Deacon, C. F., A. H., Johnsen, and J. J. Holst. Degradation of glucagon‐like peptide‐1 by human plasma in vitro yields an N‐terminally truncated peptide that is a major endogenous metabolite in vivo. J. Clin. Endocrinol Metab. 80: 952–957, 1995.
 160. Deacon, C. F., M. A., Nauck, M. Toft‐Nielsen, L. Pridal, B. Willms, and J. J. Holst. Both subcutaneously and intravenously administered glucagon‐like peptide I are rapidly degraded from the NH2 terminus in type II diabetic patients and in healthy subjects. Diabetes 44: 1126–1131, 1995.
 161. Deacon, C. F., L., Pridal, L. Klarskov, M. Olesen, and J. J. Holst. Glucagon‐like peptide 1 undergoes differential tissue‐specific metabolism in the anesthetized pig. Am. J. Physiol. 271 (Endocrinol. Metab. 34): E458–E464, 1996.
 162. de Jong, A., J. H. Strubbe, and A. B. Steffens. Hypothalamic influence on insulin and glucagon release in the rat. Am. J. Physiol. 233 (Endocrinol. Metab. Gastrointest. Physiol. 2): E380–E388, 1977.
 163. Delgado, E., M.A., Luque, A. Alantara, M. A. Traponte, F. Clemente, C. Galera, I. Valverde, and M. L. Villanueva‐Penacarillo. Glucagon‐like peptide‐1 binding to rat skeletal muscle. Peptides 16: 225–229, 1995.
 164. Deltour, L., P., Leduque, N. Blume, O. Madsen, P. Dubois, J. Jami, and D. Bocchine. Differential expression of the two non‐allelic proinsulin genes in the developing mouse embryo. Proc. Natl. Acad. Sci. U.S.A. 90: 527–531, 1993.
 165. Dencker, M., P., Hedner, J. Holst, and K. G. Tranbert. Pancreatic glucagon response to an ordinary meal. Scand. J. Gastroenterol. 10: 471–474, 1975.
 166. Devaskar, S. U., B. S., Singh, L. R. Carnaghi, P. A. Rajakumar, and S. J. Giddings. Insulin‐II gene expression in rat central nervous system. Regal. Pept. 48: 55–63, 1993.
 167. Dhanvantari, S., N. G., Seidah, and P. L. Brubaker. Role of prohormone convertases in tissue‐specific processing of proglucagon. Mol. Endocrinol. 10: 342–355, 1996.
 168. Diamond, M. P., L., Hallarman, K. Starick‐Zych, T. W. Jones, M. Connolly‐Howard, W. V. Tamborlane, and R. S. Sherwin. Suppression of counterregulatory hormone response to hypoglycemia by insulin per se. J. Clin. Endocrinol. Metab. 72: 1388–1390, 1991.
 169. Diedrich, T., U., Furstenau, and W. Knepel. Glucagon gene G3 enhancer: evidence that activity depends on combination of an islet‐specific factor and a winged helix protein. Biol. Chem. 378: 89–98, 1997.
 170. Ding, W. G., M., Fujimura, A. Mori, I. Tooyama, and H. Kimura. Light and electron microscopy of neuropeptide Y‐containing nerves in human liver, gallbladder, and pancreas. Gastroenterology 101: 1054–1059, 1991.
 171. Ding, W.‐G., E., Renström, P. Rosman, K. Bushard, and J. Gromada. Glucagon‐like peptide I and glucose dependent insulinotropic polypeptide stimulate Ca+‐induced secretion in rat α‐cells by a protein kinase A‐mediated mechanism. Diabetes 46: 792–800, 1997.
 172. Dobbins, R. L., S. N., Davis, D. W. Neal, C. Cobelli, J. Jaspan, and A. D. Cherrington. Compartmental modeling of glucagon kinetics in the conscious dog. Metabolism 44: 452–459, 1995.
 173. Dobbs, R. R., H., Sakurai, and H. Sasaki. Glucagon role in the hyperglycemia of diabetes mellitus. Science 187: 544–547, 1975.
 174. Donovan, C., J., Halter, and R. Bergman. Importance of hepatic glucoreceptors in sympathoadrenal response to hypoglycemia. Diabetes 40: 155–158, 1991.
 175. Drucker, D. J., and S. L. Asa. Glucagon gene expression in vertebrate brain. J. Biol. Chem. 263: 13475–13478, 1988.
 176. Drucker, D. J., and P. L. Brubaker. Proglucagon gene expression is regulated by a cyclic AMP–dependent pathway in rat intestine. Proc. Natl. Acad. Sci. U.S.A. 86: 3953–3957, 1989.
 177. Drucker, D. J., R., Campos, R. Reymonds, K. Stobie, and P. L. Brubaker. The rat glucagon gene is regulated by a protein kinase A‐dependent pathway in pancreatic islet cells. Endocrinology 128: 394–400, 1991.
 178. Drucker, D. J., L., DeForest, and P. L. Brubaker. Intestinal response to growth factors administered alone or in combination with human [Gly2]glucagon‐like peptide 2. Am. J. Physiol. 273 (Gastrointest. Liver Physiol. 36): G1252–G1262, 1997.
 179. Drucker, D. J., P., Ehrlich, S. L. Asa, and P. Brubaker. Induction of intestinal epithelial proliferation by glucagon‐like peptide 2. Proc. Natl. Acad. Sci. U.S.A. 93: 7911–7916, 1996.
 180. Drucker, D. J., T., Jin, S. L. Asa, T. A. Young, and P. L. Brubaker. Activation of proglucagon gene transcription by protein kinase‐A in a novel mouse enteroendocrine cell line. Mol. Endocrinol. 8: 1646–1655, 1994.
 181. Drucker, D. J., Y. C., Lee, S. L. Asa, and P. L. Brubaker. Inhibition of pancreatic glucagon gene expression in mice bearing subcutaneous glucagon‐producing intestinal GLUTag transplantable tumor. Mol. Endocrinol. 6: 2175–2184, 1992.
 182. Drucker, D. J., S., Mojsov, and J. F. Habener. Cell‐specific post‐translational processing of preproglucagon expressed from a metallothionine–glucagon fusion gene. J. Biol. Chem. 261: 9637–9643, 1986.
 183. Drucker, D. J., J., Philippe, L. Jepeal, and J. F. Habener. Glucagon gene 5′‐flanking sequences promote islet‐specific gene transcription. J. Biol. Chem. 262: 15659–15665, 1987.
 184. Drucker, D. J., J., Philippe, S. Mojsov, W. L. Chick, and J. F. Habener. Glucagon‐like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. Proc. Natl. Acad. Sci. U.S.A. 84: 3434–3438, 1987.
 185. Drucker, D. J., Q., Shi, A. Crivici, M. Sumner‐Smith, W. Tavares, M. Hill, L. DeForest, S. Cooper, and P. L. Brubaker. Regulation of the biological activity of glucagon‐like peptide 2 in vivo by dipeptidyl peptidase IV. Nat. Biotechnol. 15: 673–677, 1997.
 186. Drucker, D. J., B., Yusta, B. P. Boushey, L. DeForest, and P. L. Brubaker. Human [Gly2]GLP‐2 reduces the severity of colonic injury in a murine model of experimental colitis. Am. J. Physiol. 276: G79–G91, 1999.
 187. Duckworth, W. C.. Insulin and glucagon degradation by the kidney. Subcellular distribution under different assay conditions. Biochim. Biophys. Acta 437: 518–530, 1976.
 188. Duckworth, W. C.. Insulin and glucagon degradation by the kidney. II. Characterization of the mechanisms at neutral pH. Biochim. Biophys. Acta 437: 531–542, 1976.
 189. Duckworth, W. C.. Insulin and glucagon binding and degradation by kidney cell membranes. Endocrinology 102: 1766–1774, 1978.
 190. Duckworth, W. C., and A. E. Kitabchi. Insulin and glucagon degradation by the same enzyme. Diabetes 23: 536–543, 1974.
 191. Duguay, S. J., and T. P. Mommsen. Molecular aspects of pancreatic peptides. In: Fish Physiology, edited by N. M. Sherwood and C. L. Hews. San Diego: Academic, 1994, p. 225–271.
 192. Dumoulin, V., T., Dakka, P. Plaisancie, J.‐A. Chayvialle, and J.‐C. Cuber. Regulation of glucagon‐like peptide‐1‐(7–36)amide, peptide YY, and neurotensin secretion by neurotransmitters and gut hormones in the isolated vascularly perfused rat ileum. Endocrinology 136: 5182–5188, 1995.
 193. Dunning, B. E., B., Ahren, G. Bottcher, F. Sundler, and G. J. Taborsky, Jr.. The presence and actions of NPY in the canine endocrine pancreas. Regul. Pept. 18: 253–265, 1987.
 194. Dunning, B. E., B., Ahren, R. C. Veith, G. Buttcher, F. Sundler, and G. J. Taborsky, Jr.. Galanin: a novel pancreatic neuropeptide. Am. J. Physiol. 251 (Endocrinol. Metab. 14): E127–E133, 1986.
 195. Dunning, B. E., and G. J. Taborsky, Jr.. Galanin‐sympathetic neurotransmitter in the endocrine pancreas? Diabetes 37: 1157–1162, 1988.
 196. Dunning, B. E., and G. J. Taborsky, Jr.. Galanin release during pancreatic nerve stimulation is sufficient to influence islet function. Am. J. Physiol. 256 (Endocrinol. Metab. 19): E191–E198, 1989.
 197. Dupre, J., and J. C. Beck. Stimulation of release of insulin by an extract of intestinal mucosa. Diabetes 15: 555–559, 1966.
 198. Dupré, J., M. T., Behme, I. M. Hramiak, and T. J. McDonald. Subcutaneous glucagon‐like peptide 1 combined with insulin normalizes postcibal glycemic excursions in IDDM. Diabetes Care 20: 381–384, 1997.
 199. Dupré, J., M. T., Behme, I. M. Hramiak, P. McFarlane, M. P. Williamson, P. Zabel, and T. J. McDonald. Glucagon‐like peptide I reduces postprandial glycemic excursions in IDDM. Diabetes 44: 626–630, 1995.
 200. Dupré, J., S. A., Ross, D. Watson, and J. C. Brown. Stimulation of insulin secretion by gastric inhibitory polypeptide in man. J. Clin. Endocrinol. Metab. 37: 826–828, 1973.
 201. Ebert, R., and W. Creutzfeld. Influence of gastric inhibitory polypeptide antiserum on glucose‐induced insulin secretion in rats. Endocrinology 111: 1601–1606, 1982.
 202. Edwards, J. C., S. L., Howell, and K. W. Taylor. Fatty acids as regulators of glucagon secretion. Nature 224: 808–809, 1969.
 203. Edwards, J. C., and K. W. Taylor. Fatty acids and the release of glucagon from the guinea‐pig islets of Langerhans incubated in vitro. Biochim. Biophys. Acta 215: 310–315, 1970.
 204. Efrat, S., G., Teitelman, M. Anwar, D. Ruggiero, and D. Hanahan. Glucagon gene regulatory region directs oncoprotein expression to neurons and pancreatic α cells. Neuron 1: 605–613, 1988.
 205. Egan, J. M., C., Montrose‐Rafizadeh, Y. Wang, M. Bernier, and J. Roth. Glucagon‐like peptide‐1(7–36)amide (GLP‐1) enhances insulin‐stimulated glucose metabolism in 3T3‐L1 adipocytes: one of several potential extrapancreatic sites of GLP‐1 action. Endocrinology 135: 2070–2075, 1994.
 206. Eisentraut, A. M., N., Whissen, and R. H. Unger. Incubation damage in the radioimmunoassay for human plasma glucagon and its prevention with “Trasylol.” Am. J. Med. Sci. 235: 137–142, 1968.
 207. Eissele, R.. Morphological aspects of GLP‐1 expression in the intestine. In: The Insulinotropic Gut Hormone Glucagon‐like Peptide‐1, edited by H. C. Fehmann and B. Göke. Basel: Karger, 1997, p. 49–64.
 208. Eissele, R., R., Göke, U. Weichhardt, H. C. Fehmann, R. Arnold, and B. Göke. Glucagon‐like peptide‐I cells in the gastrointestinal tract and pancreas of rat, pig, and man. Eur. J. Clin. Invest. 22: 283–291, 1992.
 209. Eissele, R., H., Koop, and R. Arnold. Effect of glucagon‐like peptide‐1 on gastric somatostatin and gastrin secretion in the rat. Scand. J. Gastroenterol. 25: 449–454, 1985.
 210. Elahi, D., D. K., Anderson, J. C. Brown, H. T. Debas, R. J. Hershcopf, G. S. Raizes, J. D. Tobin, and R. Andres. Pancreatic α‐and β‐cell responses to GIP infusion in normal man. Am. J. Physiol. 237 (Endocrinol. Metab. Gastrointest. Physiol. 6): E185–E191, 1979.
 211. Elahi, D., M., McAloon‐Dyke, N. K. Fukagawa, G. S. Meneilly, A. L. Sclater, K. L. Minaker, J. F. Habener, and D. K. Andersen. The insulinotropic actions of glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1(7–37) in normal and diabetic subjects. Regul. Pept. 51: 63–74, 1994.
 212. Elliot, R. M., L. M., Morgan, J. A. Tredger, S. Deacon, J. Wright, and V. Marks. Glucagon‐like peptide 1(7–36)amide and glucose‐dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post‐prandial and 24‐h secretion patterns. J. Endocrinol. 138: 159–166, 1993.
 213. Elrick, H., L., Stimmler, C. J. Hlad, and Y. Arai. Plasma insulin responses to oral and intravenous glucose administration. J. Clin. Endocrinol. Metab. 24: 1076–1082, 1964.
 214. Emmanouel, D. S., J. B., Jaspan, S. F. Kuhn, A. H. Ruberstein, and A. I. Katz. Pathogenesis and characterization of hyperglucagonemia in the uremic rat. J. Clin. Invest. 58: 1266–1279, 1976.
 215. Emmanouel, D. S., J. B., Jaspan, A. H. Ruberstein, A. H.‐J. Huen, E. Fink, and A. I. Katz. Glucagon metabolism in the rat. Contribution of the kidney to the metabolic clearance rate of the hormone. J. Clin. Invest. 60: 6–13, 1978.
 216. Ensinck, J. W., R. E., Vogel, E. C. Laschansky, and B. H. Francis. Effect of ingested carbohydrate, fat and protein on the release of somatostatin‐28 in humans. Gastroenterology 99: 1283–1291, 1990.
 217. Ensinck, J. W., R. M., Walter, J. P. Palmer, R. G. Brodows, and R. G. Campbell. Glucagon response to hypoglycemia in adrenalectomized man. Metabolism 25: 227–232, 1976.
 218. Esterhuizen, A. C., and S. L. Howell. Ultrastructure of the A‐cells of cat islets of Langerhans following sympathetic stimulation of glucagon secretion. J. Cell. Biol. 46: 593–631, 1970.
 219. Evans, G. S., and C. S. Potten. The distribution of endocrine cells along the mouse intestine. A quantitative immunocytochemical study. Virchows Arch. 56: 191–199, 1988.
 220. Exton, J. H., and C. R. Park. Control of gluconeogenesis in liver. III. Effects of L‐lactate, pyruvate, fructose, glucagon, epinephrine, and adenosine 3′5′‐monophosphate on gluconeogenic intermediates in the perfused rat liver. J. Biol. Chem. 244: 1424–1433, 1969.
 221. Fahrenkrug, J., J. H., Pedersen, Y. Yamashita, B. Ottesen, T. Hokfelt, and J. M. Lundberg. Occurrence of VIP and peptide HM in human pancreas and their influence on pancreatic endocrine secretion in man. Regul. Pept. 18: 51–61, 1987.
 222. Fehmann, H.‐C., R., Göke, and B. Göke. Glucagon‐like peptide‐1(7–37)/(7–36)amide is a new incretin. Mol. Cell. Endocrinol. 85: C39–C44, 1992.
 223. Fehmann, H.‐C., and J. F. Habener. Functional receptors for the insulinotropic hormone glucagon‐like peptide‐1‐(7–37) on a somatostatin secretin cell line. FEBS Lett. 279: 335–340, 1991.
 224. Fehmann, H.‐C., and J. F. Habener. Homologous desensitization of the insulinotropic glucagon‐like peptide‐I(7–37) receptor on insulinoma HIT‐T15 cells. Endocrinology 128: 2880–2888, 1991.
 225. Fehmann, H.‐C., and J. F. Habener. Insulinotropic glucagonlike peptide‐I(7–37)/(7–36)amide: a new incretin hormone. Trends Endocrinol. Metab. 3: 158–163, 1992.
 226. Fehmann, H.‐C., and J. F. Habener. Insulinotropic hormone glucagon‐like peptide‐I(7–37) stimulation of proinsulin gene expression and proinsulin biosynthesis in βTC‐1 insulinoma cells. Endocrinology 130: 159–166, 1992.
 227. Fehmann, H. C., B. J., Hering, M. J. Wolf, H. Brandhorst, D. Brandhorst, R. G. Bretzel, K. Federlin, and B. Goke. The effects of glucagon‐like peptide‐I (GLP‐I) on hormone secretion from isolated human pancreatic islets. Pancreas 11: 196–200, 1995.
 228. Fehmann, H.‐C., M., Strowski, B. Lankat‐Buttgereit, and B. Göke. Molecular and functional characterization of insulin receptors present on hamster glucagonoma cells. Digestion 55: 214–220, 1994.
 229. Feldman, M., R. S., Kiser, R. H. Unger, and C. H. Li. Beta‐endorphin and the endocrine pancreas. Studies in healthy and diabetic human beings. N. Engl. J. Med. 308: 349–353, 1983.
 230. Felig, P., R., Gusberg, R. Hendler, F. E. Gump, J. M. Kinney, and P. J. Mulrow. Concentrations of glucagon and the insulin: glucagon ratio in the portal and peripheral circulation. Proc. Soc. Exp. Biol. Med. 147: 88–90, 1974.
 231. Felig, P. J., and R. Warren. Influence of physiologic hyperglucagonemia on basal and insulin‐inhibited splanchnic glucose output in normal man. J. Clin. Invest. 58: 761–765, 1976.
 232. Felts, D. W., M. E. C., Ferguson, K. A. Hagey, E. S. Stitt, and W. M. Mitchell. Studies on the structure function relationships of glucagon. Diabetologia 6: 44–45, 1970.
 233. Ferraris, R. P., S., Yasharpour, K. C. K. Lloyd, R. Mirzayan, and J. M. Diamond. Luminal glucose concentrations in the gut under normal conditions. Am. J. Physiol. 259 (Gastrointest. Liver Physiol. 22): G822–G837, 1990.
 234. Filipponi, P., F., Gregorio, S. Cristallini, C. Ferrandina, I. Nicoletti, and F. Santeusanio. Selective impairment of pancreatic. A cell suppression by glucose during acute alloxan‐induced insulinopenia: in vitro study on isolated perfused rat pancreas. Endocrinology 119: 408–415, 1986.
 235. Filipsson, K., K., Tornoe, J. Holst, and B. Ahren. Pituitary adenylate cyclase–activating polypeptide stimulates insulin and glucagon secretion in humans. J. Clin. Endocrinol. Metab. 82: 3093–3098, 1997.
 236. Fischer, M., R. S., Sherwin, R. Hendler, and P. Felig. Kinetics of glucagon in man. Effects of starvation. Proc. Natl. Acad. Sci. U. S.A. 73: 1735–1739, 1976.
 237. Flamez, D., A. Van Breusegem, L. A. Scrocchi, E. Quartier, D. Pipeleers, D. J. Drucker, and F. Schuit. Mouse pancreatic beta‐cells exhibit preserved glucose competence after disruption of the glucagon‐like peptide‐1 receptor gene. Diabetes 47: 646–652, 1998.
 238. Francis, B. A., D. G., Baskin, D. R. Saunders, and J. W. Ensinck. Distribution of somatostatin‐14 and somatostatin‐28 gastrointestinal pancreatic cells of rat and human. Gastroenterology 99: 1283–1291, 1990.
 239. Frandsen, E. K., F. C., Gronvald, L. G. Heding, N. L. Johansen, B. F. Lundt, A. J. Moody, J. Markussen, and A. Volund. Glucagon: structure–function relationships investigated by sequence deletions. Hoppe Seylers Z. Physiol. Chem. 362: 665–671, 1981.
 240. Frankel, B. J., J. E., Gerich, R. Hagura, R. E. Fanska, G. C. Ger‐ritsen, and G. M. Grodsky. Abnormal secretion of insulin and glucagon by the in vitro perfused pancreas of the genetically diabetic‐Chinese hamster. J. Clin. Invest. 53: 1637–1646, 1974.
 241. Freyse, E.‐J., T., Becher, O. El‐Hag, S. Knospe, B. Göke, and U. Fischer. Blood glucose lowering and glucagonostatic effects of glucagon‐like peptide I in insulin‐deprived diabetic dogs. Diabetes 46: 824–828, 1997.
 242. Fridolf, T., G., Bottcher, F. Sundler, and B. Ahren. GLP‐1 and GLP‐1(7–36) amide: influences on basal and stimulated insulin and glucagon secretion in the mouse. Pancreas 6: 208–215, 1991.
 243. Fridolf, T., F., Sundler, and B. Ahren. Pituitary adenylate cyclase–activating polypeptide (PACAP): occurrence in rodent pancreas and effects on insulin and glucagon secretion in the mouse. Cell Tissue Res. 269: 275–279, 1992.
 244. Frohman, L. A., and L. L. Bernardis. Effect of hypothalamic stimulation on plasma glucose, insulin, and glucagon levels. Am. J. Physiol. 221: 1596–1603, 1971.
 245. Frohman, L. A., L. L., Bernardis, and M. E. Strachura. Factors modifying plasma insulin and glucose responses to ventromedial hypothalamic stimulation. Metabolism 23: 1047–1056, 1974.
 246. Frohman, L. A., and K. Nagai. Central nervous system–mediated stimulation of glucagon secretion in the dog following 2‐deoxyglucose. Metabolism 25 (Suppl. 1): 1449–1452, 1976.
 247. Fujimoto, W. Y., and J. W. Ensinck. Somatostatin inhibition of insulin and glucagon secretion in rat islet culture: reversal by ionophore A23187. Endocrinology 98: 259–262, 1976.
 248. Fujimoto, W. Y., J. W., Ensinck, F. W. Merchant, R. H. Williams, P. H. Smith, and D. G. Johnson. Stimulation by gastric inhibitory polypeptide of insulin and glucagon secretion by rat islet cultures. Proc. Soc. Exp. Biol. Med. 157: 89–93, 1978.
 249. Fujimoto, W. Y., R. H., Williams, and J. W. Ensinck. Gastric inhibitory polypeptide, cholecystokinin, and secretin effects on insulin and glucagon secretion by islet cultures. Proc. Soc. Exp. Biol. Med. 160: 349–353, 1979.
 250. Fuller, P. J., D. J., Beveridge, and R. G. Taylor. Ileal proglucagon gene expression in the rat. Characterization in intestinal adaptation using in situ hybridization. Gastroenterology 104: 456–466, 1993.
 251. Fürsinn, C., and K. W. W. Ebner. Failure of GLP‐1(7–36)amide to affect glycogenesis in rat skeletal muscle. Diabetologia 38: 864–867, 1995.
 252. Furuta, M., H., Yano, A. Zhou, Y. Rouillé, J. J. Holst, R. Carroll, M. Ravazzola, L. Orci, H. Furuta, and D. F. Steiner. Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2. Proc. Natl. Acad. Sci. U.S.A. 94: 6646–6651, 1997.
 253. Fussganger, R. D., R., Goberna, H. Laube, K. E. Schroder, K. Straub, and E. F. Pfeiffer. Glucagon secretion from the isolated perfused rat pancreas: influenced by the glucose‐, tolbutamide‐ and pancreozymin‐mediated release of pancreatic insulin. Isr. J. Med. Sci. 8: 768–769, 1972.
 254. Gajic, D., and D. J. Drucker. Multiple cis‐acting domains mediate basal and adenosine 3′,5′‐monophosphate–dependent glucagon gene transcription in a mouse neuroendocrine cell line. Endocrinology 123: 1055–1062, 1993.
 255. Galera, C. F. Clemente, A. Alcantara, M. A. Trapote, A. Perea, M. I. Lopez‐Delgado, M. L. Villanueva‐Pencarrillo, and I. Valverde. Inositolphosphoglycans and diacyglycerol are possible mediators in the glycogenic effect of GLP‐1(7–36)amide in BC3H‐1 myocytes. Cell Biochem. Fund. 14: 43–48, 1996.
 256. Gallwitz, B., M., Witt, U. R. Fölsch, W. Creutzfeldt, and W. E. Schmidt. Binding specificity and signal transduction for receptors for glucagon‐like peptide‐I(7–36)amide and gastric inhibitory polypeptide. J. Mol. Endocrinol. 10: 259–268, 1988.
 257. Gallwitz, B., M., Witt, G. Paetzold, C. Morys‐Wortmann, B. Zimmermann, K. Eckart, U. R. Fölsch, and W. E. Schmidt. Structure/activity characterization of glucagon‐like peptide‐1. Eur. J. Biochem. 225: 1151–1156, 1994.
 258. Garber, A. J., P. E., Cryer, J. V. Santiago, M. W. Haymond, A. S. Pagliara, and D. M. Kipnis. The role of adrenergic mechanisms in the substrate and hormonal response to insulin‐induced hypoglycemia in man. J. Clin. Invest. 58: 7–15, 1976.
 259. Garry, D. J., R. L., Sorenson, and H. D. Coulter. Ultrastructural localization of gamma amino butyric acid immunoreactivity in B cells of the rat pancreas. Diabetologia 30: 115–119, 1987.
 260. Garry, D. J., R. L., Sorenson, R. P. Elde, B. E. Maley, and A. Madsen. Immunohistochemical colocalization of GABA and insulin in beta‐cells of rat islet. Diabetes 35: 1090–1095, 1986.
 261. Gaskins, H. R., M. E., Baldeon, L. Selassie, and J. L. Beverly. Glucose modulates gamma‐aminobutyric acid release from the pancreatic beta TC6 cell line. J. Biol. Chem. 270: 30286–30289, 1995.
 262. Gefel, D., G. K., Hendrick, S. Mojsov, J. F. Habener, and G. C. Weir. Glucagon‐like peptide‐I analogs: effects on insulin secretion and adenosine 3′,5′‐cyclic monophosphate formation. Endocrinology 126: 2164–2168, 1990.
 263. George, S. K., L. D., Uttenthal, M. Ghinglione, and S. R. Bloom. Molecular forms of glucagon‐like peptides in man. FEBS Lett. 192: 275–278, 1985.
 264. Gerich, J., J., Davis, M. Lorenzi, R. Rizza, N. Bohannon, J. Karam, S. Lewis, R. Kaplan, T. Schultz, and P. Cryer. Hormonal mechanisms of recovery from insulin‐induced hypoglycemia in man. Am. J. Physiol. 236 (Endocrinol. Metab. Gastrointest. Physiol. 5): E380–E385, 1979.
 265. Gerich, J. E., J. H., Karam, and P. Forsham. Reciprocal adrenergic control of pancreatic alpha‐and beta‐cell function in man. Diabetes 21: 332–333, 1972.
 266. Gerich, J., J., Kram, and P. Forsham. Stimulation of glucagon secretion by epinephrine in man. J. Clin. Endocrinol. Metab. 37: 479–481, 1973.
 267. Gerich, J., M., Lorenzi, E. Tsalikian, and J. Karam. Studies on the mechanism of epinephrine‐induced hyperglycemia in man. Diabetes 25: 65–71, 1976.
 268. Gerich, J. E.. Glucose in the control of glucagon secretion. In: Glucagon II, edited by G. V. R. Born, A. Farah, H. Herken, and A. D. Welch. New York: Springer‐Verlag, 1983, p. 3–15.
 269. Gerich, J. E.. Oral hypoglycemic agents. N. Engl. J. Med. 321: 1231–1245, 1989.
 270. Gerich, J. E., M. A., Charles, and G. M. Grodsky. Characterization of the effects of arginine and glucose on glucagon and insulin release from the perfused rat pancreas. J. Clin. Invest. 54: 833–841, 1974.
 271. Gerich, J. E., M., Langlois, C. Noacco, V. Schneider, and P. H. Forsham. Adrenergic modulation of pancreatic glucagon secretion in man. J. Clin. Invest. 453: 1441–1446, 1974.
 272. Gerich, J. E., M., Langlois, V. Schneider, J. H. Karam, and C. Noacco. Effects of alternations of plasma free fatty acid levels on pancreatic glucagon secretion in man. J. Clin. Invest. 53: 1284–1289, 1974.
 273. Gerich, J. E., V., Schneider, S. E. Dippe, M. Langlois, C. Nocacco, J. H. Karam, and P. H. Forsham. Characterization of the glucagon response to hypoglycemia in man. J. Clin. Endocrinol. Metab. 38: 77–82, 1974.
 274. Ghatei, M. A., L. O., Uttenthal, N. D. Christofldes, M. G. Bryant, and S. R. Bloom. Molecular forms of human enteroglucgon in tissue and plasma: plasma responses to nutrient stimuli in health and in disorders of the upper gastrointestinal tract. J. Clin. Endocrinol. Metab. 57: 448–495, 1983.
 275. Ghiglione, M., E., Blazquez, L. O. Uttenthal, J. G. de Diego, E. Alvarez, S. K. George, and S. R. Bloom. Glucagon‐like peptide‐1 does not have a role in hepatic carbohydrate metabolism. Diabetologia 28: 920–921, 1985.
 276. Gilon, P., G., Bertrand, M. M. Loubatieres‐Mariani, C. Remade, and J. C. Henquin. The influence of gamma‐aminobutyric acid on hormone release by the mouse and rat endocrine pancreas. Endocrinology 129: 2521–2529, 1991.
 277. Girardier, L., J., Seydoux, and L. A. Campfield. Control of A and B cells in vivo by sympathetic nervous input and selective hyper‐or hypoglycemia in dog pancreas. J. Physiol. (Paris) 72: 801–814, 1976.
 278. Gittes, G. K., and W. J. Rutter. Onset of cell‐specific gene expression in the developing mouse pancreas. Proc. Natl. Acad. Sci. U.S.A. 89: 1128–1132, 1992.
 279. Giugliano, D., T., Salvatore, D. Cozzolino, A. Ceriello, R. Torella, and F. D'Onofrio. Hyperglycemia and obesity as determinants of glucose, insulin, and glucagon responses to beta‐endorphin in human diabetes mellitus. J. Clin. Endocrinol. Metab. 64: 1122–1128, 1987.
 280. Gleeson, M. H., S. R., Bloom, J. M. Polak, K. Henry, and R. H. Dowling. Endocrine tumour in kidney affecting small bowel structure, motility, and absorptive function. Gut 12: 773–782, 1971.
 281. Göke, R., and J. M. Conlon. Receptors for glucagon‐like peptide‐I(7–36)amide on rat insulinoma‐derived cells. J. Endocrinol. 116: 357–363, 1988.
 282. Göke, R., H. C., Fehmann, and B. Göke. Glucagon‐like peptide‐1(7–36)amide is a new incretin‐enterogastrone candidate. Eur. J. Clin. Invest. 21: 135–144, 1991.
 283. Göke, R., H.‐C., Fehmann, T. Linn, H. Schmidt, M. Krause, J. Eng, and B. Göke. Exendin‐4 is a high potency agonist and truncated exendin‐(9–39)‐amide an antagonist at the glucagon‐like peptide 1–(7–36)‐amide receptor of insulin‐secreting β‐cells. J. Biol. Chem. 268: 19650–19655, 1993.
 284. Göke, R., P. J., Larsen, J. D. Mikkelsen, and S. Sheikh. Distribution of GLP‐1 binding sites in the rat brain. Evidence that exendin‐4 is a ligand for brain GLP‐1 binding sites. Eur. J. Neurosci. 7: 2294–2300, 1995.
 285. Goldfine, I. D., L., Kirsteins, and A. M. Lawrence. Excessive glucagon responses to arginine in active acromegaly. Horm. Metab. Res. 4: 97–100, 1972.
 286. Goldstein, S. M., M., Blecher, R. Binder, P. V. Perrino, and L. Recant. Hormone receptors: binding of glucagon and insulin to human circulating mononuclear cells in diabetes mellitus. Endocr. Res. Commun. 2: 367–376, 1975.
 287. Goodlad, R. A., M. A., Lenton, M. A. Ghatei, T. E. Adrian, S. R. Bloom, and N. A. Wright. Effects of an elemental diet, inert bluk and different types of dietary fibre on the response of the intestinal epithelium to refeeding in the rat and relationship to plasma gastrin, enteroglucagon, and PYY concentrations. Gut 28: 171–180, 1987.
 288. Goodner, C. J., D. J., Koerker, J. I. Stagner, and E. Samols. In vitro, pancreatic hormonal pulses are less regular and more frequent than in vivo. Am. J. Physiol. 260 (Endocrinol. Metab. 23): E422–E429, 1991.
 289. Goodner, C. J., D. J., Koerker, D. S. Weigle, and D. K. McCulloch. Decreased insulin‐and glucagon‐pulse amplitude accompanying B‐cell deficiency induced by streptozocin in baboons. Diabetes 38: 925–931, 1989.
 290. Goodner, C. J., I. R., Sweet, and H. C. J. Harrison. Rapid reduction and return of surface insulin receptors after exposure to brief pulses of insulin in perfused rat hapatocytes. Diabetes 37: 1316–1323, 1988.
 291. Goodner, C. J., B. C., Walike, D. J. Koerker, J. W. Ensinck, A. C. Brown, E. W. Chideckel, J. Palmer, and L. Kalnasy. Insulin, glucagon, and glucose exhibit synchronous, sustained oscillations in fasting monkeys. Science 195: 177–179, 1977.
 292. Gorus, F. K., W. J., Malaisse, and D. G. Pipeleers. Differences in glucose handling by pancreatic A‐and B‐cells. J. Biol. Chem. 259: 1196–1200, 1984.
 293. Grabner, P., O., Holian, E. Kalahanis, E. Torma Grabner, C. T. Bombeck, and L. M. Nyhus. The effect of chemical sympathectomy on insulin‐stimulated gastric secretion in dogs. Scand. J. Gastroenterol. 19: 178–183, 1984.
 294. Gratzer, W. B., E., Bailey, and G. H. Beaven. Conformational states of glucagon. Biochem. Biophys. Res. Commun. 28: 914–919, 1967.
 295. Gratzer, W. B., and G. H. Beaven. Relation between conformation and association state. A study of the association equilibrium of glucagon. J. Biol. Chem. 244: 6675–6679, 1969.
 296. Gratzer, W. B., G. H., Beaven, W. E. Rattle, and E. M. Bradbury. A conformational study of glucagon. Eur. J. Biochem. 3: 276–283, 1968.
 297. Green, A. K., P. H., Cobbold, and C. J. Dixon. Effects of the hepatocyte [Ca2+], oscillator of inhibition of the plasma membrane Ca2+ pump by carboxyeosin or glucagon‐(19–29). Cell Calcium 22: 99–109, 1997.
 298. Greenbaum, C. J., P. J., Havel, G. J. Taborsky, Jr., and L. J., Klaff. Intra‐islet insulin permits glucose to directly suppress pancreatic A cell function. J. Clin. Invest. 88: 767–773, 1991.
 299. Greenberg, G. R.. Influence of vagal integrity on gastrin and somatostatin release in dogs. Gastroenterology 93: 994–1001, 1987.
 300. Greenberg, G. R., S. L., Wolman, N. D. Christogides, S. R. Bloom, and K. N. Jeejeebhoy. Effect of total parenteral nutrition on gut hormone release in humans. Gastroenterology 80: 988–993, 1981.
 301. Grimelius, L., C., Capella, R. Buffa, J. M. Polak, A. G. E. Pearse, and E. Solcia. Cytochemical and ultrastructural differentiation of enteroglucagon and pancreatic‐type glucagon cells of the gastro intestinal tract. Virchows Arch. 20: 217–228, 1976.
 302. Gromada, J., K., Bokvist, W. G. Ding, S. Barg, K. Buschard, E. Renstrom, and P. Rorsman. Adrenaline stimulates glucagon secretion in pancreatic A‐cells by increasing the Ca2+ current and the number of granules close to the L‐type Ca2+ channels. J. Gen. Physiol. 110: 217–228, 1997.
 303. Gromada, J., S., Dissing, K. Bokvist, E. Renstrom, J. Frokjaer‐Jensen, B. S. Wulff, and P. Rorsman. Glucagon‐like peptide I increases cytoplasmic calcium in insulin‐secreting beta TC3‐cells by enhancement of intracellular calcium mobilization. Diabetes 44: 767–774, 1995.
 304. Gromada, J., P., Rorsman, S. Dissing, and B. S. Wulff. Stimulation of cloned human glucagon‐like peptide 1 receptor expressed in HEK 293 cells induces cAMP‐dependent activation of calcium‐induced calcium release. FEBS Lett. 373: 182–186, 1995.
 305. Gros, L., E., Demiprince, D. Bataille, and A. Kervran. Characterization of high affinity receptors for glucagon‐like peptide (7–36)amide on a somatostatin‐secreting cell line. Biomed. Res. 13 (Suppl. 2): 143–150, 1992.
 306. Gros, L., F., Hollande, B. Thorens, A. Kervran, and D. Bataille. Comparative effects of GLP‐1(7–36)amide, oxyntomodulin and glucagon on rabbit gastric parietal cell function. Eur. J. Pharmacol. 288: 319–327, 1995.
 307. Gutniak, M., C., Orskov, J. J. Holst, B. Ahren, and S. Efendic. Antidiabetogenic effect of glucagon‐like peptide‐1(7–36)amide in normal subjects and patients with diabetes mellitus. N. Engl. J. Med. 326: 1316–1322, 1992.
 308. Gutniak, M. K., L., Juntti‐Berggren, P. M. Hellström, A. Guenifi, J. J. Holst, and S. Effendic. Glucagon‐like peptide 1 enhances the insulinotropic effect of glibenclamide in NIDDM patients and in the perfused rat pancreas. Diabetes Care 19: 857–863, 1996.
 309. Gutniak, M. K., H., Larsson, S. J. Heiber, O. T. Juneskans, J. J. Holst, and B. Ahren. Potential therapeutic levels of glucagon‐like peptide I achieved in humans by a buccal tablet. Diabetes Care 19: 843–848, 1996.
 310. Gutniak, M. K., H., Larsson, S. W. Sanders, O. Juneskans, J. J. Holst, and B. Ahrén. GLP‐1 tablet in type 2 diabetes in fasting and postprandial conditions. Diabetes Care 20: 1874–1879, 1997.
 311. Gutniak, M. K., B., Linde, J. J. Holst, and S. Efendic. Subcutaneous injection of the incretin hormone glucagon‐like peptide 1 abolishes postprandial glycemia in NIDDM. Diabetes Care 17: 1039–1044, 1994.
 312. Habener, J. F.. The incretin notion and its relevance to diabetes. In: Gastrointestinal Hormones in Medicine. Philadelphia: Saunders, Eudocrinol. Metab. Clin. 22: 775–794, 1993.
 313. Habener, J. F.. Insulinotropic glucagon‐like peptides. In: Diabetes Mellitus, edited by D. LeRoith and S. I. Taylor. Philadelphia: Lippincott‐Raven, 1996, p. 68–78.
 314. Habener, J. F.. Proglucagon gene structure and regulation of expression. In: The Insulinotropic Gut Hormone Glucagon‐like Peptide‐1, edited by H. C. Fehmann and B. Göke. Basel: Karger, 1997, p. 15–23.
 315. Habener, J. F., D. J., Drucker, S. Mojsov, W. Knepel, and J. Philippe. Biosynthesis of glucagon. In: The Endocrine Pancreas, edited by E. Samols. New York: Raven, 1991, p. 53–71.
 316. Habener, J. F., C. P., Miller, and M. Vallejo. Cyclic AMP‐dependent regulation of gene transcription by CREB and CREM. In: Vitamins and Hormones, edited by G. Litwack. San Diego: Academic, 1995, p. 1–57.
 317. Habener, J. F., and D. A. Stoffers. A newly discovered role of transcription factors involved in pancreas development and the pathogenesis of diabetes mellitus. Proc. Assoc. Am. Physicians. 110: 12–21, 1998.
 318. Hager, J., L., Hansen, and C. Vaisse. A missense mutation in the glucagon gene is associated with non‐insulin dependent diabetes mellitus. Nat. Genet. 9: 299–304, 1995.
 319. Hagopian, W. A., and H. S. Tager. Hepatic glucagon metabolism. Correlation of hormone processing by isolated canine hepatocytes with glucagon metabolism in man and in the dog. J. Clin. Invest. 79: 409–417, 1987.
 320. Haito, K., A., Takeda, S. Kagawa, S. Shimizu, and A. Matsuoka. Cholinergic effect of 2‐deoxy‐D‐glucose on plasma glucagon levels in the rat. Horm. Metab. Res. 16: 110–113, 1982.
 321. Hampton, S. M., L. M., Morgan, J. A. Triedger, R. Cramb, and V. Marks. Insulin and C‐peptide levels after oral and intravenous glucose. Diabetes 35: 612–616, 1986.
 322. Han, V. K. M., M. A., Hynes, C. Jin, A. C. Towle, J. M. Landauer, and P. K. Lund. Cellular localization of proglucagon/glucagon‐like peptide I messenger RNAs in rat brain. J. Neurosci. Res. 16: 97–107, 1986.
 323. Hansen, A. B., C. P., Gespach, G. E. Rosselin, and J. J. Holst. Effect of truncated glucagon‐like peptide on cAMP in rat gastric glands and HFT‐1 human gastric cancer cells. FEBS Lett. 236: 119–122, 1988.
 324. Hansen, B. C., K. C., Jen, S. B. Pek, and R. A. Wolfe. Rapid oscillations in plasma insulin, glucagon, and glucose in obese and normal weight humans. J. Clin. Endocrinol. Metab. 54: 785–792, 1982.
 325. Hansen, L. H., N., Abrahamsen, and E. Nishimura. Glucagon receptor mRNA distribution in rat tissues. Peptides 16: 1163–1166, 1995.
 326. Harrington, R. A., and A. F. Kaul. Cardiopulmonary arrest following barium enema examination with glucagon. Drug Intell. Clin. Pharm. 21: 721–722, 1987.
 327. Hasegawa, S., K., Terazono, K. Nata, T. Takada, H. Yamamoto, and H. Okamoto. Nucleotide sequence determination of chicken glucagon precursor cDNA: chicken preproglucagon does not contain glucagon‐like peptide II. FEBS Lett. 264: 117–120, 1990.
 328. Hasselbalch, S. G., G. M., Knudsen, J. Jakobsen, L. P. Hageman, S. Holm, and O. B. Paulson. Brain metabolism during short‐term starvation in humans. J. Cereb. Blood Flow Metab. 14: 125–131, 1994.
 329. Havel, P., R. C., Veith, B. E. Dunning, and G. J. Taborsky, Jr.. Pancreatic noradrenergic nerves are activated by neuroglucopenia but not by hypotension or hypoxia in the dog: evidence for stress‐specific and regionally selective activation of the sympathetic nervous system. J. Clin. Invest. 82: 1538–1545, 1988.
 330. Havel, P. J., and B. Ahren. Activation of autonomic nerves and the adrenal medulla contributes to increased glucagon secretion during moderate insulin‐induced hypoglycemia in women. Diabetes 46: 801–807, 1997.
 331. Havel, P. J., J. O., Akpan, D. L. Curry, J. S. Stern, R. L. Gingerich, and B. Ahren. Autonomic control of pancreatic polypeptide and glucagon secretion during neuroglucopenia and hypoglycemia in mice. Am. J. Physiol. 265 (Regulatory Integrative Comp. Physiol. 34): R246–R254, 1993.
 332. Havel, P. J., B. E., Dunning, C. B. Verchere, D. G. Baskin, T. O'Dorisio, and G. J. Taborsky, Jr.. Evidence that vasoactive intestinal polypeptide is a parasympathetic neurotransmitter in the endocrine pancreas in dogs. Regul. Pept. 71: 163–170, 1997.
 333. Havel, P. J., T. O., Mundinger, and G. J. J. Taborsky. Pancreatic‐sympathetic nerves contribute to increased glucagon secretion during severe hypoglycemia in dogs. Am. J. Physiol. 270 (Endocrinol. Metab. 33): E20–E26, 1996.
 334. Havel, P. J., T. O., Mundinger, R. C. Veith, B. E. Dunning, and G. J. Taborsky, Jr.. Corelease of galanin and NE from pancreatic sympathetic nerves during severe hypoglycemia in dogs. Am. J. Physiol. 263 (Endocrinol. Metab. 26): E8–E16, 1992.
 335. Havel, P. J., S. J., Parry, D. L. Curry, J. S. Stern, J. O. Akpan, and R. L. Gingerich. Autonomic nervous system mediation of the pancreatic polypeptide response to insulin‐induced hypoglycemia in conscious rats. Endocrinology 130: 2225–2229, 1992.
 336. Havel, P. J., S. J., Parry, J. S. Stern, J. O. Akpan, R. L. Gingerich, G. J. Taborsky, Jr., and D. L., Curry. Redundant parasympathetic and sympathoadrenal mediation of increased glucagon secretion during insulin‐induced hypoglycemia in conscious rats. Metabolism 43: 860–866, 1994.
 337. Havel, P. J., and G. J. Taborsky, Jr.. The contribution of the autonomic nervous system to changes of glucagon and insulin secretion during hypoglycemic stress. Endocr. Rev. 10: 332–350, 1989.
 338. Havel, P. J., and G. J. Taborsky, Jr.. The contribution of the autonomic nervous system to increased glucagon secretion during hypoglycemic stress: update 1994. Endocr. Rev. 2: 201–204, 1994.
 339. Havel, P. J., and C. Valverde. Autonomic mediation of glucagon secretion during insulin‐induced hypoglycemia in rhesus monkeys. Diabetes 45: 960–966, 1996.
 340. Havel, P. J., R. C., Veith, B. E. Dunning, and G. J. Taborsky, Jr.. Role for autonomic nervous system to increase pancreatic glucagon secretion during marked insulin‐induced hypoglycemia in dogs. Diabetes 40: 1107–1114, 1991.
 341. Heding, L. G.. Radioimmunological determination of pancreatic and gut glucagon in plasma. Diabetologia 7: 10–19, 1971.
 342. Hedo, J. A., M. L., Villanueva, and J. Marco. Stimulation of pancreatic polypeptide and glucagon secretion by 2‐deoxy‐D‐glucose in man: evidence for cholinergic mediation. J. Clin. Endocrinol. Metab. 47: 366–371, 1978.
 343. Heinrich, G. P. Gros, and J. F. Habener. Glucagon gene sequence: four of six exons encode separate functional domains of rat preproglucagon. J. Biol. Chem. 259: 14082–14084, 1983.
 344. Heinrich, G., P., Gros, P. K. Lund, R. C. Bentley, and J. F. Habener. Pre‐proglucagon messenger ribonucleic acid: nucleotide and encoded amino acid sequences of the rat pancreatic complementary deoxyribonucleic acid. Endocrinology 115: 2176–2181, 1984.
 345. Heller, H.. Uber den blutzuckerwirksamen Stoff in Sekretinextrakten. Naunyn Schmiedebergs Arch. Pharmacol. 145: 343–358, 1929.
 346. Heller, H.. Uber das insulinotrope Hormon der Darmschleimhaut (Duodenin). Naunyn Schmiedebergs Arch. Pharmacol. 177: 127–133, 1935.
 347. Heller, R. S., and G. W. Aponte. Intra‐islet regulation of hormone secretion by glucagon‐like peptide‐1(7–36)amide. Am. J. Physiol. 269 (Gastrointest. Liver Physiol. 32): G853–G860, 1995.
 348. Heller, R. S., T. J., Kieffer, and J. F. Habener. Point mutations in the first and third intracellular loops of the glucagon‐like peptide‐1 receptor alter intracellular signaling. Biochem. Biophys. Res. Commun. 223: 624–632, 1996.
 349. Heller, R. S., T. J., Kieffer, and J. F. Habener. Insulinotropic glucagon‐like peptide I receptor expression in glucagon‐producing α‐cells of the rat endocrine pancreas. Diabetes 46: 785–791, 1997.
 350. Hellerstrom, C., S. L., Howell, J. C. Edwards, and A. Anderson. An investigation of glucagon biosynthesis in isolated pancreatic islets of guinea pigs. FEBS Lett. 27: 97–101, 1972.
 351. Hendrick, G. K., A., Gjinovci, L. A. Baxter, S. Mojsov, C. B. Wollheim, J. F. Habener, and G. C. Weir. Glucagon‐like peptide‐I‐(7–37) suppresses hyperglycemia in rats. Metabolism 42: 1–6, 1993.
 352. Herald, K. C., and J. B. Jaspan. Hepatic glucagon clearance during insulin induced hypoglycemia. Horm. Metab. Res. 18: 431–435, 1986.
 353. Herrera, P. L., J., Huarte, F. Sanvito, P. Meda, L. Orci, and J. D. Vassalli. Embryogenesis of the murine endocrine pancreas: early expression of pancreatic polypeptide gene. Development 113: 1257–1265, 1991.
 354. Herrera, P. L., J., Huarte, R. Zuffery, A. Nichols, B. Mermillod, J. Philippe, P. Muniesa, F. Sanvito, L. Orci, and J. D. Vassalli. Ablation of islet endocrine cells by targeted expression of hormone promoter‐driven toxigenes. Proc. Natl. Acad. Sci. U.S.A. 91: 12999–13003, 1994.
 355. Herrmann, C., R., Göke, G. Richter, H. C. Fehmann, R. Arnold, and B. Göke. Glucagon‐like peptide‐1 and glucose‐dependent insulin‐releasing polypeptide plasma levels in response to nutrients. Digestion 56: 117–26, 1995.
 356. Herrmann, C., A., Vöge, and B. Göke. Regulation of glucagon‐like peptide release from the isolated perfused rat ileum by nutrients, peptides and neuromediators. Digestion 54: 367, 1993.
 357. Herrmann‐Rinke, C., D., Hörsch, G. P. McGregor, and B. Göke. Galanin is a potent inhibitor of glucagon‐like peptide‐1 secretion from rat ileum. Peptides 17: 571–576, 1996.
 358. Herrmann‐Rinke, C., A., Vöge, M. Hess, and B. Göke. Regulation of glucagon‐like peptide‐1 secretion from rat ileum by neurotransmitters and peptides. J. Endocrinol. 147: 25–31, 1995.
 359. Hii, C. S., and S. L. Howell. Restoration of the A cell response to glucose in isolated rat islets of Langerhans. Mol. Cell. Endocrinol. 48: 199–204, 1986.
 360. Hii, C. S., and S. L. Howell. Role of second messengers in the regulation of glucagon secretion from isolated rat islets of Langerhans. Mol. Cell. Endocrinol. 50: 37–44, 1987.
 361. Hii, C. S., J., Stutchfield, and S. L. Howell. Enhancement of glucagon secretion from isolated rat islets of Langerhans by phorbol 12‐myristate 13‐acetate. Biochem. J. 233: 287–289, 1986.
 362. Hildebrandt, W., W., Blech, and K. D. Kohnert. Kinetic studies on hepatic handling of glucagon using the model of non‐recirculating perfused rat livers. Horm. Metab. Res. 23: 410–413, 1991.
 363. Hildebrandt, W., K. D., Kohnert, and W. Blech. Glucagon and insulin degradation by hemolysate of human erythrocytes. Biomed. Biochem. Acta 46: 557–563, 1987.
 364. Hilsted, J., H., Frandsen, J. J. Holst, N. J. Christensen, and S. L. Nielsen. Plasma glucagon and glucose recovery after hypoglycemia: the effect of total autonomic blockade. Acta Endocrinol. (Copenh.) 125: 466–469, 1991.
 365. Hirose, H., H., Maruyama, K. Ito, K. Kido, K. Koyama, and T. Saruta. Effects of alpha 2‐and beta‐adrenergic agonism on glucagon secretion from perfused pancreata of normal and streptozocin‐induced diabetic rats. Metabolism 42: 1072–1076, 1993.
 366. Hirota, M., M., Hashimoto, M. Hiratsuka, C. Oboshi, S. Yoshimoto, M. Yano, A. Mizuno, and K. Shima. Alterations of plasma immunoreactive glucagon‐like peptide‐1 behaviour in non‐insulin‐dependent diabetics. Diabetes Res. Clin. Pract. 9: 179–185, 1990.
 367. Hjorth, S., K. Adelhorst, B. B. Pedersen, O. Kirk, and T. W. Schwartz. Glucagon and glucagon‐like peptide 1: selective receptor recognition via distinct peptide epitopes. J. Biol. Chem. 269: 30121–30124, 1994.
 368. Hochhuth, C., A., Neubauer, and W. Knepel. Transactivation of the rat glucagon gene promoter by the CCAAT/enhancer binding protein. Endocrine 2: 833–839, 1994.
 369. Holst, J. J.. Evidence that glicentin contains the entire glucagon sequence. Biochem. J. 187: 337–343, 1980.
 370. Holst, J. J.. Glucagonlike peptide 1: a newly discovered gastrointestinal hormone. Gastroenterology 107: 1848–1855, 1994.
 371. Holst, J. J.. Enteroglucagon. Annu. Rev. Physiol. 59: 257–271, 1997.
 372. Holst, J. J., M., Bersani, A. H. Johnsen, H. Kofod, B. Hartmann, and C. Ørskov. Proglucagon processing in porcine and human pancreas. J. Biol. Chem. 269: 18827–18833, 1994.
 373. Holst, J. J., J., Fahrenkrug, S. Knuhtsen, S. L. Jensen, and O. V. Nielsen. Vasoactive intestinal polypeptide in the pig pancreas: role of VIPergic nerves in control of fluid and bicarbonate secretion. Regul. Pept. 8: 245–259, 1984.
 374. Holst, J. J., R. Gronholt, O. B. Schaffalitzky de Muckadell, and J. Fahrenkrug. Nervous control of pancreatic endocrine secretion in pigs. I. Insulin and glucagon responses to electrical stimulation of the vagus nerves. Acta Physiol. Scand. 111: 1–7, 1981.
 375. Holst, J. J., C. Orskov, O. Van Nielsen, and T. W. Schwartz. Truncated glucagon‐like peptide I, an insulin‐releasing hormone from the distal gut. FEBS Lett. 211: 169–173, 1987.
 376. Holst, J. J., H. Von Schenck, and S. Lindkaer. Gel filtration pattern of immunoreactive glucagon secreted by the isolated, perfused, porcine pancreas. Scand. J. Clin. Lab. Invest. 39: 47–52, 1979.
 377. Holst, J. J., A., Wettergren, M. Wojdemann, S. S. Poulsen, and C. Ørskov. Glucagon‐like peptide‐1 (GLP‐1): an important enterogastrone acting via the central nervous system. Hepatogastroenterology 42: 1071, 1995.
 378. Holz, G. G., and J. F. Habener. Signal transduction crosstalk in the endocrine system: pancreatic β‐cells and the glucose competence concept. Trends Biochem. Sci. 17: 388–393, 1992.
 379. Holz, G. G., W. M., Kühtreiber, and J. F. Habener. Pancreatic beta‐cells are rendered glucose‐competent by the insulinotropic hormone glucagon‐like peptide‐1(7–37). Nature 361: 362–365, 1993.
 380. Holz, G. G., C. A., Leech, and J. F. Habener. Activation of a cAMP‐regulated Ca2+‐signaling pathway in pancreatic β‐cells by the insulinotropic hormone glucagon‐like peptide‐1. J. Biol. Chem. 270: 17749–17757, 1995.
 381. Honey, R. N., A., Arimura, and G. C. Weir. Somatostatin neutralization stimulates glucagon and insulin secretion from the avian pancreas. Endocrinology 109: 1971–1974, 1981.
 382. Honnor, R. C., and E. D. Saggerson. Altered lipolytic response to glucagon and adenosine deaminase in adipocytes from starved rats. Biochem. J. 188: 757–761, 1980.
 383. Hoosein, N. M., and R. Gand. Human glucagon‐like peptides 1 and 2 activate rat brain adenylate cyclase. FEBS Lett. 178: 83–86, 1984.
 384. Hoosein, N. M., and R. S. Gurd. Identification of glucagon receptors in rat brain. Proc. Natl. Acad. Sci. U.S.A. 81: 4368–4372, 1984.
 385. Hruby, V. J., J., Krstenansky, B. Gysin, J. T. Pelson, D. Trivedi, and R. L. Mckee. Conformational considerations in the design of glucagon agonists and antagonists: examination using synthetic analogs. Biopolymers 25: S135–S155, 1986.
 386. Huang, T. H. J., and P. L. Brubaker. Synthesis and secretion of glucagon‐like peptide‐1 by fetal rat intestinal cells in culture. Endocrine 3: 499–503, 1995.
 387. Huchtebrock, H. J., W., Niebel, M.V. Singer, and W. G. Forssmann. Intrinsic pancreatic nerves after mechanical denvervation of the extrinsic pancreatic nerves in dogs. Pancreas 61: 1–8, 1991.
 388. Hupe‐Sodmann, K., B., Göke, H. H. Thole, B. Zimmermann, K. Voigt, and G. P. McGregor. Endoproteolysis of glucagon‐like peptide (GLP)‐1(7–36) amide by ectopeptidases in RINm5F cells. Peptides 18: 625–632, 1997.
 389. Hupe‐Sodmann, K., G. P., McGregor, R. Bridenbaugh, R. Göke, B. Göke, H. Thole, B. Zimmermann, and K. Voigt. Characterization of the processing by human neutral endopeptidase 24.11 of GLP‐1(7–36) amide and comparison of the substrate specificity of the enzyme for other glucagon‐like peptides. Regal. Pept. 58: 149–156, 1995.
 390. Hussain, M. A., J., Lee, C. P. Miller, and J. F. Habener. POU domain transcription factor brain 4 confers pancreatic α‐cell‐specific expression of the proglucagon gene through interaction with a novel proximal promoter G1 element. Mol. Cell. Biol. 17: 7186–7194, 1997.
 391. Inagaki, N., T., Gonoi, J. T. Clement, N. Namba, J. Inazawa, G. Gonzalez, L. Aguilar‐Bryan, S. Seino, and J. Bryan. Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Science 270: 1166–1170, 1995.
 392. Ipp, E., R., Dobbs, and R. H. Unger. Morphine and beta‐endorphin influence the secretion of the endocrine pancreas. Nature 276: 190–191, 1978.
 393. Ipp, E., R. E., Dobbs, A. Arimura, W. Vale, V. Harris, and R. H. Unger. Release of immunoreactive somatostatin from the pancreas in response to glucose, amino acids, pancreozymin‐cholecystokinin, and tolbutamide. J. Clin. Invest. 60: 760–765, 1977.
 394. Ipp, E., C., Garberoglio, H. Richter, A. R. Moossa, and A. H. Rubenstein. Naloxone decreases centrally induced hyperglycemia in dogs. Evidence for an opioid role in glucose homeostasis. Diabetes 33: 619–621, 1984.
 395. Ipp, E., J., Rivier, R. E. Dobbset, et. al. Somatostatin analogs inhibit somatostatin release. Endocrinology 104: 1270–1273, 1979.
 396. Irwin, D. M., M., Satkunarajah, Y. Wen, P. L. Brubaker, R. A. Pederson, and M. B. Wheeler. The Xenopus proglucagon gene encodes novel GLP‐1‐like peptides with insulinotropic properties. Proc. Natl. Acad. Sci. U.S.A. 94: 7915–7920, 1997.
 397. Irwin, D. M., and J. Wong. Trout and chicken proglucagon: alternative splicing generates mRNA transcripts encoding glucagon‐like peptide 2. Mol. Endocrinol. 9: 267–277, 1995.
 398. Ishida, T., M. C. Y., Chou, R. M. Lewis, C. J. Hartley, M. Entman, and J. B. Field. The effect of tolbutamide on hepatic extraction of insulin and glucagon and hepatic glucose output in anesthetized dogs. Endocrinology 109: 443–450, 1981.
 399. Ishida, T., S., Rojdmark, G. Bloom, M. C. Y. Chou, and J. B. Field. The effect of somatostatin on the hepatic extraction of insulin and glucagon in the anesthetized dog. Endocrinology 106: 220–230, 1980.
 400. Ishihara, T., S., Nakamura, and Y. Kaziro. Molecular cloning and expression of a cDNA encoding the secretin receptor. EMBO J. 10: 1635–1641, 1991.
 401. Ishihara, T., R., Shigemoto, K. Mori, K. Takkahashi, and S. Nagata. Functional expression and tissue distribution of a novel receptor for vasoactive intestinal peptide. Neuron 8: 811–819, 1992.
 402. Ito, K., H., Maruyama, H. Hirose, K. Kido, K. Koyama, K. Kataoka Kotaoka, and T. Saruta. Exogenous insulin dose‐dependently suppresses glucopenia‐induced glucagon secretion from perfused rat pancreas. Metabolism 44: 358–362, 1995.
 403. Itoh, M., L., Mandarino, and J. E. Gerich. Antisomatostatin gamma globulin augments secretion of both insulin and glucagon in vitro: evidence for a physiologic role for endogenous somatostatin in the regulation of pancreatic A‐and B‐cell function. Diabetes 29: 693–696, 1980.
 404. Iversen, J.. Secretion of glucagon from the isolated, perfused canine pancreas. J. Clin. Invest. 50: 2123–2136, 1971.
 405. Iversen, J.. Adrenergic receptors and the secretion of glucagon and insulin from the isolated, perfused canine pancreas. J. Clin. Invest. 52: 2101–2116, 1973.
 406. Iversen, J.. Effect of acetylcholine on the secretion of glucagon and insulin from the isolated, perfused canine pancreas. Diabetes 22: 381–387, 1973.
 407. Iversen, J., and K. Hermansen. Characterization of the inhibitory effect of somatostatin upon insulin and glucagon release in the isolated perfused canine pancreas: evidence for interaction with calcium. Metabolism 29: 151–160, 1980.
 408. Iyengar, R., K. A., Rich, J. T. Herberg, R. T. Fremont, and J. Codina. Glucagon receptor–mediated activation of Gsis accompanied by subunit dissociation. J. Biol. Chem. 263: 15348–15353, 1988.
 409. Jacobson, H., A., Demandt, A. J. Moody, and F. Sundby. Sequence analysis of porcine gut GLI‐1. Biochim. Biophys. Acta 493: 452–459, 1977.
 410. Jarhult, J., L., Farnebo, B. Hamberger, J. J. Holst, and T. W. Schwartz. The relation between catecholamines, glucagon and pancreatic polypeptide during hypoglycemia in man. Acta Endocrinol. (Copenh.) 98: 402–406, 1981.
 411. Jaspan, J. B., A. H.‐J., Huen, C. G. Morley, A. R. Moossa, and A. H. Rubenstein. The role of the liver in glucagon metabolism. J. Clin. Invest. 60: 421–428, 1977.
 412. Jaspan, J. B., E., Lever, K. S. Polonsky, and E. Van Cauter. In vivo pulsatility of pancreatic islet peptides. Am. J. Physiol. 251 (Endocrinol. Metab. 14): E215–E226, 1986.
 413. Jaspan, J. B., K. S., Polonsky, M. Lewis, J. Pensler, W. Pugh, A. R. Moossa, A. H. Rubenstein. Hepatic metabolism of glucagon in the dog. Am. J. Physiol. 240 (Endocrinol. Metab. 3): E233–E244, 1981.
 414. Jelinek, L. J., S., Lok, and G. B. Rosenberg. Expression cloning and signaling properties of the rat glucagon receptor. Science 259: 1614–1616, 1993.
 415. Jennings, A. S., A. D., Cherrington, J. E. Liljenquist, et al. The roles of insulin and glucagon in the regulation of gluconeogenesis in the postabsorptive dog. Diabetes 26: 847–856, 1977.
 416. Jensen, M. D., V., Heiling, and J. Miles. Effects of glucagon on free fatty acid metabolism in humans. J. Clin. Endocrinol. Metab. 72: 308–315, 1991.
 417. Jensen, S. L., J., Fahrenkrug, J. J. Holst, O. V. Nielsen, and O. B. Schaffalitzky de Muckadell. Secretory effects of VIP on isolated perfused porcine pancreas. Am. J. Physiol. 235 (Endocrinol. Metab. Gastrointest. Physiol. 4): E387–E391, 1978.
 418. Jensen, S. L., C., Kuhl, O. V. Nielsen, and J. J. Holst. Isolation and perfusion of the porcine pancreas. Scand. J. Gastroenterol. Suppl. 37: 57–61, 1976.
 419. Jetton, T. L., Y., Liang, C. C. Pettepher, E. C. Zimmerman, F. G. Cox, K. Horvath, F. M. Matschinsky, and M. A. Magnuson. Analysis of upstream glucokinase promoter activity in transgenic mice and identification of glucokinase in rare neuroendocrine cells in the brain and gut. J. Biol. Chem. 269: 3641–3654, 1994.
 420. Jin, S. L., V. K. M., Han, J. G. Simmons, A. C. Towle, and P. K. Lund. Distribution of glucagon‐like peptide I (GLP‐1) glucagon, and glicentin in the rat brain. An immunohistochemical study. J. Comp. Neurol. 271: 519–532, 1988.
 421. Jin, T., and D. J. Drucker. The proglucagon gene upstream enhancer contains positive and negative domains important for tissue‐specific proglucagon gene transcription. Mol. Endocrinol. 9: 1306–1320, 1995.
 422. Jin, T., D. K. Y., Trinh, F. Wang, and D. J. Drucker. The caudal homeobox protein cdx‐2/3 activates endogenous proglucagon gene expression in InR1‐G9 islet cells. Mol. Endocrinol. 11: 203–209, 1997.
 423. Johansson, H., E., Gylfe, and B. Hellman. The actions of arginine and glucose on glucagon secretion are mediated by opposite effects on cytoplasmic Ca2+ Biochem. Biophys. Res. Commun. 147: 309–314, 1987.
 424. Johansson, H., E., Gylfe, and B. Hellman. Cyclic AMP raises cytoplasmic calcium in pancreatic alpha 2‐cells by mobilizing calcium incorporated in response to glucose. Cell Calcium 10: 205–211, 1989.
 425. Johnson, D. G., J. W., Ensinck, D. Koerker, J. Palmer, and C. J. Goodner. Inhibition of glucagon and insulin secretion by somatostatin in the rat pancreas perfused in situ. Endocrinology 96: 370–374, 1975.
 426. Jonsson, J., L., Carlsson, T. Edlund, and H. Edlund. Insulin‐promoter‐factor 1 is required for pancreas development in mice. Nature 371: 606–609, 1994.
 427. Juntti‐Berggren, L., J., Pigon, F. Karpe, A. Hamsten, M. Gutniak, L. Vignati, and S. Efendic. The antidiabetogenic effect of GLP‐1 is maintained during a 7‐day treatment period and improves diabetic dyslipoproteinemia in NIDDM patients. Diabetes Care 19: 1200–1206, 1996.
 428. Jüppner, H., A. B., Abou‐Samra, and M. Freeman. A G protein–linked receptor for parathyroid hormone and parathyroid hormone related peptide. Science 254: 1024–1026, 1991.
 429. Kainberger, F., H., Lindemayr, F. Fruhwald, and B. Schwaighofer. Intolerance reaction following glucagon administration in a double‐contrast study. Radiologe 26: 531–533, 1986.
 430. Kalant, N.. The effect of glucagon on metabolism of glycine‐1‐C14 Arch. Biochem. Biophys. 65: 469–473, 1956.
 431. Kaneto, A., H., Kajinuma, and K. Kosaka. Effect of splanchnic nerve stimulation on glucagon and insulin output in the dog. Endocrinology 96: 143–150, 1975.
 432. Kaneto, A., H., Kajinuma, and K. Kosaka. Effect of alpha adreno‐receptor stimulants infused intrapancreatically on glucagon and insulin secretion. Horm. Metab. Res. 9: 267–271, 1977.
 433. Kaneto, A., T., Kaneko, H. Kajinuma, and K. Kosaka. Effect of vasoactive intestinal polypeptide infused intrapancreatically on glucagon and insulin secretion. Metabolism 26: 781–786, 1977.
 434. Kaneto, A., E., Miki, and K. Kosaka. Effects of vagal stimulation on glucagon and insulin secretion. Endocrinology 95: 1005–1010, 1974.
 435. Kaneto, A., E., Miki, and K. Kosaka. Effect of beta and beta2 adrenoreceptor stimulants infused intrapancreatically on glucagon and insulin secretion. Endocrinology 97: 1166–1173, 1975.
 436. Kanse, S., M. B., Kreymann, M. A. Ghatei, and S. R. Bloom. Identification and characterization of glucagon‐like peptide‐1–7–36 amide in rat brain and lung. FEBS Lett. 267: 78–80, 1988.
 437. Kanter, R. A., J. W., Ensinck, and W. Y. Fujimoto. Disparate effects of enkephalin and morphine upon insulin and glucagon secretion by islet cell cultures. Diabetes 29: 84–86, 1980.
 438. Karlsson, S., and B. Ahren. Inhibition of 2‐deoxy‐glucose‐induced glucagon secretion by muscarinic and alpha‐adrenoceptor blockade in the mouse. Diabetes Res. Clin. Pract. 3: 239–242, 1987.
 439. Kauth, T., and J. Metz. Immunohistochemical localization of glucagon‐like peptide‐1: use of poly‐ and monoclonal antibodies. Histochemistry 86: 509–515, 1987.
 440. Kawai, K., E., Ipp, L. Orci, et al. Circulating somatostatin acts on the islets of Langerhans by way of somatostatin‐poor compartment. Science 218: 477–478, 1982.
 441. Kawai, K., K., Sasaki, C. Yokota, T. Sato, and K. Yamashita. Recombinant DNA glicentin and its biological activity. Diabetologia 38 (Suppl. 1): A130, 1995.
 442. Kawai, K., S., Suzuki, and S. Ohashi. Comparison of the effects of glucagon‐like peptide‐I(1–37) and (7–37) and glucagon on islet hormone release from isolated perfused canine and rat pancreas. Endocrinology 124: 1768–1773, 1989.
 443. Kawai, K., S., Suzuki, S. Ohashi, H. Mukai, Y. Murayma, and K. Yamashita. Effects of truncated glucagon‐like peptide‐1 on pancreatic hormone release in normal conscious dogs. Acta Endorinol. (Copenh.) 123: 661–667, 1990.
 444. Kawamoto, H., H., Yamamura, M. Tatsuta, and S. Okuda. Effect of glucagon on gastric motility examined by the acetaminophen absorption method and the endoscopic procedure. Arzneimittelforschung 35: 1475–1477, 1985.
 445. Keller, U., J.‐L., Chiasson, J. E. Liljenquist, A. D. Cherrington, A. S. Jennings, and O. S. Crofford. The roles of insulin, glucagon, and free fatty acids in the regulation of ketogenesis in dogs. Diabetes 26: 1040–1051, 1977.
 446. Kemmer, F. W., and M. Vranic. The role of glucagon and its relationship to other glucoregulatory hormones in exercise. In: Glucagon: Physiology, Pathophysiology, and Morphology of the Pancreatic A Cells, edited by R. H. Unger and L. Orci. New York: Elsevier, 1981, p. 297–331.
 447. Kendall, D. M., V., Poitout, L. K. Olson, R. L. Sorenson, and R. P. Robertson. Somatostatin coordinately regulates glucagon gene expression and exocytosis in HIT‐T15 cells. J. Clin. Invest. 96: 2496–2502, 1995.
 448. Kenny, A. J., and N. M. Hooper. Peptidases involved in the metabolism of bioactive peptides. In: Degradation of BioActive Substances: Physiology and Pathophysiology, edited by J. Henrrickson. Boca Raton, FL: CRC, 1991, p. 47–79.
 449. Kervran, A., P., Blache, and D. Bataille. Distribution of oxyntomodulin and glucagon in the gastrointestinal tract and the plasma of the rat. Endocrinology 121: 704–713, 1987.
 450. Kieffer, T. J., R. S., Heller, and J. F. Habener. Leptin receptors expressed on pancreatic β‐cells. Biochem. Biophys. Res. Commun. 224: 522–527, 1996.
 451. Kieffer, T. J., R. S., Heller, C. A. Leech, G. G. Holz, and J. F. Habener. Leptin suppression of insulin secretion by the activation of ATP‐sensitive K+ channels in pancreatic β‐cells. Diabetes 46: 1087–1093, 1997.
 452. Kieffer, T. J., R. S., Heller, C. G. Unson, G. C. Weir, and J. F. Habener. Distribution of glucagon receptors on hormone‐specific endocrine cells of rat pancreatic islets. Endocrinology 137: 5119–5125, 1996.
 453. Kieffer, T. J., C. H. S., McIntosh, and R. A. Pederson. Degradation of glucose‐dependent insulinotropic polypeptide and truncated glucagon‐like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology 136: 3585–3596, 1995.
 454. Kimball, C. P., and J. R. Murlin. Some precipitation reactions of insulin. J. Biol Chem. 243: 1031–1038, 1923.
 455. King, M. V.. A low resolution structural model for cubic glucagon based on packing of cylinders. J. Mol. Biol. 11: 549–561, 1965.
 456. Kisanuki, K., H., Kishikawa, E. Araki, T. Shirotani, M. Uehara, S. Isami, S. Ura, H. Jinnouchi, N. Miyamura, and M. Shichiri. Expression of insulin receptor on clonal pancreatic alpha cells and its possible role for insulin‐stimulated negative regulation of glucagon secretion. Diabetologia 38: 422–429, 1995.
 457. Klaff, L. J., and G. J. Taborsky, Jr.. Pancreatic somatostatin is a mediator of glucagon inhibition by hyperglycemia. Diabetes 36: 592–596, 1987.
 458. Kleinman, R., G., Ohning, H. Wong, P. Watt, J. Walsh, and F. C. Frunicardi. Regulatory role of intraislet somatostatin on insulin secretion in the isolated perfused human pancreas. Pancreas 9: 172–178, 1994.
 459. Knapper, J. M. E., A., Heath, J. M. Fletcher, L. M. Morgan, and V. Marks. GIP and GLP‐1(7–36)amide secretion in response to intraduodenal infusion of nutrients in pigs. Comp. Biochem. Physiol. C Pharmacol. Toxicol. Endocrinol. 111: 445—450, 1995.
 460. Knepel, W., J., Chafitz, and J. F. Habener. Transcriptional activation of the rat glucagon gene by the cAMP‐response element in pancreatic islet cells. Mol. Cell. Biol. 10: 6799–6804, 1990.
 461. Knepel, W., L., Jepeal, and J. F. Habener. A pancreatic islet cell‐specific enhancer‐like element in the glucagon gene contains two domains binding distinct cellular proteins. J. Biol. Chem. 265: 8725–8735, 1990.
 462. Knepel, W., M., Vallejo, J. Chafitz, and J. F. Habener. The pancreatic islet–specific glucagon G3 transcription factor recognizes control elements in the rat somatostatin and insulin‐1 genes. Mol. Endocrinol. 5: 1457–1466, 1991.
 463. Knudsen, L. B., and L. Pridal. Glucagon‐like‐peptide‐1‐(9–36) amide is a major metabolite of glucagon‐like peptide‐1‐(7–36) amide after in vivo administration to dogs, and it acts as an antagonist on the pancreatic receptor. Eur. J. Pharmacol. 318: 429–435, 1996.
 464. Knuhtsen, S., J. J., Holst, S. L. Jensen, U. Knigge, and O. V. Nielsen. Gastrin‐releasing peptide: effect on exocrine secretion and release from isolated perfused porcine pancreas. Am. J. Physiol. 248: (Gastrointest. Liver Physiol. 11): G281–G286, 1985.
 465. Koerker, D. J., W., Ruch, E. Chideckel, et al. Somatostatin: hypothalamic inhibitor of the endocrine pancreas. Science 184: 482–484, 1974.
 466. Kolb, H. J., and E. Standl. Purification to homogeneity of an insulin‐degrading enzyme from human erythrocytes. Hoppe Seylers Z. Physiol. Chem. 361: 1029–1039, 1980.
 467. Kollee, L. A., L. A., Monnens, V. Cecjka, and R. N. Wilms. Persistent neonatal hypoglycemia due to glucagon deficiency. Arch. Dis. Child. 53: 422–424, 1978.
 468. Kollings, F., H. C., Fehmann, R. Göke, and B. Göke. Reduction of the incretin effect in rats by the glucagon‐like peptide 1 receptor antagonist exendin (9–39)amide. Diabetes 44: 16–19, 1995.
 469. Komatsu, R., T., Matsuyama, M. Namba, N. Watanabe, H. Itoh, N. Kono, and S. Tami. Glucagonostatic and insulinotropic action of glucagonlike peptide I‐(7–36)‐amide. Diabetes 38: 902–905, 1989.
 470. Korn, A. F., and R. P. Ottensmeyer. A model for the three‐dimensional structure of glucagon. J. Theor. Biol. 105: 403–425, 1983.
 471. Kozak, R. I., J. D., Bennett, T. C. Brown, and T. Y. Lee. Reduction of bowel motion artifact during digital subtraction angiography: a comparison of hyoscine butylbromide and glucagon. Can. Assoc. Radiol. J. 45: 209–211, 1994.
 472. Krarup, T.. Immunoreactive gastric inhibitory polypeptide. Endocr. Rev. 9: 122–134, 1982.
 473. Krarup, T., N., Saubrey, A. J. Moody, C. Kuhl, and S. Madsbad. Effect of porcine gastric inhibitory polypeptide on beta‐cell function in type I and type II diabetes mellitus. Metabolism 36: 677–682, 1987.
 474. Kreel, L.. Pharmaco‐radiology in barium examinations with special reference to glucagon. Br. J. Radiol. 48: 691–703, 1975.
 475. Kreymann, B., M. A., Ghatei, P. Burnet, G. Williams, S. Kanse, A. R. Diani, and S. R. Bloom. Characterization of glucagon‐like peptide‐1‐(7–36)amide in the hypothalamus. Brain Res. 502: 325–331, 1989.
 476. Kreymann, B., M. A., Ghatei, G. Williams, and S. R. Bloom. Glucagon‐like peptide I(7–36): a physiological incretin in man. Lancet 2: 1300–1304, 1987.
 477. Kuhl, C., S. L., Jensen, O. V. Nielsen, and J. J. Holst. Influence of basal plasma glucose concentration on the glucagon response to arginine. Scand. J. Gastroenterol. Suppl. 37: 53–56, 1976.
 478. Kuku, S. F., J. B., Jaspan, D. S. Emmanouel, A. Zeidler, A. I. Katz, and A. H. Rubenstein. Heterogeneity of plasma glucagon. Circulating components in normal subjects and patients with chronic renal failure. J. Clin. Invest. 58: 742–750, 1976.
 479. La Barre, J., and E. U. Still. Studies on the physiology of secretin. Am. J. Physiol. 91: 649–653, 1930.
 480. Laburthe, M., A., Couvineau, P. Gaudin, J. J. Maoret, C. Royer‐Fessard, and P. Nicole. Receptors for VIP, PACAP, secretin, GRF, glucagon, GLP‐1, and other members of their new family of G protein–linked receptors: structure–function relationship with special reference to the human VIP‐1 receptor. Ann. N.Y. Acad. Sci. 805: 94–109, 1996.
 481. Lane, M. A.. The cytological characters of the areas of Langerhans. Am. J. Anat. 7: 409–422, 1907.
 482. Lang, D. A., D. R., Matthews, M. Burnett, and R. C. Turner. Brief, irregular oscillations of basal plasma insulin and glucose concentrations in diabetic man. Diabetes 30: 435–439, 1981.
 483. Lang, D. A., D. R., Matthews, M. Burnett, G. M. Ward, and R. C. Turner. Pulsatile, synchronous basal insulin and glucagon secretion in man. Diabetes 31: 22–26, 1982.
 484. Larsen, J., N., Jalland, and P. Damsbo. One‐week continuous infusion of GLP‐1 (7–37) improves glycemic control in NIDDM. Diabetes 45 (Suppl. 2): 233A, 1996.
 485. Larsen, P. J., M., Tang‐Christensen, J. J. Holst, and C. Ørskov. Distribution of glucagon‐like peptide‐1 and other preproglucagon‐derived peptides in the rat hypothalamus and brainstem. Neuroscience 77: 257–270, 1997.
 486. Larsson, L.‐I., J., Holst, R. Hakanson, and F. Sundler. Distribution and properties of glucagon immunoreactivity in the digestive tract of various mammals: an immunohistochemical and immunochemical study. Histochemistry 44: 281–290, 1975.
 487. Laurent, F., and P. Mailhe. Insulin and the glucose‐glucagon feedback mechanism in the duck. Diabetologia 12: 23–33, 1976.
 488. Lawrence, A. M., S., Tan, S. Jojvat, and L. Kirsteins. Salivary gland hyperglycemic factor: an extrapancreatic source of glucagon‐like material. Science 195: 70–72, 1997.
 489. Layer, P., and J. J. Holst. GLP‐1: a humoral mediator of the ileal brake in humans? Digestion 54: 385–386, 1993.
 490. Layer, P., and J. J. Holst, D. Grandt, and H. Goebell. Ileal release of glucagon‐like peptide‐1 (GLP‐1): association with inhibition of gastric acid secretion in humans. Dig. Dis. Sci. 40: 1074–1082, 1995.
 491. Leclercq‐Meyer, V., G. R., Brisson, and W. J. Malaisse. Effect of adrenaline and glucose on release of glucagon and insulin in vitro. Nature (New Biol.) 231: 248–249, 1971.
 492. Leclercq‐Meyer, V., and W. J. Malaisse. Pulsatility of arginine‐stimulated insulin, glucagon and somatostatin release. Med. Sci. Res. 22: 151–154, 1994.
 493. Le Douarin, N. M.. The origin of the pancreatic endocrine cells. Cell 53: 169–171, 1988.
 494. LeDouarin, N. M., and M. A. Teillet. The migration of neural crest cells to the wall of the digestive tract in avian embryos. Embryol. Exp. Morphol. 30: 31–48, 1973.
 495. Lee, Y. C., S. L., Asa, and D. J. Drucker. Glucagon gene 5′‐flanking sequence direct expression of SV40 large T antigen to the intestine producing carcinoma of the large bowel in transgenic mice. J. Biol. Chem. 267: 10705–10708, 1992.
 496. Leech, C. A., and J. F. Habener. Insulinotropic glucagon‐like peptide‐1‐mediated activation of non‐selective cation currents in insulinoma cells is mimicked by maitotoxin. J. Biol. Chem. 272: 17987–17993, 1997.
 497. Lefèbvre, P. J., and A. S. Luyckx. Plasma glucagon after kidney exclusion: experiments in somatostatin‐infused and in eviscerated dogs. Metabolism 25: 761–768, 1976.
 498. Lefèbvre, P. J., and A. S. Luyckx. Glucagon and the kidney. In: Glucagon: Its Role in Physiology and Clinical Medicine, edited by P. P. Foá, J. S. Bajaj, and N. Foá. Berlin: Springer, 1977, p. 167.
 499. Lefèbvre, P. J., and A. S. Luyckx. Glucagon and diabetes: a reappraisal. Diabetologia 16: 347–354, 1979.
 500. Lefèbvre, P. J., A. S., Luyckx, and A. H. Nizet. Renal handling of endogenous glucagon in the dog: comparison with insulin. Metabolism 23: 753–761, 1974.
 501. Lefèbvre, P. J., A. S., Luyckx, and A. H. Nizet. Independence of glucagon and insulin handling by the isolated perfused dog kidney. Diabetologia 12: 359–365, 1976.
 502. Lefèbvre, P. J., G., Paolisso, and A. J. Scheen. Pulsatility of glucagon. In: Glucagon III, edited by P. J. Lefèbvre. Berlin: Springer, 1996, p. 105–113.
 503. Lefèbvre, P. J., G., Paolisso, A. J. Scheen, and J. C. Henquin. Pulsatility of insulin and glucagon release: physiological significance and pharmacological implications. Diabetologia 30: 443–452, 1987.
 504. Lenzen, S.. The effect of hydrocortisone treatment and adrenalectomy on insulin and glucagon secretion from the perfused rat pancreas. Endokrinologie 68: 189–197, 1976.
 505. Leonard, J., B., Peers, T. Johnson, K. Ferreri, S. Lee, and M. R. Montminy. Characterization of somatostatin transactivating factor‐1, a novel homeobox factor that stimulates somatostatin expression in pancreatic islet cells. Mol. Endocrinol. 7: 1275–1283, 1993.
 506. Le Quellec, A., A. Kervarn, P. Blache, A. J. Ciurana, and D. Bataille. Diurnal profile of oxyntomodulin‐like immunoreactivity in duodenal ulcer patients. Scand. J. Gastroenterol. 28: 816–820, 1993.
 507. Levy, L., G., Spergel, and S. J. Bleicher. Glucagon deficient man: model for the role of glucagon in fasting [abstract]. In: Proc. Annu. Meeting Endoc. Soc. 52nd 1970, p. 134. St. Louis, Missouri June 10–12 Published by the Endocrine Society J. B. Lippincott Company.
 508. Lickley, H. L. A., F. W., Kemmer, D. E. Gray, N. Kovacevic, T. W. Hatton, G. Perez, and M. Vranic. Chromotagraphic pattern of extrapancreatic glucagon and glucagon‐like immunoreactivity before and during stimulation by epinephrine and participation of glucagon in epinephrine‐induced hepatic glucose overproduction. Surgery 90: 186–194, 1981.
 509. Lilavivat, U., R. G., Brodows, and R. G. Campbell. Adrenergic influence on counteregulation in man. Diabetologia 20: 482–488, 1981.
 510. Liljenquest, J. E., A. D., Müller, A. D. Cherrington, et al. Hyperglycemia per se (insulin and glucagon withdrawn) can inhibit glucose production in man. J. Clin. Endocrinol. Metab. 48: 171–175, 1979.
 511. Liljenquest, J. E., A. D., Müller, A. D. Cherrington, U. Keller, J.‐L. Chiasson, J. M. Perry, W. W. Lacy, and D. Rabinowitz. Evidence for an important role of glucagon in the regulation of hepatic glucose production in normal man. J. Clin. Invest. 59: 369–374, 1977.
 512. Lin, H. Y., T. T. L., Harris, M. S. Flannery, et al. Expression cloning of an adenylate cyclase‐coupled calcitonin receptor. Science 254: 1022, 1991.
 513. Lin, M. D., D. E., Wright, V. J. Hruby, and M. Rodbell. Structure‐function relationships in glucagon: properties of highly purified Des‐His1‐, monoiodo‐, and [Des‐Asn28, Thr29] (homoserine lactone27)‐glucagon. Biochemistry 14: 1559–1563, 1975.
 514. Lincoln, J., J. T., Bokor, R. Crowe, S. G. Griffity, A. J. Haven, and G. Bumstock. Myenteric plexus of streptozotocin‐treated rats. Neurochemical and histochemical evidence for diabetic neuropathy in the gut. Gastroenterology 86: 654–661, 1984.
 515. Liu, D., E., Moberg, M. Kollind, P. E. Lins, and U. Adamson. A high concentration of circulating insulin suppresses the glucagon response to hypoglycemia in normal man. J. Clin. Endocrinol. Metab. 73: 1123–1128, 1991.
 516. Locatelli, A., D., Spotti, and F. Caviezel. The regulation of insulin and glucagon secretion by opiates: a study with naloxone in healthy humans. Acta Diabetol. Lat. 22: 25–31, 1985.
 517. Loew, E. R., J. S., Grey, and A. C. Ivy. Is a duodenal hormone involved in carbohydrate metabolism? Am. J. Physiol. 129: 659–663, 1940.
 518. Lok, S., J. L., Kuijper, L. J. Jelinek, J. M. Kramer, T. E. Whitmore, C. A. Sprecher, S. Mathewes, F. J. Grant, S. H. Biggs, G. B. Rosenberg, P. O. Sheppard, O. H. P. J. D. C. Foster, and W. Kindsvogel. The human glucagon receptor encoding gene: cDNA sequence and chromosomal localization. Gene 40: 203–209, 1994.
 519. Long, R. G., R. H., Albuquerque, A. Prata, A. J. Barnes, T. E. Adrian, N. D. Christofides, and S. R. Bloom. Responses of pancreatic and gastrointestinal hormones and growth hormone to oral and intravenous glucose and insulin hypoglycemia in Chaga's disease. Gut 21: 772–777, 1980.
 520. Lopez, L. C., M. L., Frazier, C. J. Su, A. Kumar, and G. F. Saunders. Mammalian pancreatic preproglucagon contains three glucagon‐related peptides. Proc. Natl. Acad. Sci. U.S.A. 80: 5485–5489, 1983.
 521. Lopez, L. C., W. H., Li, M. L. Frazier, C. C. Luo, and G. F. Saunders. Evolution of glucagon genes. Mol. Biol. Evol. 1: 335–344, 1984.
 522. Lotersztajn, S., R. M., Epand, A. Mallat, and F. Pecker. Inhibition by glucagon of the calcium pump in liver plasma membranes. J. Biol. Chem. 259: 8195–8201, 1984.
 523. Lotersztajn, S., C., Pavoine, V. Brechler, B. Roche, M. Dufour, D. Le‐Nguyen, D. Bataille, and F. Pecker. Glucagon‐(19–29) exerts a biphasic action on the liver plasma membrane Ca2+ pump which is mediated by G proteins. J. Biol. Chem. 265: 9876–9880, 1990.
 524. Lund, P. K., R. H., Goodman, P. C. Dee, and J. F. Habener. Pancreatic preproglucagon cDNA contains two glucagon‐related coding sequences arranged in tandem. Proc. Natl. Acad. Sci. U.S.A. 79: 345–349, 1982.
 525. Lund, P. K., R. H., Goodman, and J. F. Habener. Pancreatic pre‐pro‐glucagons are encoded by two separate mRNAs. J. Biol. Chem. 256: 6515–6518, 1981.
 526. Lund, P. K., R. H., Goodman, J. W. Jacobs, and J. F. Habener. Glucagon precursors identified by immunoprecipitation of products of cell free translation of messenger RNA. Diabetes 29: 583–586, 1980.
 527. Lund, P. K., R. H., Goodman, M. R. Montminy, P. C. Dee, and J. F. Habener. Angler fish islet pre‐proglucagon II. Nucleotide and corresponding amino acid sequence of the cDNA. J. Biol. Chem. 258: 3280–3284, 1983.
 528. Luyckx, A., and P. J. Lafèbvre. Pharmacological compounds affecting plasma glucagon levels in rats. Biochem. Pharmacol. 25: 2703–2708, 1976.
 529. Luyckx, A. S., U., Gaspard, and P. J. Lafèbvre. Influence of elevated plasma free fatty acids on the glucagon response to hypoglycemia in normal and in pregnant women. Metabolism 27: 1033–1040, 1978.
 530. Luyckx, A. S., F., Massi‐Bendetti, and P. J. Lafèbvre. Influence of metabolic substrates on the secretion of glucagon and insulin by the isolated perfused rat pancreas. Isr. J. Med Sci. 8: 759–760. 1972.
 531. Luyckx, A. S. and P. J., Lafèbvre. The role of energy substrates in controlling glucagon secretion. Experimental studies. In: Diabetes. Proceedings of the VIIIth Congress of the IDF, edited by W. Malaisse. Brussels: Excerpta Mediea, 1973, pp. 190–202.
 532. Madison, L. L., W. A., Seyffert, R. H. Unger, and B. Barker. Effect of plasma free fatty acids on plasma glucagon and serum insulin concentration. Metabolism 17: 301–304, 1968.
 533. Maget, B., M., Tastenoy, and M. Svoboda. Sequencing of eleven introns in genomic DNA encoding rat glucagon receptor and multiple alternative splicing of its mRNA. FEBS Lett. 351: 271–275, 1994.
 534. Mallat, A., C., Pavoine, M. Dufour, S. Lotersztajn, D. Bataille, and F. Pecker. A glucagon fragment is responsible for the inhibition of the liver Ca2+ pump by glucagon. Nature 325: 620–622, 1987.
 535. Mallette, L. E., J. H., Exton, and C. R. Park. Control of gluconeogenesis from amino acids in the perfused rat liver. J. Biol. Chem. 244: 5713–5723, 1969.
 536. Mallinson, C. N., S. R., Bloom, A. P. Warin, et al. A glucagonoma syndrome. Lancet 2: 1–5, 1974.
 537. Mandarino, L., D., Stenner, W. Blanchard, S. Nissen, J. Gerich, N. Ling, P. Brazeau, P. Bohlen, F. Esch, and R. Guillemin. Selective effects of somatostatin‐14,‐25 and‐28 on in vitro insulin and glucagon secretion. Nature 291: 76–77, 1981.
 538. Mandell, G. A., and S. K. Teplick. Glucagon—its application to childhood gastrointestinal radiology. Gastrointest. Radiol. 7: 7–13, 1982.
 539. Maran, A., I., Cranston, J. Lomas, I. Macdonald, and S. A. Amiel. Protection by lactate of cerebral function during hypoglycemia. Lancet 343: 16–20, 1994.
 540. Marco, J., C., Calle, J. A. Hedo, and M. L. Villanueva. Enhanced glucagon secretion by pancreatic islets from prednisolone‐treated mice. Diabetologia 12: 307–311, 1976.
 541. Marco, J., C., Calle, D. Roman, M. Diaz‐Fierros, M. L. Villanueva, and I. Valverde. Hyperglucagonism induced by glucocorticoid treatment in man. N. Engl. J. Med. 288: 128–131, 1973.
 542. Marco, J., J. A., Hedo, and M. L. Villanueva. Control of pancreatic polypeptide secretion by glucose in man. J. Clin. Endocrinol. Meta‐b. 46: 140–145, 1978.
 543. Marie, J.‐C., C. Boissard, G. Skoglund, G. Rosselin, and B. Breant. Glucagon acts through its own receptors in the presence of functional glucagon‐like peptide‐1 receptors on hamster insulinoma. Endocrinology 137: 4108–4114, 1996.
 544. Marliss, E. B., L., Dirardier, J. Seydoux, C. B. Wollheim, Y. Kanazawa, L. Orci, A. E. Renold, and D. Porte Jr., Glucagon release induced by pancreatic nerve stimulation in the dog. J. Clin. Invest. 52: 1246–1259, 1973.
 545. Marsh, B. D., D. J., Marsh, and R. N. Bergman. Oscillations enhance the efficiency and stability of glucose disposal. Diabetes 37: E576–E582, 1986.
 546. Martin, R. A., D. L., Cleary, D. M. Guido, H. A. Zurcher‐Neely, and T. M. Kubiak. Dipeptidyl peptidase IV (DPP‐IV) from pig kidney cleaves analogs of bovine growth hormone‐releasing factor (bGRF) modified at position 2 with Ser, Thr, or Val. Extendend DPP‐IV substrate specificity? Biochim. Biophys. Acta 1164: 252–260, 1993.
 547. Marubashi, S., M. Tominaga, T. Karagiri, K. Yamanati, Y. Yawata, M. Hara, and H. Sasaki. Hyperglycemic effect of glucagon administered intracerebroventricularly in the rat. Acta Endocrinol. (Copenh.) 108: 6–10, 1984.
 548. Maruyama, H., A. Hisatomi, L. Orci, G. M. Grodsky, and R. H. Under. Insulin within islets is a physiologic glucagon release inhibitor. J. Clin. Invest. 74: 2296–2299, 1984.
 549. Maruyama, H., M., Tominaga, G. Bolli, L. Orci, and R. H. Unger. The alpha cell response to glucose change during perfusion of anti‐insulin serum in pancreas isolated from normal rats. Diabetologia 28: 836–840, 1985.
 550. Mathi, S. K., Y., Chan, X. Li, and M. B. Wheeler. Scanning of the glucagon‐like peptide‐1 receptor localizes G protein‐activating determinants primarily to the N terminus of the third intracellular loop. Mol. Endocrinol. 11: 424–432, 1997.
 551. Matschinsky, F. M., A. S., Pagliara, B. A. Hover, C. S. Pace, J. A. Ferrendelli, and A. Williams. Hormone secretion and glucose metabolism in islets of Langerhans of the isolated perfused pancreas from normal and streptozotocin diabetic rats. J. Biol. Chem. 251: 6053–6061, 1976.
 552. Matsumura, T., H., Itoh, N. Watanabe, Y. Oda, M. Tanaka, M. Namba, N. Kono, T. Matsuyama, R. Komastsu, and Y. Matsuzawa. Glucagonlike peptide‐1(7–36) amide suppresses glucagon secretion and decreases cyclic AMP concentration in cultured In‐R1‐G9 cells. Biochem. Biophys. Res. Commun. 186: 503–508, 1992.
 553. Matsuyama, T., W. H., Hoffman, J. C. Dunbar, N. L. Foa, and P. P. Foa. Glucose, insulin, pancreatic glucagon‐like immunoreactive materials in the plasma of normal and diabetic children: effect of the initial insulin treatment. Horm. Metab. Res. 7: 452–456, 1975.
 554. Matsuyama, T., R., Komatsu, M. Namba, N. Watanabe, H. Itoh, and S. Tarui. Glucagon‐like peptide‐1(7–36) amide: a potent glucagonostatic and insulinotropic hormone. Diabetes Res. Clin. Prac. 5: 281–284, 1988.
 555. Matsuyama, T., M., Namba, K. Nonaka, S. Tarui, R. Tanaka, and K. Shima. Decrease in blood glucose and release of gut glucagon‐like immunoreactive materials by bombesin infusion in the dog. Endocrinol. Jpn. 27 (Suppl. 1): 115–119, 1980.
 556. Mayo, I. E.. Molecular cloning and expression and a pituitary‐specific receptor for growth hormone‐releasing hormone. Mol. Endocrinol. 6: 1734–1744, 1992.
 557. McCall, A. L.. Effects of glucose deprivation on glucose metabolism in the central nervous system. In: Hypoglycaemia and Diabetes, edited by B. M. Frier and B. M. Fisher. London: Arnold, 1993, p. 56–71.
 558. McDonald, T. J., M. A., Ghatei, S. R. Bloom, T. E. Adrian, T. Mochizuke, C. Yanaihara, and N. Yauaihara. Dose‐response comparisons of canine plasma gastroenteropancreatic hormone responses to bombesin and the porcine gastrin‐releasing peptide (GRP). Regul. Pept. 5: 125–137, 1983.
 559. McEvoy, J., and A. M. McCarrol. High circulating concentrations of glucagon in non‐anaemic uraemie patients. BMJ 2: 17–18, 1978.
 560. McGarry, J. D.. New perspectives in the regulation of ketogenesis. Diabetes 28: 517–523, 1979.
 561. McGarry, J. D., and D. W. Foster. Regulation of fatty acid oxidation and ketone body production. Annu. Rev. Biochem. 49: 395–420, 1980.
 562. McGavran, M. H., R. H., Unger, L. Recant, Polk H C, Kilo C, and Levin M E. A glucagon‐seereting alpha‐cell carcinoma of the pancreas. N. Engl. J. Med. 274: 1408–1413, 1966.
 563. McIntyre, N., D. C., Holsworth, and D. S. Turner. New interpretation of oral glucose tolerance. Lancet 2: 20–21, 1964.
 564. McLoughlin, J. C., J. R., Hayes, K. D. Buchanan, and J. G. Kelley. Role of neural influences in the release of gastrin, glucagon, and secretin during hypoglycaemia in man. Gut 19: 632–639, 1978.
 565. Medbak, S., D. F. J., Mason, and L. H. Rees. Plasma Metenkephalin and catecholamine responses to insulin‐induced hypoglycemia in greyhounds. J. Endocrinol. 114: 81–87, 1987.
 566. Mentlein, R., B., Gallwitz, and W. E. Schmidt. Dipeptidyl‐peptidase IV hydrolyses gastric inhibitory polypeptide, a glucagon‐like peptide‐1(7–36) amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur. J. Biochem. 214: 829–835, 1993.
 567. Menzel, S., M. Stoffe, R. Espinosa III, A. A. Fernald, M. M. Le Beau, and G. I. Bell. Localization of the glucagon receptor gene to human chromsome band 17q25. Genomics 20: 327–328, 1994.
 568. Mery, P. F., V., Brechler, C. Pavoine, F. Pecker, and R. Fischmeister. Glucagon stimulates the cardiac Ca2+ current by activation of adenylyl cyclase and inhibition of phosphodiesterase. Nature 345: 158–161, 1990.
 569. Meyer, T. E., and J. F. Habener. Cyclic AMP response element binding protein CREB and related transcription‐activating DNA‐binding proteins. Endocr. Rev. 14: 269–290, 1993.
 570. Michalik, M., J., Nelson, and M. Erecinska. GABA production in rat islets of Langerhans. Diabetes 42: 1506–1513, 1993.
 571. Miholic, J., C., Ørskov, J. J. Holst, J. Kotzerke, and H. J. Meyer. Emptying of the gastric substitute, glucagon‐like peptide‐1 (GLP‐1), and reactive hypoglycemia after total gastrectomy. Dig. Dis. Sci. 36: 1361–1370, 1991.
 572. Miki, H., M., Namba, T. Nishimura, I. Mineo, T. Matsumura, J. Miyagawa, H. Nakajima, M. Kuwajima, T. Hanafusa, and Y. Matsuzawa. Glucagon‐like peptide‐1(7–36) amide enhances insulin‐stimulated glucose uptake and decreases intracellular cAMP content in isolated rat adipocytes. Biochem. Biophys. Acta 1312: 132–136, 1996.
 573. Miller, C. P., J. C., Lin, and J. F. Habener. Transcription of the rat glucagon gene by the cyclic AMP response element‐binding protein CREB is modulated by adjacent CREB‐associated proteins. Mol Cell. Biol. 1993: 7080–7090, 1993.
 574. Miller, C. P., R. E. J., McGehee, and J. F. Habener. IDX‐1: a new homeodomain transcription factor expressed in rat pancreatic islets and duodenum that transactivates the somatostatin gene. EMBO J. 13: 1145–1156, 1994.
 575. Miller, R. E., and E. S. Horton. Neural release of glucagon is inhibited by hyperglycemia and enhanced by phentolamine. Diabetes 28: 762–768, 1979.
 576. Mirsky, I. A., G., Perisutti, and N. C. Davis. The destruction of glucagon by the blood plasma from various species. Endocrinology 64: 992–1001, 1959.
 577. Mizuno, A., M., Kuwajima, K. Ishida, Y. Noma, T. Murakami, K. Tateishi, I. Sato, and K. Shima. Extrapancreatic action of truncated glucagon‐like peptide‐I in Otsuka Long‐Evans Tokushima fatty rats, an animal model for non‐insulin‐dependent diabetes mellitus. Metabolism 46: 745–749, 1997.
 578. Moens, K., H., Heimberg, D. Flamez, P. Huypens, E. Quartier, Z. Ling, D. Pipeleers, S. Gremlich, B. Thorens, and F. Schuit. Expression and functional activity of glucagon, glucagon‐like peptide I, and glucose‐dependent insulinotropic peptide receptors in rat pancreatic islet cells. Diabetes 45: 257–261, 1996.
 579. Moghimzdeh, E., R., Ekman, R. Hakanson, N. Yanaihara, and F. Sundler. Neuronal gastrin‐releasing peptide in the mammalian gut and pancreas. Neuroscience 10: 553–563, 1983.
 580. Mojsov, S.. Structural requirements for biological activity of glucagon‐like peptide‐I. Int. J. Pept. Protein Res. 40: 333–343, 1992.
 581. Mojsov, S., G., Heinrich, I. B. Wilson, M. Ravazzola, L. Orci, and J. F. Habener. Preproglucagon gene expression in pancreas and intestine diversifies at the level of post‐translational processing. J. Biol. Chem. 261: 11880–11889, 1986.
 582. Mojsov, S., M. G., Kopczynski, and J. F. Habener. Both amidated and nonamidated forms of glucagon‐like peptide I are synthesized in the rat intestine and the pancreas. J. Biol. Chem. 265: 8001–8008, 1990.
 583. Mojsov, S., G. C., Weir, and J. F. Habener. Insulinotropin: glucagon‐like peptide‐I (7–37) co‐encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. J. Clin. Invest. 79: 616–619, 1987.
 584. Montrose‐Rafizadeh, C., H., Yang, Y. Wang, J. Roth, M. H. Montrose, and L. G. Adams. Novel signal transduction and peptide specificity of glucagon‐like peptide receptor in 3T3–L1 adipocytes. J. Cell. Physiol. 172: 275–283, 1997.
 585. Moody, A. J.. Gut glucagon‐like immunoreactiviry. Clin. Gastroenterol. 9: 699–709, 1980.
 586. Moore, B., E. S., Edie, and J. H. Abram. On the treatment of diabetes mellitus by acid extract of duodenal mucous membrane. Biochem. J. 1: 28–38, 1906.
 587. Morel, C., M., Cordier‐Bussat, and J. Philippe. The upstream promoter element of the glucagon gene G1 confers pancreatic alpha cell‐specific expression. J. Biol. Chem. 270: 3046–3055, 1995.
 588. Muller, W. A., G. R., Faloona, E. Aguilar‐Parada, and R. H. Under. Abnormal alpha‐cell function in diabetes. Response to carbohydrate and protein ingestion. N. Engl. J. Med. 283: 109–115, 1970.
 589. Muller, W. A., G. R., Faloona, and R. H. Unger. The effect of experimental insulin deficiency on glucagon secretion. J. Clin. Invest. 50: 1992–1999, 1971.
 590. Muller, W. A., G. R., Faloona, and R. H. Unger. The influence of the antecedent diet upon glucagon and insulin secretion. N. Engl. J. Med. 285: 1450–1454, 1971.
 591. Müller, W. A., L., Girardier, J. Deydoux, M. Berger, A. E. Renold, and M. Vranic. Extrapancreatic glucagon and glucagonlike immunoreactivity in depancreatized dogs. A quantitative assessment of secretion rates and anatomical delineation of sources. J. Clin. Invest. 62: 124–132, 1978.
 592. Munroe, D. G., A. K., Gupta, F. Kooshesh, T. B. Vyas, G. Rizkalla, L. Demchyshyn, Z. J. Yang, R. K. Kamboj, H. Chen, K. McCallum, M. Sumner‐Smith, D. J. Drucker, and A. Crivici. Prototypic G protein‐coupled receptor for the intestinotrophic factor glucagon‐like peptide2. Proc. Natl. Acad. Sci. U.S.A. 96: 1569–1573, 1999.
 593. Murphy, J., W.‐J., Zhang, W. Macaulay, G. Fasman, and R. B. Merrifield. The relation of predicted structure to observed conformation and activity of glucagon analogs containing replacements at positions 19, 22, and 23. J. Biol. Chem. 262: 17304–17312, 1987.
 594. Nakamura, R., M., Hayaski, D. S. Emmanouel, and A. I. Katz. Sites of insulin and glucagon metabolism in the rabbit nephron. Am. J. Physiol. 250 (Renal Fluid Electrolyte Physiol. 19): F144–F150, 1986.
 595. Nakayama, H., M., Tju, and S. Nakagawa. Influence of diet on intestinal cell DNA synthesis in the diabetic rat. Diabetes 23: 793–795, 1974.
 596. Namba, M., T., Matsuyama, H. Horie, K. Nonaka, and S. Tarui. Inhibition of pancreatic exocrine secretion and augmentation of the release of gut glucagon‐like immunoreactive materials by intraileal administration of bile in the dog. Regul. Pept. 5: 257–262, 1983.
 597. Nathan, D. M., E., Schreiber, H. Fogel, S. Mojsov, and J. F. Habener. Insulinotropic action of glucagon‐like peptide‐I (7–37) administered to diabetic and non‐diabetic subjects. Diabetes Care 15: 270–276, 1992.
 598. Nauck, M., F., Stockmann, R. Ebert, and W. Creutzfeld. Reduced incretin effect in type‐2 (non‐insulin dependent) diabetes. Diabetologia 29: 46–52, 1986.
 599. Nauck, M. A., E., Bartels, C. Ørskov, R. Ebert, and W. Creutzfeldt. Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon‐like peptide‐1‐(7–36) amide infused at near‐physiological insulinotropic hormone and glucose concentrations. J. Clin. Endocrinol. Metab. 76: 912–917, 1993.
 600. Nauck, M. A., M. M., Heimestaat, C. Ørskov, J. J. Holst, R. Ebert, and W. Creutzfeldt. Preserved incretin activity of glucagon‐like peptide 1(7–36) amide), but not of synthetic human gastric inhibitory polypeptide in patients with type‐2 diabetes mellitus. J. Clin. Invest. 91: 301–307, 1993.
 601. Nauck, M. A., J. J., Holst, B. Willms, and W. Schmiegel. Glucagon‐like peptide 1 (GLP‐1) as a new therapeutic approach for type 2‐diabetes. Exp. Clin. Endocrinol. Diabetes 105: 187–195, 1997.
 602. Nauck, M. A., E., Homberger, E. G. Siegel, R. C. Allen, R. P. Eaton, R. Ebert, and W. Creutzfeldt. Incretin effects of increasing glucose loads in man calculated from venous insulin and C‐peptide responses. J. Clin. Endocrinol. Metab. 63: 492–498, 1986.
 603. Nauck, M. A., N., Kleine, C. Ørskov, J. J. Holst, B. Willms, and W. Creutzfeldt. Normalization of fasting hyperglycemia by exogenous glucagon‐like peptide 1(7–36) in type 2 (non‐insulin‐dependent) diabetes patients. Diabetologia 36: 741–744, 1993.
 604. Nauck, M. A., U., Niedereichholz, R. Ettler, J. J. Holst, C. Ørskov, R. Ritzel, and W. H. Schmiegel. Glucagon‐like peptide 1 inhibition of gastrie emptying outweighs its insulinotropic effects in healthy humans. Am. J. Physiol 273 (Endocrinol. Metab. 36): E981–E988, 1997.
 605. Nauck, M. A., D., Wollschläger, J. Werner, J. J. Holst, C. Ørskov, W. Creutzfeldt, and B. Willms. Effects of subscutaneous glucagon‐like peptide 1 (GLP‐1 [7–36 amide]) in patients with NIDDM. Diabetologia 39: 1546–1553, 1996.
 606. Naya, F. J., H. P., Huang, Y. Qiu, H. Mutoh, F. J. DeMayo, A. B. Leiter, and M. J. Tsai. Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in beta2/neuroD‐deficient mice. Genes Dev. 11: 2323–2334, 1997.
 607. Neal, G. W., and A. E. Kitabchi. Insulin degradation by human skeletal muscle. Biochim. Biophys. Acta 719: 259–266, 1982.
 608. Neal, G. W., S. S., Solomon, and W. C. Duckworth. Glucagon degradation by human mononuclear cells. Diabetologia 25: 404–410, 1983.
 609. Niijima, A.. Control of liver function and neuroendocrine regulation of blood glucose levels. In: Integrative Functions of the Autonomic Nervous System, edited by C. M. Brooks, K. Koizumi, and A. Sato. Tokyo: University of Tokyo Press, 1979, p. 68–83.
 610. Nilsson, T., R., Arkhammer, P. Rorsman, and P. O. Berggren. Inhibition of glucose‐stimulated insulin release by alpha 2‐adrenoceptor activation is paralleled by both a repolarization and a reduction in cytoplasmic free Ca2+ concentration. J. Biol. Chem. 263: 1855–1860, 1988.
 611. Nishimura, E., N., Abrahamsen, L. H. Hansen, K. Lundgren, and O. Madsen. Regulation of glucagon receptor expression. Acta Physiol. Scand. 157: 329–332, 1996.
 612. Nishizawa, M., Y., Hayakawa, N. Yanaihara, and H. Okamoto. Nucleotide sequence divergence and functional constraint in vasoactive intestinal peptide precursor mRNA evolution between human and rat. FEBS Lett. 183: 55–59, 1985.
 613. Noe, B. D., and G. E. Bauer. Evidence for glucagon biosynthesis involving a protein intermediate in islets of the anglerfish (Lophius americanus). Endocrinology 89: 642–651, 1971.
 614. Noe, B. D., and G. E. Bauer. Evidence of sequential metabolic cleavage of proglucagon to glucagon in glucagon biosynthesis. Endocrinology 97: 868–877, 1975.
 615. Oben, J., L., Morgan, J. Flitcher, and V. Marks. Effect of the entero‐pancreatic hormones, gastrie inhibitory polypeptide and glucagon‐like polypeptide‐1(7–36)aminde, on fatty acid synthesis in explants of rat adipose tissue. J. Endocrinol. 130: 267–272, 1991.
 616. O'Connor, F. A., J. M., Conlon, K. D. Buchanan, and R. F. Murphy. The use of perfused rat intestine to characterize the glucagon‐like immunoreactivity released into serosal secretions following stimulation by glucose. Horm. Metab. Res. 11: 19–23, 1979.
 617. Offield, M. F., T. L., Jetton, P. A. Labosky, M. Ray, R. W. Stein, M. A. Magnuson, B. L. Hogan, and C. G. Wright. PDX‐1 is required for pancreatic outgrowth and differentiation of the rostal duodenum. Development 122: 983–995, 1996.
 618. O'Halloran, D. J., G. C., Nikou, B. Kreymann, M. A. Ghatei, and S. R. Bloom. Glucagon‐like peptide‐1(7–36)‐NH2: a physiological inhibitor of gastric acid secretion in man. J. Endocrinol. 126: 169–173, 1990.
 619. Ohlsson, H., K., Karlsson, and T. Edlund. IPF1, a homeodomain‐containing transactivator of the insulin gene. EMBO J. 12: 4251–4259. 1993.
 620. Ohneda, A., E., Aguilar‐Parada, A. M. Eisentraut, and R. H. Unger. Control of pancreatic glucagon secretion by glucose. Diabetes 18: 1–10, 1969.
 621. Ohneda, A., S., Ishii, K. Horigome, M. Chiba, T. Sakai, Y. Kai, K. Watanabe, and S. Yamagata. Effect of intrapancreatic administration of vasoactive intestinal peptide upon the release of insulin and glucagon in dogs. Horm. Metab. Res. 9: 447–452, 1977.
 622. Ohneda, A., K., Ohneda, T. Nagasaki, and K. Sasaki. Insulinotropic action of human glicentin. Metabolism 44: 47–51, 1995.
 623. Ohneda, A., K., Ohneda, M. Ohneda, F. Koizumi, S. Ohashi, K. Kawai, and S. Suzuki. The structure‐function relationship of GLP‐1 related peptides in the endocrine function of the canine pancreas. Tohoku J. Exp. Med. 165: 209–221, 1991.
 624. Ohneda, A., E., Parada, A. M. Eisentraut, and R. H. Unger. Characterization of response of circulating gulcagon to introduodenal and intravenous administration of amino acids. J. Clin. Invest. 47: 2305–2322, 1968.
 625. Ohneda, A., I., Sasaki, H. Naito, M. Toda, M. Ohneda, and F. Koizumi. Response of gut glucagon‐like immunoreactivity to hypoglycemia in dogs. Am. J. Physiol. 256 (Endocrinol. Metab. 19): E431–E438, 1989.
 626. Ohneda, A., M., Sato, K. Matsuda, A. Yanbe, Y. Maruhama, and S. Yamagata. Plasma glucagon response to blood glucose fall, gastrointestinal hormones and arginine in man. Tohoku J. Exp. Med. 107: 241–251, 1972.
 627. Ohneda, A., H., Takahashi, and Y. Maruyama. Response of plasma glicentin to fat ingestion in piglets. Diabetes Res. Clin. Pract. 3: 103–109, 1987.
 628. O'Rahilly, S., R. C., Turner, and D. R. Matthews. Impaired pulsatile secretion of insulin in relatives of patients with non‐insulin dependent diabetes. N. Engl. J. Med. 318: 1225–1230, 1988.
 629. Okada, Y., H., Taniguchi, and C. Schimada. High concentration of GABA and high glutamate decarboxylase activity in rat pancreatic islets and human insulinoma. Science 194: 620–622, 1976.
 630. Olson, L. K., A., Sharma, M. Peshavaria, C. V. E. Wright, H. C. Towle, R. P. Robertson, and R. Stein. Reduction of insulin gene transcription in HIT‐T15 β‐cells chronically exposed to a supra‐physiologic glucose concentration is associated with loss of STF‐1 transcription factor expression. Proc. Natl. Acad. Sci. U.S.A. 92: 9127–9131, 1995.
 631. Opara, E. C., and V. L. W. Go. Influence of gastric inhibitory polypeptide (GIP) and glucose on the regulation of glucagon secretion by pancreatic alpha cells. Regul. Pept. 32: 65–73, 1991.
 632. Orci, L.. The microanatomy of the islets of Langerhans. Metabolism 25 (Suppl. 1): 1303–1313, 1976.
 633. Orci, L., C., Bordi, R. H. Unger, and A. Perrelet. Glucagon and glicentin producing cells. In: Glucagon I, edited by P. J. Lefèbvre. Berlin: Springer, 1983, p. 57–80.
 634. Orci, L., F., Malaisse‐Lagae, D. Baetens, and A. Perretet. Pancreatic‐polypeptide rich regions in human pancreas. Lancet 2: 1200–1201, 1978.
 635. Orci, L., F., Malaisse‐Lagae, M. Ravazzola, et al. A morphological basis for intercellular communication between a‐ and b‐cells in the endocrine pancreas. J. Clin. Invest. 56: 1066–1070, 1975.
 636. Orci, L., and R. H. Unger. Functional subdivisions of islets of Langerhans and possible role of D‐cells. Lancet 2: 1243–1244, 1975.
 637. Ørskov, C.. Glucagon‐like peptide‐1, a new hormone of the entero‐insular axis. Diabetologia 35: 701–711, 1992.
 638. ørskov, C., J., Andreasen, and J. J. Holst. All products of proglucagon are elevated in plasma from uremic patients. J. Clin. Endocrinol. Metab. 74: 379–384, 1992.
 639. Ørskov, C., M. Bersani, A. H. Johnsen, P. Hojrup, and J. J. Holst. Complete sequences of glucagon‐like peptide‐1 from human and pig small intestine. J. Biol. Chem. 264: 12826–12829, 1989.
 640. Ørskov, C., and J. J. Holst. Radio‐immunoassays for glucagon‐like peptides 1 and 2 (GLP‐1 and GLP‐2). Scand. J. Gastroenterol. 47: 165–174, 1987.
 641. Ørskov, C., J. J., Holst, S. Knuhtsen, F. G. A. Baldissera, S. S. Poulsen, and O. V. Nielsen. Glucagon‐like peptides GLP‐1 and GLP‐2, predicted products of the glucagon gene, are secreted separately from pig small intestine but not pancreas. Endocrinology 119: 1467–1475, 1986.
 642. Ørskov, C., J. J., Holst, and O. V. Nielsen. Effect of truncated glucagon‐like peptide‐I [proglucagon‐(78–107)amide] on endocrine secretion from pig pancreas, antrum, and nonantral stomach. Endocrinology 123: 2009–2013, 1988.
 643. Ørskov, C., J. J., Holst, S. S. Poulsen, and P. Kirkegaard. Pancreatic and intestinal processing of proglucagon in man. Diabetologia 30: 874–881, 1987.
 644. Ørskov, C., J., Jeppesen, S. Madsbad, and J. J. Holst. Proglucagon products in plasma of noninsulin‐dependent diabetics and nondiabetic controls in the fasting state and after oral glucose and intravenous arginine. J. Clin. Invest. 87: 415–423, 1991.
 645. Ørskov, C., and J. H. Nielsen. Truncated glucagon‐like peptide‐I (proglucagon 78–107aimde), an intestinal insulin‐releasing peptide, has specific receptors on rat insulinoma cells (RIN 5AH). FEBS Lett. 229: 175–179, 1988.
 646. Ørskov, C., S. S., Poulsen, M. Moller, and J. J. Holst. GLP‐1 receptors in the subfornical organs and the area postrema are accessible to circulation glucagon‐like peptide. Diabetes 45: 832–835, 1996.
 647. Ørskov, C., L., Rabenhoj, A. Wettergren, H. Kofod, and J. F. Holst. Tissue and plasma concentrations of amidated and glycine‐extended glucagon‐like peptide I in humans. Diabetes 43: 535–539, 1994.
 648. Ørskov, C., A., Wettergren, and J. J. Holst. Biological effects and metabolic rates of glucagon‐like peptide‐1 7–36 amide and glucagon‐like peptide‐1 7–37 in healthy subjects are indistinguishable. Diabetes 42: 658–661, 1993.
 649. Ørskov, L., J. J., Holst, J. Moller, C. Ørskov, N. Moller, K. G. Alberti, and O. Schmitz. GLP‐1 does not not actutely affect insulin sensitivity in healthy man. Diabetologia 39: 1227–1232, 1996.
 650. Ostenson, C. G.. Regulation of glucagon release: effects of insulin on the pancreatic A2‐cell of the guinea pig. Diabetologia 17: 325–330, 1979.
 651. Pacchioni, M., C., Orena, P. Panizza, E. Cucchi, A. Del Maschio, and A. E. Pontiroli. The hypotonic effect of intranasal and intravenous glucagon in gastrointestinal radiology. Abdom. Imaging 20: 44–46, 1995.
 652. Pagliara, A. S., S. N., Stillings, M. W. Haymond, B. A. Hover, and F. M. Matschinsky. Insulin and glucose as modulators of the amino acid‐induced glucagon release in the isolated pancreas of alloxan and streptozotocin diabetic rats. J. Clin. Invest. 55: 244–255, 1975.
 653. Pagliara, A. S., S. N., Stillings, B. Hover, D. M. Martin, and F. M. Matschinsky. Glucose modulation of amino acid‐induced glucagon and insulin release in the isolated perfused rat pancreas. J. Clin. Invest. 54: 819–832, 1974.
 654. Palmer, J. P., P. L., Werner, P. Hollander, and J. W. Ensinck. Evaluation of the control of glucagon secretion by the parasympathetic nervous system in man. Metabolism 28: 549–552, 1979.
 655. Palmiter, R. D., R. R., Behringer, C. J. Quaife, F. Maxwell, L. H. Maxwell, and R. L. Brinster. Cell lineage ablation in transgenic mice by cell specific expression of a toxin gene. Cell 50: 435–443, 1987.
 656. Paolisso, G., D., Giugliano, A. J. Scheen, P. Franchimont, F. D'Onofrio, and P. J. Lafèbvre. Primary role of glucagon release in the effect of beta‐endorphin on glucose homeostasis in normal man. Acta Endocrinol. (Copenh.) 115: 161–169, 1987.
 657. Patel, D. G.. Role of parasympathetic nervous system in the glucagon response to insulin‐induced hypoglycemia in normal and diabetic rats. Metabolism 33: 1123–1127, 1984.
 658. Patel, D. G.. Role of the sympathetic nervous system in glucagon response to insulin hypoglycemia in normal and diabetic rats. Diabetes 33: 1154–1159, 1984.
 659. Patton, G. S., E., Ipp, R. E. Dobbs, et al. Pancreatic immunoreactive somatostatin release. Proc. Natl. Acad. Sci. U.S.A. 4: 2140–2143, 1977.
 660. Patzelt, C., H. S., Tager, R. J. Carroll, and D. F. Steiner. Identification and processing of proglucagon in pancreatic islets. Nature 282: 260–266, 1979.
 661. Pauly, R. P., F., Rosche, M. Wermann, C. H. S. Mcintosh, R. A. Pederson, and H.‐U. Demuth. Investigation of glucose‐dependent insulinotropic polypeptide (1–42) and glucagon‐like peptide‐1‐(7–36) degradation in vitro by dipeptidyl peptidase IV using matrix assisted laser desorption/ionization‐time of flight mass spectrometry. J. Biol. Chem. 271: 23222–23229, 1996.
 662. Pavoine, C., V., Brechler, A. Kervran, P. Blache, D. Le‐Nguyen, S. Laurent, D. Bataille, and F. Pecker. Miniglucagon [glucagon‐(19–29)] is a component of the positive inotropic effect of glucagon. Am. J. Physiol. 260 (Cell Physiol. 29): C993–C999, 1991.
 663. Peacey, S. R., A., Rostami‐Hodjegan, E. George, G. T. Tucker, and S. R. Heller. The use of tolbutamide‐induced hypoglycemia to examine the intraislet role of insulin in mediating glucagon release in normal humans. J. Clin. Endocrinol. Metab. 82: 1458–1461, 1997.
 664. Pearse, A. G.. Islet cell precursors are neurons. Nature 295: 96–97, 1982.
 665. Pederson, R. A., and J. C. Brown. The insulinotropic actions of gastric inhibitory polypeptide in the perfused isolated rat pancreas. Endocrinology 99: 780–785, 1976.
 666. Pederson, R. A., and J. C. Brown. Interaction of gastric inhibitory polypeptide, glucose, and arginine on insulin and glucagon secretion from the perfused rat pancreas. Endocrinology 103: 610–615, 1978.
 667. Pederson, R. A., M., Satkunarajah, C. H. McIntosh, L. A. Scrocchi, D. Flamez, F. Schuit, D. J. Drucker, and M. B. Wheeler. Enhanced glucose‐dependent insulinotropic polypeptide secretion and insulinotropic action in glucagon‐like peptide 1 receptor‐/‐ mice. Diabetes 47: 1046–1052, 1998.
 668. Peers, B., J., Leonard, S. Sharma, G. Teitelman, and M. R. Montminy. Insulin expression in pancreatic islet cells relies on cooperative interactions between the helix loop helix factor E47 and the homeobox factor STF‐1. Mol. Endocrinol. 8: 1798–1806, 1994.
 669. Pek, S., S. S., Fajans, J. C. Floyd, and R. F. Knopf. Clinical conditions associated with elevated plasma levels of glucagon. Excerpta Med. Int. Congr. Ser. 312: 207–213, 1973.
 670. Pek, S., S. S., Fajans, J. C. Floyd, Jr., R. F. Knopf, and J. N. Conn. Effect of amino‐acids on plasma glucagon in man. J. Lab. Clin. Med. 72: 1003, 1968.
 671. Pek, S., J. C., Santiago, and T. Y. Tai. L‐Leucine‐induced secretion of glucagon and insulin, and the “off‐response” to L‐leucine in vitro. I. Characterization of the dynamics of secretion. Endocrinology 103: 1208–1218, 1978.
 672. Perea, A., F., Clemente, J. Martinell, M. L. Villanueva‐Penacarillo, and I. Valverde. Physiological effect of glucagon in human isolated adipocytes. Horm. Metab. Res. 27: 372–375, 1995.
 673. Perea, A., C., Vinambres, F. Clemente, M. L. Villanueva‐Penacarrillo, and I. Valverde. GLP‐1 (7–36) amide: effects on glucose transport and metabolism in rat adipose tissue. Horm. Metab. Res. 29: 417–421, 1997.
 674. Perley, M. J., and D. M. Kipnis. Plasma insulin responses to oral and intravenous glucose. Studies in normal and diabetic subjects. J. Clin. Invest. 46: 1954–1962, 1967.
 675. Peterson, D. R., F. A., Carone, S. Oparil, and E. I. Christensen. Differences between renal tubular processing of glucagon and insulin. Am. J. Physiol. 242 (Renal Fluid Electrolyte Physiol. 11): F112–F118, 1982.
 676. Pettersson, M., and B. Ahren. Insulin and glucagon secretion in rats: effects of calcitonin gene‐related peptide. Regul. Pept. 23: 37–50, 1988.
 677. Pettersson, M., and B. Ahren. Insulin and glucagon secretion in the rat: effects of gastrin releasing peptide. Neuropeptides 12: 159–163, 1988.
 678. Pettersson, M., and B. Ahren, I. Lundquist, G. Bottcher, and F. Sundler. Neuropeptide Y: intrapancreatic neuronal localization and effects on insulin secretion in the mouse. Cell Tissue Res. 248: 43–48, 1987.
 679. Philippe, J.. Insulin regulation of the glucagon gene is mediated by an insulin‐responsive DNA element. Proc. Natl. Acad. Sci. U.S.A. 88: 7224–7227, 1991.
 680. Philippe, J.. Hepatocyte‐nuclear factor 3b gene transcripts generate protein isoforms with different transactivation properties on the glucagon gene. Mol. Endocrinol. 9: 368–374, 1995.
 681. Philippe, J., D. J., Drucker, and J. F. Habener. Glucagon gene transcription in an islet cell line is regulated via a protein kinase C‐activated pathway. J. Biol. Chem. 262: 1823–1828, 1987.
 682. Philippe, J., D. J., Drucker, W. Knepel, L. Jepeal, Z. Misulovin, and J. F. Habener. Alpha cell‐specific expression of the glucagon gene is conferred to the glucagon promoter element by the interactions of DNA‐binding proteins. Mol. Cell. Biol. 8: 4877–4888, 1988.
 683. Philippe, J., D. J., Drucker, S. Mojsov, and J. F. Habener. Proglucagon processing in a rat islet cell line resembles phenotype of intestine rather than pancreas. Endocrinology 119: 2833–2839, 1986.
 684. Philippe, J., C., Morel, and M. Cordier‐Bussat. Islet‐specific proteins interact with the insulin‐response element of the glucagon gene. J. Biol. Chem. 270: 3039–3045, 1995.
 685. Philippe, J., C., Morel, and V. R. Prezioso. Glucagon gene expression is negatively regulated by hepatocyte nuclear factor 3b. Mol. Cell. Biol. 14: 3514–3523, 1994.
 686. Pictet, R. L., W. R., Clarke, R. H. Williams, and W. J. Rutter. An ultrastructural analysis of the developing embryonic pancreas. Dev. Biol. 29: 436–467, 1972.
 687. Pipeleers, D. G., P. A. in't Veld, M. Van de Winkel, E. Maes, F. C. Schuit, and W. Gepts. A new in vitro model for the study of pancreatic A and B cells. Endocrinology 117: 806–816, 1985.
 688. Pipeleers, D. G., F. C. Schuit, C. F. H. Van Schravendijk, and M. Van De Winkel. Interplay of nutrients and hormones in the regulation of glucagon release. Endocrinology 117: 817–823, 1985.
 689. Plaisancie, P., C., Bernard, J.‐A. Chayvialle, and J.‐C. Cuber. Regulation of glucagon‐like peptide‐1(7–36) amide secretion by intestinal neurotransmitters and hormones in the isolated vascularly perfused rat colon. Endocrinology 135: 2398–2403, 1994.
 690. Plaisancie, P., V., Dumoulin, J.‐A. Chayvialle, and J.‐C. Cuber. Luminal glucagon‐like peptide‐1(7–36) amide releasing factors in the isolated vascularly perfused rat colon. J. Endocrinol. 145: 521–526, 1995.
 691. Plisetsdaya, E. M., and T. P. Mommsen. Glucagon and glucagon‐like peptides in fishes. Int. Rev. Cytol. 168: 187–257, 1996.
 692. Polak, J. M., S. R., Bloom, I. Coulling, and A. G. E. Pearse. Immunofluorescent localization of enteroglucagon cells in the gastrointestinal tract of the dog. Gut 12: 311–318, 1971.
 693. Polonsky, K., J., Jaspan, D. Emmanouel, K. Holmes, and A. R. Moossa. Differences in the hepatic and renal extraction of insulin and glucagon in the dog: evidence for saturability of insulin metabolism. Acta Endocrinol. (Copenh.) 102: 420–427, 1983.
 694. Polonsky, K., J., Jaspan, and A. H. Rubenstein. The metabolic clearance rate of glucagon. In: Glucagon II, edited by P. J. Lefèbvre. New York: Springer‐Verlag, 1983, p. 353–359.
 695. Polonsky, K. S., B. D., Given, L. J. Hirsch, H. Tillil, E. T. Shapiro, C. Beebe, B. H. Frank, J. A. Galloway, and E. Van Cauter. Abnormal patterns of insulin secretion in non‐insulin dependent diabetes mellitus. N. Engl. J. Med. 318: 1231–1239, 1988.
 696. Polonsky, K. S., B. D. Given, and E. Van Cauter. Twenty‐four‐hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. J. Clin. Invest. 31: 442–448, 1988.
 697. Porte, J. D., and R. P. Robertson. Control of insulin secretion by catecholamines, stress and the sympathetic nervous system. Federation Proc. 32: 1792–1796, 1973.
 698. Portela‐Gomes, G. M., E., Wilander, L. Grimelius, R. Bergstrom, and G. Ruhn. The enterochromaffin cells in the mouse gastrointestinal tract after streptozotocin treatment. Pathol. Res. Pract. 186: 2933–2939, 1986.
 699. Potten, C. S., and M. Loeffler. Stem cells: attributes, cycles, spirals, pitfalls and uncertainties: lessons for and from the crypt. Development 110: 1001–1020, 1990.
 700. Premont, R. T., and R. Iyengar. Glucagon‐induced desensitization of adenylyl cyclase in primary cultures of chick hepatocytes. Evidence for multiple pathways. J. Biol. Chem. 263: 16087–16095, 1988.
 701. Pridal, L., C. F., Deacon, O. Kirk, J. V. Christensen, R. D. Carr, and J. J. Holst. Glucagon‐like peptide(7–37) has a larger volume of distribution than glucagon‐like peptide‐1(7–36)amide in dogs and is degraded more quickly in vitro by dog plasma. Eur. J. Drug Metab. Pharniacokinet. 21: 51–59, 1996.
 702. Printz, R. L., M. A., Magnuson, and D. K. Granner. Mammalian glucokinase. Annu. Rev. Nutr. 13: 463–496, 1993.
 703. Prinz, R. A., H., Sabbagh, T. E. Adrian, I. Gardner, J. M. Polak, H. Inokuchi, A. E. Bishop, and R. B. Welbourn. Neural regulation of pancreatic polypeptide release. Surgery 94: 1011–1018, 1983.
 704. Quabbe, H. J., W., Ramek, and A. S. Luyckx. Growth hormone, glucagon and insulin response to depression of plasma free fatty acids and the effect of glucose infusion. J. Clin. Endocrinol. 44: 383–391, 1977.
 705. Rabinovitch, A., and J. Dupre. Effects of the gastric inhibitory polypeptide present in impure pancreozymin‐cholecystokinin on plasma insulin and glucagon in the rat. Endocrinology 94: 1139–1144, 1974.
 706. Rachman, J., B. A., Barrow, J. C. Levy, and R. C. Turner. Near‐normalisation of diurnal glucose concentrations by continuous administration of glucagon‐like peptide‐1 (GLP‐1) in subjects with NIDDM. Diabetologia 40: 205–211, 1997.
 707. Rachman, J., F. M., Gobble, B. A. Barrow, J. C. Levy, K. D. Buchanan, and R. C. Turner. Normalization of insulin responses to glucose by overnight infusion of glucagon‐like peptide 1(7–36) amide in patients with NIDDM. Diabetes 45: 1524–1530, 1996.
 708. Rajan, A. S., L., Aguilar‐Bryan, D. A. Nelson, G. C. Yaney, W. H. Hsu, D. L. Kunze, and A. E. I. Boyd. Ion channels and insulin secretion. Diabetes Care 13: 340–363, 1990.
 709. Raptis, S., F., Escobar‐Jimenez, J. Rosenthal, H. Ditschuneit, and E. Pfeiffer. Somatostatin modulation of pancreatic glucagon, insulin, glucose and free fatty acids following beta adrenergic stimulation. J. Clin. Endocrinol. Metab. 44: 1088–1093, 1977.
 710. Raskin, P., E., Aydin, T. Yamamoto, and R. H. Unger. Abnormal alpha cell function in human diabetes: the response to oral protein. Am. J. Med. 64: 988–997, 1978.
 711. Raskin, P., and R. H. Unger. Hyperglucagonemia and its suppression: importance in the metabolic control of diabetes. N. Engl. J. Med. 299: 433–436, 1978.
 712. Ravazzola, M., A., Siperstein, A. J. Moody, F. Sundby, H. Jacobsen, and L. Orci. Glicentin immunoreactive cells: their relationship to glucagon‐producing cells. Endocrinology 105: 499–508, 1979.
 713. Read, N. W., A., McFarlane, R. E. Kinsman, T. E. Bates, N. W. Blackhall, G. B. J. Farrar, J. C. Hall, G. Moss, A. P. Morris, B. O'Neill, I. Welch, Y. Lee, and S. R. Bloom. Effect of infusion of nutrient solutions into the ileum on gastrointestinal transit and plasma levels of neurotensin and enteroglucagon. Gastroenterology 86: 274–280, 1984.
 714. Reaven, G. M., Y. D., Chen, A. Golay, A. L. Swislocki, and J. B. Jaspan. Documentation of hyperglucagonemia throughout the day in nonobese and obese patients with noninsulin‐dependent diabetes mellitus. J. Clin. Endocrinol. Metab. 64: 106–110, 1987.
 715. Reetz, A., M., Solimena, M. Matteoli, F. Folli, K. Takei, and P. De Camilli. GABA and pancreatic beta‐cells: colocalization of glutamic acid decarboxylase (GAD) and GABA with synaptic‐like microvesicles suggests their role in GABA storage and secretion. EMBO J. 10: 1275–1284, 1991.
 716. Rehfeld, J. F., L. I., Larsson, N. R. Golterman, T. W. Schwartz, J. J. Holst, S. L. Jensen, and J. S. Morley. Neural regulation of pancreatic hormone secretion by the C‐terminal tetrapeptide of CCK. Nature 284: 33–38, 1980.
 717. Reichlin, S.. Somatostatin N. Engl. J. Med. 309: 1495–1501, 1556–1563, 1983.
 718. Reid, R. L., and S. S. Yen. beta‐Endorphin stimulates the secretion of insulin and glucagon in humans. J. Clin. Endocrinol. Metab. 52: 592–594, 1981.
 719. Reimer, R. A., and M. I. McBurney. Dietary fiber modulates intestinal proglucagon messenger ribonucleic acid and postprandial secretion of glucagon‐like peptide‐1 and insulin in rats. Endocrinology 137: 3948–3956, 1996.
 720. Renstrom, E., W. G., Ding, K. Bokvist, and P. Rorsman. Neurotransmitter‐induced inhibition of exocytosis in insulin‐secreting beta cells by activation of calcineurin. Neuron 17: 513–522, 1996.
 721. Richter, G., R., Güke, B. Güke, H. Schmidt, and R. Arnold. Characterization of glucagon‐like peptide‐1(7–36)amide receptors of rat lung membranes by covalent cross‐linking. FEBS Lett. 280: 247–250, 1991.
 722. Richter, G., R., Güke, B. Güke, and R. Arnold. Characterization of receptors for glucagon‐like peptide‐1(7–63)amide on rat lung membranes. FEBS Lett. 267: 78–80, 1990.
 723. Rigopoulou, D., I., Valverde, J. Marco, G. R. Faloona, and R. H. Unger. Large glucagon immunoreactivity in extracts of pancreas. J. Biol. Chem. 245: 496–501, 1970.
 724. Rindi, G. S., G. N., Grant, Y. Yiangou, M. A. Ghatei, S. R. Bloom, V. L. Bautch, E. Solcia, and J. M. Polak. Development of neuroendocrine tumors in the gastrointestinal tract of transgenic mice. Am. J. Pathol. 136: 1349–1363, 1990.
 725. Ritzel, R., C., Orskov, J. J. Holst, and M. A. Nauck. Pharmacokinetic, insulinotropic, and glucagonostatic properties of GLP‐1[7–36 amide] after subcutaneous injection in healthy volunteers. Dose‐response relationships. Diabetologia 38: 720–725, 1995.
 726. Ritzel, U., A., Fromme, M. Ottleben, U. Leonhardt, and G. Ramadori. Release of glucagon‐like peptide‐1 (GLP‐1) by carbohydrates in the perfused rat ileum. Acta Diabetol. 34: 18–21, 1997.
 727. Rizza, R., C., Verdonk, J. Miles, et al. Effect of intermittent endogenous hyperglucagonemia on glucose homeostasis in normal and diabetic man. J. Clin. Invest. 63: 1119–1123, 1979.
 728. Rizza, R. A., P. E., Cryer, and J. E. Gevich. Role of glucagon, catecholamines, and growth hormone in human glucose counterregulation. Effects of somatostatin and combined δ and β‐adrenergic blockade on plasma glucose recovery and glucose flux rates after insulin‐induced hypoglycemia. J. Clin. Invest. 64: 62–71, 1979.
 729. Rizza, R. A., J. E., Gerich, M. W. Hamond, R. E. Westland, L. D. Hall, A. H. Clemens, and F. J. Service. Control of blood sugar in insulin‐dependent diabetes: comparison of an artificial endocrine pancreas, continuous subcutaneous insulin infusion, and intensified conventional insulin therapy. N. Engl. J. Med. 303: 1313–1318, 1980.
 730. Roberge, J. N., and P. L. Brubaker. Secretion of proglucagon‐derived peptides in response to intestinal luminal nutrients. Endocrinology 128: 3169–3174, 1991.
 731. Roberge, J. N., and P. L. Brubaker. Regulation of intestinal proglucagon‐derived peptide secretion by glucose‐dependent insulinotropic peptide in a novel enteroendocrine loop. Endocrinology 133: 233–240, 1993.
 732. Roberge, J. N., K. A., Gronau, and P. L. Brubaker. Gastrin‐releasing peptide is a novel mediator of proximal nutrient‐induced intestinal proglucagon‐derived peptide secretion. Endocrinology 137: 2383–2388, 1996.
 733. Rocca, A. S., and P. L. Brubaker. Stereospecific effects of fatty acids on proglucagon‐derived peptide secretion in fetal rat intestinal cultures. Endocrinology 136: 5593–3599, 1995.
 734. Rodbell, M., L., Birnbaumer, S. L. Pohl, and F. Sundby. The reaction of glucagon with its receptor: evidence for discrete regions of activity and binding in the glucagon molecule. Proc. Natl. Acad. Sci. U.S.A. 68: 909–913, 1971.
 735. Röjdmark, S., G., Bloom, M. C. Y. Chou, and J. B. Field. Hepatic extraction of exogenous insulin and glucagon in the dogs. Endocrinology 102: 806–813, 1978.
 736. Röjdmark, S., G., Bloom, M. C. Y. Chou, J. B. Jaspan, and J. B. Field. Hepatic insulin and glucagon extraction after their augmented secretion in dogs. Am. J. Physiol. 235 (Endocrinol. Metab. Gastrointest. Physiol. 4): E88–E96, 1978.
 737. Röjdmark, S., T., Ishida, G. Bloom, M. C. Y. Chou, and J. B. Field. Effect of intraportal calcium infusion on insulin and glucagon secretion and hepatic glucose output in anesthetized dogs. Endocrinology 104: 814–821, 1979.
 738. Ronner, P., F., Matschinsky, T. Hang, A. Epstein, and C. Buettger. Sulfonylurea‐binding sites and ATP‐sensitive K+ channels in alpha‐TC glucagonoma and beta‐TC insulinoma cells. Diabetes 42: 1760–1772, 1993.
 739. Rorsman, P.. Two types of Ca2+ currents with different sensitivities to organic Ca2+ channel antagonists in guinea pig pancreatic alpha 2 cells. J. Gen. Physiol. 91: 243–254, 1988.
 740. Rorsman, P., F. M., Ashcroft, and P. O. Berggren. Regulation of glucagon release from pancreatic A‐cells. Biochem. Pharmacol. 41: 1783–1790, 1991.
 741. Rorsman, P., P. O., Berggren, K. Bokvist, H. Ericson, H. Mohler, C. G. Ostenson, and P. A. Smith. Glucose‐inhibition of glucagon secretion involves activation of GABAA‐receptor chloride channels. Nature 341: 233–236, 1989.
 742. Rorsman, P., and B. Hellman. Voltage‐activated currents in guinea pig pancreatic alpha 2 cells. Evidence for Ca2+ dependent action potentials. J. Gen. Physiol. 91: 223–242, 1988.
 743. Ross, S. A., J. C., Brown, and J. Dupre. Hypersecretion of gastric inhibitory polypeptide (GIP) following oral glucose in diabetes mellitus. Diabetes 26: 525–529, 1977.
 744. Ross, S. A., and J. Dupre. Effects of ingestion of triglyceride or galactose on secretion of gastric inhibitory polypeptide and on responses to intravenous glucose in normal and diabetic subjects. Diabetes 27: 327–333, 1978.
 745. Rothenberg, M. E., C. D., Eilerston, K. Klein, R. B. Mackin, and B. Noe. Evidence of redundancy in propeptide/Prohormone convertase activities in processing proglucagon: an antisense study. Mol. Endocrinol. 10: 331–341, 1996.
 746. Rouillé, Y., S., Martin, and D. F. Steiner. Differential processing of proglucagon by the subtilisin‐like prohormone convertases PC2 and PC3 to generate either glucagon or glucagon‐like peptide. J. Biol. Chem. 270: 26488–26496, 1995.
 747. Rountree, D. B., M. H., Ulshen, S. Selub, C. R. Fuller, S. R. Bloom, M. A. Ghatei, and P. K. Lund. Nutrient‐independent increases in proglucagon and ornithine decarboxylase messenger RNAs after jujunoileal resection. Gastroenterology 103: 462–468, 1992.
 748. Rovira, A., J. M., Lopez‐Novoa, M. Zubiaur, R. Metasanz, M. Ghiglione, J. M. Pascual, and I. Valverde. Renal metabolism of gut glucagon‐like immunoreactivity. Endocrinology 110: 2030–2036, 1982.
 749. Ruiz‐Grande, C., C., Alarcón, A. Alcántara, C. Castilla, J. M. López Novoa, M. L. Villanueva‐Penacarrillo, and I. Valverde. Renal catabolism of truncated glucagon‐like peptide‐1. Horm. Metab. Res. 25: 612–616, 1993.
 750. Ruiz‐Grande, C., C., Alarcon, E. Merida, and I. Valverde. Lipolytic action of glucagon‐like peptides in isolated rat adipocytes. Peptides 13: 13–16, 1992.
 751. Sacca, L., G., Perez, G. Carteni, B. Trimarco, and F. Rengo. Role of glucagon in the glucoregulatory response to insulin‐induced hypoglycemia in the rat. Horm. Metab. Res. 9: 209–212, 1977.
 752. Sagor, G. R., M. A., Ghatei, D. J. O'Shaughnessy, M. Y. T. Al‐Mukhtar, N. A. Wright, and S. R. Bloom. Influence of somatostatin and bombesin on plasma enteroglucagon and cell proliferation after intestinal resection in the rat. Gut 26: 89–94, 1985.
 753. Sagor, G. R., M. Y. T., Mukhtar, M. A. Ghatei, N. A. Wright, and S. R. Bloom. The effect of altered liminal nutrition on cellular proliferation and plasma concentrations of enteroglucagon and gastrin after small bowel resection in the rat. Br. J. Surg. 69: 14–18, 1982.
 754. Sakurai, H., R. E., Dobbs, and R. H. Unger. The effect of somatostatin on the response of GLI to the intraduodenal administration of glucose, protein and fat. Diabetologia 11: 427–430, 1975.
 755. Salazaar, I., and C. Vaillant. Glucagon‐like immunoreactivity in hypothalamic neurons of the rat. Cell Tissue Res. 261: 255–260, 1990.
 756. Samols, E., G., Marri, and V. Marks. Promotion of insulin secretion by glucagon. Lancet 2: 415–416, 1965.
 757. Samols, E., J. I., Stagner, R. B. L. Ewart, and V. Marks. The order of islet microvascular perfusion is B→A, A→D in the perfused rat pancreas. J. Clin. Invest. 82: 350–353, 1988.
 758. Samols, E., J. I., Stagner, and G. C. Weir. Autonomic function and control of pancreatic somatostatin. Diabetologia 20: 338–392, 1981.
 759. Samols, E., and G. Weir. Adrenergic modulation of pancreatic A, B, and D cells. J. Clin. Invest. 63: 230–238, 1979.
 760. Sander, M., A., Neubuser, J. Kalamaras, H. C. Ee, G. R. Martin, and M. S. German. Genetic analysis reveals that PAX6 is required for normal transcription of pancreatic hormone genes and islet development. Genes Dev. 11: 1662–1673, 1997.
 761. Sasaki, H., H., Manakja, K. Yamatani, and M. Tominaga. GLP‐1 secretion coupled with Na/glucose transporter from the isolated perfused canine ileum. Digestion 54: 365–367, 1993.
 762. Sasaki, K., A., Matsuhashi, S. Murabayashi, K. Aoyagi, T. Baba, M. Matsunaga, and K. Takebè. Hormonal response to insulin‐induced hypoglycemia in patients with Shy‐Drager syndrome. Metabolism 32: 977–981, 1983.
 763. Saski, K., S., Dockerill, D. A. Adamiak, I. J. Tickle, and T. J. Blundell. x‐Ray analysis of glucagon and its relationship to receptor binding. Nature 257: 751–757, 1975.
 764. Sauvadet, A., F., Pecker, and C. Pavoine. Inhibition of the sarcolemmal Ca2+ pump in embryonic chick heart cells by miniglucagon. Cell Calcium 18: 76–85, 1995.
 765. Sauvadet, A., T., Rohn, F. Pecker, and C. Pavoine. Synergistic actions of glucagon and miniglucagon on Ca2+ mobilization in cardiac cells. Circ. Res. 78: 102–109, 1996.
 766. Sauvadet, A., T., Rohn, F. Pecker, and C. Pavoine. Arachidonic acid drives mini‐glucagon action in cardiac cells. J. Biol. Chem. 272: 12437–12445, 1997.
 767. Schade, D., and R. Eaton. The regulation of plasma ketone body concentration by counterregulatory hormones in man. Diabetes 26: 989–996, 1977.
 768. Schade, D., and R. Eaton. The regulation of plasma ketone body concentration by counterregulatory hormones in man. III. Effects of norepinephrine in normal man. Diabetes 28: 5–10, 1979.
 769. Schade, D. S., and R. Eaton. The metabolic response to norepinephrine in normal versus diabetic man. Diabetologia 16: 433–439, 1978.
 770. Schaffalitzky de Muckadell, O. B., J. Fahrenkrug, and J. J. Holst. Release of vasoactive intestinal polypeptide (VIP) by electrical stimulation of the vagal nerves. Gastroenterology 72: 373–375, 1977.
 771. Schebalin, M., S. I., Said, and G. M. Makhlouf. Stimulation of insulin and glucagon secretion by vasoactive intestinal peptide. Am. J. Physiol. 232: 197–200, 1977.
 772. Scheurink, A. J., A. B., Steffens, H. Bouritius, G. H. Dreteler, R. Bruntink, R. Remie, and J. Zaagsma. Adrenal and sympathetic catecholamines in exercising rats. Am. J. Physiol. 256 (Regulatory Integrative Comp. Physiol. 25): R155–R160, 1989.
 773. Schirra, J., M., Katschinski, C. Weidmann, T. Schäfer, U. Wank, R. Arnold, and B. Göke. Gastric emptying and release of incretin hormones after glucose ingestion in humans. J. Clin. Invest. 97: 92–103, 1996.
 774. Schirra, J., P., Kuwert, U. Wank, P. Leicht, R. Arnold, B. Göke, and M. Katschinski. Differential effects of subcutaneous GLP‐1 on gastric emptying, antroduodenal motility, and pancreatic function in men. Proc. Assoc. Am. Physicians 109: 84–97, 1997.
 775. Schjoldager, B. T. C., F. G. A., Baldissera, P. E. Mortensen, J. J. Holst, and J. Christiansen. Oxyntomodulin: a potential hormone from the distal gut: pharmacokinetics and effects on gastric acid and insulin secretion in man. Eur. J. Clin. Invest. 18: 499–503, 1988.
 776. Schjoldager, B. T., P. E., Mortensen, J. Christiansen, C. Ørskov, and J.J. Holst. GLP‐1 (glucagon‐like peptide 1) and truncated GLP‐1, fragments of human proglucagon, inhibit gastric acid secretion in humans. Dig. Dis. Sci. 34: 703–708, 1989.
 777. Schmidt, W. E., E. G., Siegel, and W. Creutzfeld. Glucagon‐like peptide‐1 but not glucagon‐like peptide‐2 stimulates insulin release from isolated rat pancreatic islets. Diabetologia 28: 704–707, 1985.
 778. Schmidtler, J., K., Dehne, H. D. Allescher, V. Schusdziarra, M. Classen, J. J. Holst, A. Polack, and W. Schepp. Rat parietal cell receptors for GLP‐1‐(7–36)amide: Northern blot, cross‐linking, and radioligand binding. Am J. Physiol. 267 (Gastrointest. Liver Physiol. 30): G423–G432, 1994.
 779. Schmidtler, J., W., Schepp, I. Janczewska, C. Weigert Fütlinger, V. Schusdziarra, and M. Classen. GLP‐1‐(7–36)amide,‐(1–37), and‐(1–36)amide: potent cAMP dependent stimuli of rat parietal cell function. Am. J. Physiol. 260 (Gastrointest. Liver Physiol. 23): G940–G950, 1991.
 780. Schuit, F. C., M. P., Derde, and D. G. Pipeleers. Sensitivity of rat pancreatic A and B cells to somatostatin. Diabetologia 32: 207–212, 1989.
 781. Schuit, F. C., and D. G. Pipeleers. Differences in adrenergic recognition by pancreatic A and B cells. Science 232: 875–877, 1986.
 782. Schwaninger, M., G., Lux, R. Blune, E. Oetjen, H. Hidaka, and W. Knepel. Membrane depolarization and calcium influx induce glucagon gene transcription in pancreatic islet cells through the cyclic AMP‐responsive element. J. Biol. Chem. 268: 5168–5177, 1993.
 783. Schwartz, N. S., W. E., Clutter, S. D. Shah, and P. E. Cryer. Glycemic thresholds for activation of glucose counterregulatory systems are higher than the threshold for symptoms. J. Clin. Invest. 79: 777–781, 1987.
 784. Schwartz, T. W.. Pancreatic polypeptide (PP). Adv. Exp. Med. Biol. 106: 165–168, 1978.
 785. Schwartz, T. W.. Pancreatic polypeptide: a hormone under vagal control. Gastroenterology 85: 1411–1425, 1983.
 786. Schwartz, T. W.. Molecular structure of G‐protein coupled receptors. In: Textbook of Receptor Pharmacology, edited by J. C. Foreman and T. Johansen. Boca Raton, FL: CRC, 1996, p. 65–84.
 787. Scott, R. B., D., Kirk, W. K. MacNaughton, and J. B. Meddings. GLP‐2 augments the adaptive response to massive intestinal resection in rat. Am. J. Physiol. 275: G911–G921, 1998.
 788. Scow, R. D., and J. Cornfield. Quantitative relations between the oral and intravenous glucose tolerance curves. Am. J. Physiol. 179: 435–438, 1954.
 789. Scrocchi, L. A, T. J., Brown, and D. J. Drucker. Leptin sensitivity in non‐obese glucagon‐like peptide I receptor‐/‐ mice. Diabetes 46: 2029–2034, 1997.
 790. Scrocchi, L. A., T. J., Brown, N. MacLusky, P. L. Brubaker, A. B. Auerbach, A. L. Joyner, and D. J. Drucker. Glucose intolerance but normal satiety in mice with a null mutation in the glucagon‐like peptide 1 receptor gene. Nat. Med. 2: 1254–1258, 1966.
 791. Scrocchi, L. A., and D. J. Drucker. Effects of aging and a high fat diet on body weight and glucose tolerance in glucagon‐like peptide‐1 receptor‐/‐mice. Endocrinology 39: 3127–3132, 1998.
 792. Scrocchi, L. A., B. A., Marshall, S. M. Cook, P. L. Brubaker, and D. J. Drucker. Identification of glucagon‐like peptide 1 (GLP‐1) actions essential for glucose homeostasis in mice with disruption of GLP‐1 receptor signaling. Diabetes 47: 632–639, 1998.
 793. Segre, G. V., and S. R. Goldring. Receptors for secretin, calcitonin, parathyroid hormone (PTH)/PTH‐related peptide, vasoactive intestinal peptide, glucagon peptide 1, growth hormone‐releasing hormone, and glucagon belong to a newly discovered G‐protein‐linked receptor family. Trends Endocrinol. Metab. 4: 309–314, 1993.
 794. Seino, S., H., Sakurai, Y. Seino, K. Tsuda, K. Tanigawa, H. Kuzuya, Y. Goto, and H. Imura. Starvation‐induced changes of somatostatin, glucagon, and insulin secretion from the isolated perfused rat pancreas. Diabetes 29: 323–325, 1980.
 795. Serup, P., J., Jensen, F. G. Andersen, M. C. Jorgensen, N. Blume, J. J. Holst, and O. D. Madsen. Induction of insulin and islet amyloid polypeptide production in pancreatic islet glucagonoma cells by insulin promoter factor 1. Proc. Natl. Acad. Sci. U.S.A. 93: 9015–9020, 1996.
 796. Seyffert, W. A., and L. L. Madison. Physiologic effect of metabolic fluels on carbohydrate metabolism. I. Acute effect of elevation of plasma free fatty acids on hepatic glucose output, peripheral glucose utilization, serum insulin and plasma glucagon levels. Diabetes 16: 765–777, 1967.
 797. Shapiro, E. T., H., Tillil, K. S. Polonsky, V. S. Fang, A. H. Rubenstein, and E. Van Cauter. Oscillations in insulin secretion during constant glucose infusion in normal man: relationship to changes in plasma glucose. J. Clin. Endocrinol. Metab. 67: 307–313, 1988.
 798. Sheetz, M. J., and H. S. Tager. Characterization of a glucagon receptor‐linked protease from canine hepatic plasma membranes. Partial purification, kinetic analysis, and determination of sites for hormone processing. J. Biol. Chem. 263: 19210–19217, 1988.
 799. Sheetz, M. J., and H. S. Tager. Receptor‐linked proteolysis of membrane‐bound glucagon yields a membrane‐associated hormone fragment. J. Biol. Chem. 263: 8509–8514, 1988.
 800. Sherwin, R., C., Bastl, F. O. Finkelstein, M. Fisher, M. Black, R. Hendler, and P. Felig. Influence of uremia and hemodialysis on the turnover and metabolic effects of glucagon. J. Clin. Invest. 57: 722–731, 1976.
 801. Shii, K., S., Baba, K. Yokono, and R. A. Roth. Covalent linkage of 125I‐insulin to a cytosolic insulin‐degrading enzyme. J. Biol. Chem. 260: 6503–6506, 1985.
 802. Shima, K., M., Hirota, C. Ohboshi, M. Sato, and T. Nishino. Release of glucagon‐like peptide‐1 immunoreactivity from the perfused rat pancreas. Acta Endocrinol. (Copenh.) 114: 531–536, 1987.
 803. Shima, K., T., Suda, K. Nishimoto, and S. Yoshimoto. Relationship between molecular structures of sugars and their ability to stimulate the release of glucagon‐like peptide‐1 from canine ileal loops. Acta Endocrinol. (Copenh.) 123: 464–470, 1990.
 804. Shimazu, T., and K. Ishikawa. Modulation by the hypothalamus of glucagon and insulin secretion in rabbits: studies with electrical and chemical stimulations. Endocrinology 108: 605–611, 1981.
 805. Shimizu, I., M., Hirota, C. Ohboshi, and K. Shima. Identification and localization of glucagon‐like peptide‐1 and its receptor in rat brain. Endocrinology 121: 1076–1082, 1987.
 806. Shimosegawa, T. S. Moriizumi, M. Koizumi, J. Kashimura, N. Yanaihara, and T. Toyota. Immunohistochemical demonstration of galaninlike immunoreactive nerves in the human pancreas. Gastroenterology 102: 263–271, 1992.
 807. Sidhu, G. S.. The endodermal origin of digestive and respiratory tract APUD cells. Am. J. Pathol. 96: 5–17, 1979.
 808. Sirek, A. M. Vranic, O. V. Sirek, M. Vigas, and Z. Policova. Effect of growth hormone on acute glucagon and insulin release. Am J. Physiol. 237: (Endocrinol. Metab. Gastrointest. Physiol. 6) E107–E112, 1979.
 809. Sirinek, K. R., B. A., Levine, S. E. Crockett, and S. Cataland. Cholecystokinin and gastric inhibitory polypeptide not glucagonotropic in dogs. J. Surg. Res. 28: 367–372, 1980.
 810. Sjolund, D., G., Sanden, R. Hakanson, and F. Sundler. Endocrine cells in human intestine. An immunocytochemical study. Gastroenterology 85: 1120–1130, 1983.
 811. Slack, J. M.. Developmental biology of the pancreas. Development 121: 1569–1580, 1995.
 812. Smith, P. H., F. W., Merchant, D. G. Johnson, W. Y. Fujimoto, and R. H. Williams. Immunocytochemical localization of a gastric inhibitory polypeptide‐like material within A‐cells of the endocrine pancreas. Am. J. Anat. 149: 585–590, 1977.
 813. Sokoloff, L.. Circulation and energy metabolism of the brain. In: Basic Neurochemistry, edited by G. Siegel, B. Agranoff, R. W. Albers, and P. Molinoff. New York: Raven, 1989, p. 565–590.
 814. Sorenson, R. L., and R. P. Elde. Dissociation of glucose stimulation of somatostatin and insulin release from glucose inhibition of glucagon release in the isolated perfused rat pancreas. Diabetes 32: 561–567, 1983.
 815. Sorenson, R. L., D. G., Garry, and T. C. Brelje. Structural and functional considerations of GABA in islets of Langerhans. Beta‐cells and nerves. Diabetes 40: 1365–1376, 1991.
 816. Sosa‐Pineda, B., K., Chowdhury, M. Torres, G. Oliver, and P. Gruss. The Pax4 gene is essential for differentiation of insulin‐producing β cells in the mammalian pancreas. Nature 386: 399–402, 1997.
 817. Spengler, D., C., Waeber, C. Pataloni, F. Holsboer, J. Bockaert, P. H. Seeburg, and L. Journot. Differential signal transduction by five splice variants of the PACAP receptor. Nature 365: 170–175, 1993.
 818. Spiller, R. C., I. F., Trotman, T. E. Adrian, S. R. Bloom, J. J. Misiewicz, and D. B. A. Silk. Further characterization of the “ileal brake” reflex in man: effect of ileal infusion of partial digests of fat, protein, and starch on jejunal motility and release of neurotensin, enteroglucagon, and peptide YY. Gut 29: 1042–1051, 1988.
 819. Srikant, C. B., K., McKorlde, and R. H. Unger. Characteristics of tissue IRGs in the dog. Metabolism 25: 1403–1404, 1976.
 820. Stagner, J. I.. Pulsatile secretion from the endocrine pancreas: metabolic, hormonal, and neural modulation. In: The Endocrine Pancreas, edited by E. Simols. New York: Raven, 1991, p. 283–302.
 821. Stagner, J. I., and E. Samols. Perturbation of insulin oscillations by nerve blockade in the in vitro canine panceas. Am J. Physiol. 248 (Endocrinol. Metab. 11): E516–E521, 1985.
 822. Stagner, J. I., and E. Samols. Role of intrapancreatic ganglia in regulation of periodic insular secretion. Am. J. Physiol. 248 (Endocrinol. Metab. 11): E522–E530, 1985.
 823. Stagner, J. I., and E. Samols. Retrograde perfusion as a model for testing the relative effects of glucose versus insulin on the A cell. J. Clin. Invest. 77: 1034–1037, 1986.
 824. Stagner, J. I., and E. Samols. Comparison of insulin and glucagon pulsatile secretion between the rat and dog pancreas in vitro. Life Sci. 43: 929–934, 1988.
 825. Stagner, J. I., E., Samols, and G. C. Weir. Sustained oscillations of insulin, glucagon and somatostatin from the isolated canine pancreas during exposure to a constant glucose concentration. J. Clin. Invest. 65: 939–942, 1980.
 826. Starke, A., T., Imamura, and R. H. Unger. Relationship of glucagon suppression by insulin and somatostatin to the ambient glucose concentration. J. Clin. Invest. 79: 20–24, 1987.
 827. Starke, A., S., Grundy, J. D. McGarry, and R. H. Unger. Correction of hyperglycemia with phloridzin restores the glucagon response glucose in insulin‐deficient dogs: implications for human diabetes. Proc. Natl. Acad. Sci. U.S.A. 82: 1544–1546, 1985.
 828. Staub, A., L., Sinn, and O. K. Behrens. Purification and crystallization of hyperglycemic glycogenolytic factor (HGF). Science 117: 628–629, 1953.
 829. Staub, A., L., Sinn, and O. K. Behrens. Purification and crystallization of glucagon. J. Biol. Chem. 214: 619–632, 1955.
 830. Steffens, A. B.. The modulatory effect of the hypothalamus on glucagon and insulin secretion in the rat. Diabetologia 20: 411—416, 1981.
 831. Steinberg, D. M., E., Shafrir, and M. Vaughan. Direct effect of glucagon on release of unesterified fatty acids (UFA) from adipose tissue. Clin. Res. 7: 250, 1959.
 832. Sternini, C., R. De Giorgio, K. Anderson, P. C. Watt, F. C. Brunicardi, A. L. Widdison, H. Wong, H. A. Reber, J. H. Walsh, and V. L. Go. Species differences in the immunoreactive patterns of calcitonin gene‐related peptide in the pancreas. Cell Tissue Res. 269: 447–158, 1992.
 833. Stevens, F. M., R. W., Flanagan, D. O'Gorman, and K. D. Buchanan. Glucagonoma syndrome demonstrating giant duodenal villi. Gut 25: 784–791, 1984.
 834. Stoffel, M., R., Espinoza, M. M. LeBeau, and G. I. Bell. Human glucagon‐like peptide‐1 receptor gene. Localization to chromosome 6p21 by fluorescence in situ hybridization and linkage of a highly polymorphic simple tandem repeat DNA polymorphism to other markers on chromosome 6. Diabetes 42: 1215–1218, 1993.
 835. St.‐Onge, L., and B. Sosa‐Pineda. Pax6 is required for differentiation of glucagon‐producing alpha‐cells in mouse pancreas. Nature 387: 406–409, 1997.
 836. Sturm, N. S., A. M., Hutzler, C. S. David, B. Y. Azizeh, D. Trivedi, and V. J. Hruby. Structure activity studies of hydrophobic amino acid replacements at positions 9, 11, and 16 of glucagon. J. Pept. Res. 49: 293–299, 1997.
 837. Sugiyama, K., H., Manaka, T. Kato, K. Yamatani, M. Tominaga, and H. Sasaki. Stimulation of truncated glucagon‐like peptide‐1 release from the isolated perfused canine ileum by glucose absorption. Digestion 55: 24–28, 1994.
 838. Sutherland, E. W., C. F., Cori, R. Haynes, and N. S. Olsen. Purification of the hyperglycemic‐glycogenolytic factor from insulin and from gastric mucosa. J. Biol. Chem. 180: 825–837, 1949.
 839. Sutherland, E. W., and C. DeDuve. Origin and distribution of the hyperglycemic‐glycogenolytic factor of the pancreas. J. Biol. Chem. 175: 663–674, 1948.
 840. Suzuki, J., K., Fujikura, N. Inagaki, S. Seino, and K. Takata. Localization of the ATP‐sensitive K+ channel subunit Kir6.2 in mouse pancreas. Diabetes 46: 1440–1444, 1997.
 841. Suzuki, S., K., Kawai, S. Ohashi, H. Mukai, and K. Yamashita. Comparison of the effects of various C‐terminal and N‐terminal fragment peptides of glucagon‐like peptide‐1 on insulin and glucagon release from the isolated perfused rat pancreas. Endocrinology 125: 3109–3114, 1989.
 842. Suzuki, S., K., Kawai, S. Ohashi, H. Mukai, and K. Yamashita. Reduced insulinotropic effect of glucagon‐like peptide‐I(7–36)‐amide and gastric inhibitory polypeptide in isolated perfused diabetic rat pancreas. Diabetes 39: 1320–1325, 1990.
 843. Suzuki, S., K., Kawai, S. Ohasi, Y. Watanabe, and K. Yamashita. Interaction of glucagon‐like peptide‐1(7–36)amide and gastric inhibitory polypeptide or cholecystokinin on insulin and glucagon secretion from the isolated perfused rat pancreas. Metabolism 41: 359–363, 1992.
 844. Svoboda, M., M., Tastenoy, P. Vertongen, and R. Robberecht. Relative quantitative analysis of glucagon receptor mRNA in rat tissues. Mol. Cell. Endocrinol. 105: 131–137, 1994.
 845. Szecowka, J., P. E., Lins, K. Tatemoto, and S. Efendic. Effects of porcine heptacosapeptide and vasoactive intestinal peptide on insulin and glucagon secretion in rats. Endocrinology 112: 1469–1473, 1983.
 846. Taborsky, G. J., Jr., P. J. Havel, and D. Porte, Jr.. Stress‐induced activation of the neuroendocrine system and its effects on carbohydrate metabolism. In: Diabetes Mellitus, edited by D. Porte, Jr. and R. S. Sherwin. Norwalk, C. T. Appleton and Lange, 1997, p. 141–168.
 847. Tager, H. S., and J. Markese. Intestinal and pancreatic glucagon‐like peptides: evidence for identity of higher molecular weight forms. J. Biol. Chem. 254: 2229–2233, 1979.
 848. Tager, H. S., and D. F. Steiner. Isolation of a glucagon‐containing peptide: primary structure of a possible fragment of proglucagon. Proc. Natl. Acad. Sci. U.S.A. 70: 2321–2324, 1973.
 849. Tai, T. Y., and S. Pek. Direct stimulation by growth hormone of glucagon and insulin release from isolated rat pancreas. Endocrinology 99: 669–677, 1976.
 850. Takahashi, H., H. S., Mamaka, K. N. Fukase, A. Sekikawa, H. Eguchi, M. Tominaga, and H. Sasaki. Hyperglycemia but not hyperinsulinemia prevents the secretion of glucagon‐like peptide‐1(7–36)amide stimulation by fat ingestion. Scand. J. Clin. Lab. Invest. 51: 499–507, 1991.
 851. Takhar, S., S., Gyomorey, R. C. Su, S. K. Mathi, X. Li, and M. B. Wheeler. The third cytoplasmic domain of the GLP‐1(7–36)amide receptor is required for coupling to the adenylyl cyclase system. Endocrinology 137: 2175–2178, 1996.
 852. Talor, Z., D. S., Emmanouel, and A. I. Katz. Glucagon degradation by luminal and basolateral renal tubular cell membranes. Am. J. Physiol. 244 (Renal Fluid Electrolyte Physiol. 13: F297–F303, 1983.
 853. Taminato, T., Y., Seino, Y. Goto, Y. Inoue, and S. Kadowaki. Synthetic gastric inhibitory polypeptide. Stimulatory effect on insulin and glucagon secretion in the rat. Diabetes 26: 480–484, 1977.
 854. Tang‐Christensen, M., P. J., Larsen, R. Göke, A. Fink‐Jensen, D. S. Jessop, M. Moller, and S. P. Sheikh. Central administration of GLP‐1‐(7–36)amide inhibits food and water intake in rats. Am. J. Physiol. 271 (Regulatory Integrative Comp. Physiol. 40): R848–R856, 1996.
 855. Taniguchi, H., Y., Okada, C. Shimada, and S. Baba. GABA in pancreatic islets. Arch. Histol. Jpn. 40 (Suppl): 87–97, 1977.
 856. Tanizawa, Y., A. C., Riggs, S. C. Elebein, A. Whelan, H. Donis‐Keller, and M. A. Permutt. Human glucagon‐like peptide receptor gene in NIDDM: identification and use of simple sequence repeat polymorphisms in genetic analysis. Diabetes 43: 752—757, 1994.
 857. Taylor, R. G., K., Verity, and P. J. Fuller. Ileal glucagon gene expression. Ontogeny and response to massive bowel resection. Gastroenterology 99: 724–729, 1990.
 858. Teitelman, G.. Insulin cells of the pancreas extend neurites but do not arise from the neuroectoderm. Dev. Biol. 142: 368–379, 1990.
 859. Teitelman, G., S., Alpert, J. M. Polak, A. Martinez, and D. Hanahan. Precursor cells of mouse endocrine pancreas coexpress insulin, glucagon, and the neuronal protease tyrosine hydroxylase and neuropeptide Y but not pancretic polypeptide. Development 118: 1031–1039, 1990.
 860. Teitelman, G., and J. K. Lee. Cell lineage analysis of the pancreatic islet cell development: glucagon and insulin cells arise from catecholaminergic precursors present in the pancreatic ducts. Dev. Biol. 121: 454–466, 1987.
 861. Thim, L., and A. Moody. The primary structure of porcine glicentin (proglucagon). Regul. Pept. 2: 139–150, 1981.
 862. Thorens, B.. Expression cloning of the pancreatic β cell receptor for the glucoincretin hormone glucagon‐like peptide 1. Proc. Natl. Acad. Sci. U.S.A. 89: 8641–8645, 1992.
 863. Thorens, B., and G. Waeber. Glucagon‐like peptide‐1 and the control of insulin secretion in the normal state and in NIDDM. Diabetes 42: 1219–1225, 1993.
 864. Thornton, K., and D. G. Gorenstein. Structure of glucagon‐like peptide (7–36) amide in a dodecylphosphocholine micelle as determined by 2D NMR. Biochemistry 33: 3532–3539, 1994.
 865. Todd, J. F., J. P. H., Wilding, C. M. B. Edwards, F. A. Khan, M. A. Ghatei, and S. R. Bloom. Glucagon‐like peptide‐1 (GLP‐1): a trial of treatment in non‐insulin‐dependent diabetes mellitus. Eur. J. Clin. Invest. 27: 533–536, 1997.
 866. Toft‐Nielsen, M., S., Madsbad, and J. J. Holst. The effect of GLP‐1 on glucose elimination. Diabetes 45: 552–556, 1996.
 867. Tominaga, M., H., Maruyama, G. Bolli, J. H. Helderman, and R. H. Unger. Stimulation of the normal glucopenia‐induced decline in insulin partially restores the glucagon response to glucopenia in isolated perfused pancreata of streptozotocin‐diabetic rats. Endocrinology 118: 886–887, 1986.
 868. Towler, D. A., C. E., Havlin, S. Craft, and P. Cryer. Mechanism of awareness of hypoglycemia: perception of neurogenic (predominantly cholinergic)rather than neuroglycopenic symptoms. Diabetes 42: 1791–1798, 1993.
 869. Trapote, M. A., F., Clemente, C. Galera, M. Morales, A. Alcantara, L. Lopez‐Delgado, M. L. Villanueva‐Penacarrillo, and I. Valverde. Inositolphosphoglycans are possible mediators of the glucagon‐like peptide 1 (7–36)amide action in the liver. J. Endocrinol. Invest. 19: 114–118, 1996.
 870. Tronier, B., A., Deigard, T. Anderson, and S. Mabsbad. Absence of incretin effect in obese type II and diminished effect in lean type II and obese subjects [abstract]. Diabetes Res. Clin. Pract. (Suppl. 1): S586, 1985.
 871. Tsai, C.‐H., and D. J. Drucker. Biological determinants of intestinotrophic properties of glucagon‐like peptide 1 in vivo. Am. J. Pysiol. 272 (Gastrointest. Liver Physiol. 35): G662–G665, 1997.
 872. Tsai, C.‐H., M., Hill, S. L. Asa, P. L. Brucbaker, and D. J. Drucker. Intestinal growth‐promoting properties of glucagon‐like peptide 2 in mice. Am. J. Physiol. (Endocrinol. Metab. 36) 273: E77–E84, 1997.
 873. Tsubouchi, H., J., Miyazaki, E. Gohda, H. Nakayama, Y. Nakazono, Y. Kaikuhara, and S. Hashimoto. Degradation of [125I] odoglucagon by normal rat plasma in radioimmunoassay mixture containing aprotinin and its prevention by p‐chloromercuriphenyl sulfonate and leupeptin. Endocrinology 119: 1137–1145, 1986.
 874. Tucker, J. D., S., Dhanvantari, and P. L. Brubaker. Processing of proglucagon in islet and intestinal cell lines. Regul. Pept. 62: 29–35, 1996.
 875. Turton, D. D., D., O'Shea, J. Gunn, S. A. Beak, C. M. Edwards, K. Meeran, S. J. Choi, G. M. Taylor, M. M. Heath, P. D. Lambert, J. P. Wilding, D. M. Smith, M. A. Ghatei, J. Herbert, and S. R. Bloom. A role for glucagon‐like peptide‐1 in the central regulation of feeding. Nature 379: 69–72, 1996.
 876. Ullrich, S., and C. B. Wollheim. GTP‐dependent inhibition of insulin secretion by epinephrine in permeabilized RINm5F cells. Lack of correlation between insulin secretion and cyclic AMP levels. J. Biol. Chem. 263: 8615–8620, 1988.
 877. Ulshen, M. H., E. C., Hoyt, C. R. Fuller, M. A. Ghatei, S. R. Bloom, and P. K. Lund. Increased ileal proglucagon expression after jejunectomy in not suppressed by inhibition of bowel growth. Dig. Dis. Sci. 41: 677–683, 1996.
 878. Unger, R. H.. Glucagon and the insulin: glucagon ratio in diabetes and other catabolic illnesses. Diabetes 20: 834–838, 1971.
 879. Unger, R. H.. Diabetes and the alpha cell. Diabetes 25: 136–151, 1976.
 880. Unger, R. H., E., Aguilar‐Parada, W. A. Muller, and A. M. Eisentraut. Studies of pancreatic alpha cell function in normal and diabetic subjects. J. Clin. Invest. 49: 837–848, 1970.
 881. Unger, R. H., and A. M. Eisentraut. Entero‐insular axis. Arch. Intern. Med. 123: 261–266, 1969.
 882. Unger, R. H., A. M., Eisentraut, and L. L. Madison. The effects of total starvation upon the levels of circulating glucagon and insulin in man. J. Clin. Invest. 49: 837–848, 1970.
 883. Unger, R. H., A. M., Eisentraut, M. S. McCall, S. Keller, H. C. Lanz, and L. L. Madison. Glucagon antibodies and their use for immunoassay for glucagon. Proc. Soc. Exp. Biol. Med. 102: 621–623, 1959.
 884. Unger, R. H., A. M., Eisentraut, M. S. McCall, and L. L. Madison. Glucagon antibodies and an immunoassay for glucagon. J. Clin. Invest. 40: 1280–1289, 1961.
 885. Unger, R. H., A. M., Eisentraut, M. S. McCall, and L. L. Madison. Demonstration of the hormonal status of endogenous glucagon. In: Immunoassay of Hormones. CIBA Foundation Colloquia on Endocrinology, edited by G. E. W. Wolstenholme and M. P. Cameron. London: Churchill, 1962, p. 212–223.
 886. Unger, R. H., A. M., Eisentraut, K. Sims, M. S. McCall, and L. L. Madison. Sites of origin of glucagon in dogs and humans. Clin. Res. 53: 1961.
 887. Unger, R. H., W. A., Muller, and G. R. Faloona. Insulin glucagon ratio. Trans. Assoc. Am. Physicians 84: 122–129, 1971.
 888. Unger, R. H., A., Ohneda, E. Aguilar‐Parada, and A. M. Eisentraut. The role of aminogenic glucagon secretion in blood glucose homeostasis. J. Clin. Invest. 48: 810–922, 1969.
 889. Unger, R. H., A., Ohneda, and I. Valverde. Characterization of the responses of circulating glucagon‐like immunoreactivity to intraduodenal and intravenous administration of glucose. J. Clin. Invest. 47: 48–65, 1968.
 890. Unger, R. H., and L. Orci. The essential role of glucagon in the pathogenesis of diabetes mellitus. Lancet 1: 14–16, 1975.
 891. Unger, R. H., and L. Orci. Hypothesis: the possible role of the pancreatic D‐cell in the normal and diabetic states. Diabetes 26: 241–244, 1977.
 892. Unger, R. H., and L. Orci. Glucagon and the A cell: physiology and pathophysiology. N. Engl. J. Med. 304: 1518–1524, 1981.
 893. Unger, R. H., and L. Orci. Glucagon secretion, alpha cell metabolism, and glucagon action. In: Endocrinology, edited by L. J. DeGroot, M. Besser, H. G. Burger, L. J. Jameson, D. L. Loriaux, J. C. Marshall, W. D. Odell, J. T. Potts, Jr., and A. H. Rubenstein. Philadelphia: Saunders, 1995, p. 1337–1353.
 894. Unson, C. G., D., Andreu, E. M. Gurzenda, and R. B. Merrifield. Synthetic peptide antagonists of glucagon. Proc. Natl. Acad. Sci. U.S.A. 84: 4083–4087, 1987.
 895. Unson, C. G., A. N. Cypess, H. N. Kim, P. K. Goldsmith, C. J. Carruthers, R. B. Merifield, and T. P. Sakmar. Characterization of deletion and truncation mutants of the rat glucagon receptor. Seven transmembrane segments are necessary for receptor transport to the plasma membrane and glucagon binding. J. Biol Chem. 270: 27720–27727, 1995.
 896. Unson, C. G., A. N., Cypess, C.‐R. Wu, P. K. Goldsmith, R. B. Merrifield, and T. P. Sakmar. Antibodies against specific extracellular epitopes of the glucagon receptor block glucagon binding. Proc. Natl. Acad. Sci. U.S.A. 93: 310–315, 1996.
 897. Unson, C. G., E. M., Gurzenda, K. Iwasa, and R. B. Merrifield. Glucagon antagonists: contribution to binding and activity of the amino‐terminal sequence 1–5, position 12, and the putative α‐helical segment 19–27. J. Biol. Chem. 264: 789–794, 1989.
 898. Unson, C. G., E. M., Gurzenda, and R. B. Merrifield. Biological activities of des‐His1[Glu9]glucagon amide, a glucagon antagonist. Peptides 10: 1171–1177, 1989.
 899. Unson, C. G., D., Macdonald, and R. B. Merrifield. The role of the histidine in glucagon action. Arch. Biochem. Biophys. 300: 747–750, 1993.
 900. Unson, C. G., D., Macdonald, K. Ray, T. L. Durrah, and R. B. Merrifield. Position 9 replacement analogs of glucagon uncouple biological activity and receptor binding. J. Biol. Chem. 266: 2763–2766, 1991.
 901. Unson, C. G., and R. B. Merrifield. Identification of an essential serine residue in glucagon: implication for an active site triad. Proc. Natl. Acad. Sci. U.S.A. 91: 454–458, 1994.
 902. Upchurch, B. H., G. W., Aponte, and A. B. Leiter. Expression of peptide YY in all four islet types in the developing mouse pancreas suggests a common peptide YY‐producing progenitor. Development 120: 245–252, 1994.
 903. Usdin, T. B., E., Mezey, and D. C. Button. Gastric inhibitory polypeptide receptor, a member of the secretin‐vasoactive intestinal peptide receptor family, is widely distributed in peripheral organs and the brain. Endocrinology 133: 2861–2870, 1993.
 904. Uttenthal, L. O., and E. Blazquez. Characterization of high‐affinity receptors for truncated glucagon‐like peptide‐1 in rat gastric glands. FEBS Lett. 262: 139–141, 1990.
 905. Uttenthal, L. O., A., Toledano, and E. Blazquez. Autoradiographic localization of receptors for glucagon‐like peptide‐1(7–36)amide in rat brain. Neuropeptides 21: 143–146, 1992.
 906. Valverde, I., M., Ghiglione, R. Matesanz, and S. Casado. Chromatographic pattern of gut glucagon‐like immunoreactivity (GLI) in plasma before and after glucose absorption. Horm. Metab. Res. 11: 343–346, 1979.
 907. Valverde, I., E., Merida, E. Delgado, M. A. Trapote, and M. L. Villanueva‐Penacarrillo. Presence and characterization of glucagon‐like peptide‐1(7–36)amide receptors in solubilized membranes of rat adipose tissue. Endocrinology 132: 75–79, 1993.
 908. Valverde, I., M., Morales, F. Clemente, M. I. Lopez‐Delgado, E. Delgado, A. Perea, and M. L. Villanueva‐Penacarrillo. Glucagon‐like peptide 1: a potent glycogenic hormone. FEBS Lett. 349: 313–316, 1994.
 909. Valverde, I., D., Rigopoulou, J. Marco, G. R. Faloona, and R. H. Unger. Characterization of glucagon‐like immunoreactivity (GLI). Diabetes 19: 614–623, 1970.
 910. Valverde, I., M. L., Villanueva, I. Lonzano, and J. Marco. Presence of glucagon immunoreactivity in the globulin fraction of human plasma (“big plasma glucagon”). J. Clin. Endocrinol. Metab. 39: 1020–1028, 1974.
 911. Vance, J. E., A. E., Kitabchi, K. D. Buchanan, and R. H. Williams. Effect of adrenalectomy on glucagon and insulin release from isolated islets of Langerhans. Clin. Res. 16: 131, 1968.
 912. Van Delft, J., L. O. Uttenthal, O. G. Hermida, T. Fontela, and M. Ghiglione. Identification of amidated forms of GLP‐1 in rat tissues using a highly sensitive radioimmunoassay. Regul. Pept. 70: 191–198, 1997.
 913. Van Hoorn, W. A., A. Vinik, and A. Hickman. The metabolic clearance of endogenous immunoreactive glucagon in pancreatectomized and sham operated pigs. Endocrinology 103: 1084–1089, 1978.
 914. VanSchravendijk, C. G. H., A., Foriers, E. L. Hooghe‐Peters, V. Rogiers, P. DeMeyts, C. Sodoyez, and D. G. Pipeleers. Pancreatic hormone receptors on islet cells. Endocrinology 117: 841–848, 1985.
 915. Van Tine, D. A., B. Y. Azizeh, D. Trivedi, J. R. Phelps, M. D. Houslay, D. G. Johnson, and V. J. Hruby. Low level cyclic adenosine 3′,5′‐monophosphate accumlation analysis of [des‐His1.des‐Phe6,Glu9]glucagon‐NH2 identifies glucagon antagonists from weak partial agonists/antagonists. Endocrinology 137: 3316–3322, 1996.
 916. Veneman, T. A., A., Mitrakou, M. Mokan, P. Cryer, and J. Gerich. Effect of hyperketonemia and hyperlactacidemia on symptoms, cognitive dysfunction, and counterregulatory hormone responses during hypoglycemia in normal humans. Diabetes 43: 1311–1317, 1994.
 917. Verchere, C. B., S., Kowalyk, D. J. Koerker, D. G. Baskin, and G. J. Taborsky, Jr.. Evidence that galanin is a parasympathetic, rather than a sympathetic, neurotransmitter in the baboon pancreas. Regul. Pept. 67: 93–101, 1996.
 918. Verchere, C. B., S., Kowalyk, G. H. Shen, M. R. Broown, M. W. Schwartz, D. G. Baskin, and G. J. Taborsky, Jr.. Major species variation in the expression of galanin messenger ribonucleic acid in mammalian celiac ganglion. Endocrinology 135: 1052–1059, 1994.
 919. Verdonk, C. A., R. A., Rizza, R. L. Nelson, V. L. Go, J. E. Gerich, and F. J. Service. Interaction of fat‐stimulated gastric inhibitory polypeptide on pancreatic alpha and beta cell function. J. Clin. Invest. 65: 1119–1125, 1980.
 920. Vidnes, J., and S. Oyassaeter. Glucagon deficiency causing severe neonatal hypoglycemia in a patient with normal insulin secretion. Pediatr. Res. 11: 943–949, 1977.
 921. Villanueva‐Penacarrillo, M. L., A. I., Alcantara, F. Clemente, E. Delgado, and I. Valverde. Potent glycogenic effect of GLP‐1(7–36)amide in rat skeletal muscle. Diabetologia 37: 1163–1166, 1994.
 922. Villanueva‐Penacarrillo, M. L., E., Delgado, M. A. Trapote, A. Alcantara, F. Clemente, M. A. Luque, A. Perea, and I. Valverde. Glucagon‐like peptide‐1 binding to rat hepatic membranes. J. Endocrinol. 146: 183–189, 1995.
 923. Violett, C., G., Prévost, E. Maubert, A. Faivre‐Bauman, R. Gardette, C. Kordon, C. Loudes, A. Slama, and J. Epelbaum. Molecular pharmacology of somatostatin receptors. Fundam. Clin. Pharmacol. 9: 107–113, 1995.
 924. Waeber, G., N., Thompson, P. Nicod, and C. Bonny. Transcriptional activation of the GLUT2 gene by the IPF‐1/STF‐1/IDX‐1 homeobox factor. Mol. Endocrinol. 10: 1327–1334, 1996.
 925. Wahren, J., P., Felig, and L. Hagenfeldt. Physical exercise and fuel homeostasis in diabetes mellitus. Diabetologia 14: 213–222, 1978.
 926. Walter, R. M., J., Dudl, J. P. Palmer, and J. W. Ensinck. The effect of adrenergic blockade on the glucagon responses to starvation and hypoglycemia in man. J. Clin. Invest. 54: 1214–1220, 1974.
 927. Wang, M., and D. J. Drucker. The LIM domain homeobox gene isl‐1 is a positive regulator of islet cell–specific proglucagon gene transcription. J. Biol. Chem. 270: 12646–12652, 1995.
 928. Wang, Y., H. K., Kole, C. Montrose‐Rafizadeh, R. Perfetti, M. Bernier, and J. M. Egan. Regulation of glucose transporters and hexose uptake in 3T3‐L1 adipocytes: glucagon‐like peptide‐1 and insulin interactions. J. Mol. Endocrinol. 19: 241–248, 1997.
 929. Watada, H., Y., Kajimoto, Y. Umayahara, T. Matsuoka, H. Kaneto, Y. Fujitani, T. Kamada, R. Kawamori, and Y. Yamasaki. The human glucokinase gene β‐cell‐type promoter: an essential role of insulin promoter factor 1/PDX‐1 in its activation in HIT‐T15 cells. Diabetes 45: 1478–1488, 1996.
 930. Wei, Y., and S. Mojsov. Tissue specific expression of the human receptor for glucagon‐like peptide‐1. Brain, heart and pancreatic forms have the same deduced amino acid sequences. FEBS Lett. 358: 219–224, 1995.
 931. Weigle, D. S.. Pulsatile secretion of fuel‐regulatory hormones. Diabetes 36: 764–775, 1987.
 932. Weinges, K. F.. Influence of a prolonged action glucagon on blood sugars, inorganic serum phosphate, and the total amino acids in serum. Arch. Exp. Pathol. Pharmakol. 237: 22–26, 1959.
 933. Weinges, K. F.. Der Einfluss von Glukagon und Insulin auf den Stoffwecshel der nicht versterten Fettsäuren am isolierten Fettgewebe der Ratte in vitro. Klin. Wochenschr. 39: 293–298, 1961.
 934. Weinges, K. F., E., Wünsch, G. Biro, H. Ketti, and M. Mitzuno. The immunologic reactivity and biological activity of synthetic glucagon. Diabetologia 5: 97–100, 1969.
 935. Weir, G. C., R. F., Atkins, and D. B. Martin. Glucagon secretion from the perfused rat pancreas following acute and chronic streptozotocin. Metabolism 25: 1519–1521, 1976.
 936. Weir, G. C., and S. Bonner‐Weir. Islets of Langerhans: the puzzle of intraislet interactions and their relevance to diabetes. J. Clin. Invest. 85: 983–987, 1990.
 937. Weir, G. C., S. D., Knowlton, and D. B. Martin. Glucagon secretion from the perfused rat pancreas. Studies with glucose and catecholamines. J. Clin. Invest. 54: 1403–1412, 1974.
 938. Weir, G. C., S., Mojsov, G. K. Hendrick, and J. F. Habener. Glucagon‐like peptide 1(7–37) actions on the endocrine pancreas. Diabetes 38: 338–342, 1989.
 939. Wessels, N. K., and J. H. Cohen. Early pancreas organogenesis: morphogenesis, tissue interactions, and mass effects. Dev. Biol. 15: 237–270, 1967.
 940. Wesslen, N., D. Pipeleers, M. Van de Winkel, P. Rorsman, and B. Hellman. Glucose stimulates the entry of Ca2+ into the insulin‐producing beta cells but not into the glucagon‐producing alpha 2 cells. Acta Physiol. Scand. 131: 230–234, 1987.
 941. Wettergren, A., P., Maina, S. Boesby, and J. J. Holst. Glucagon‐like peptide‐1 7–36 amide and peptide YY have additive inhibitory effect on gastric acid secretion in man. Scand. J. Gastroenterol. 32: 552–555, 1997.
 942. Wettergren, A., H., Petersen, C. Ørskov, J. Christiansen, S. P. Sheikh, and J. J. Holst. Glucagon‐like peptide‐1 (GLP‐1) 7–36 amide and peptide YY from the L cell in the ileal mucosa are potent inhibitors of vagally induced gastric acid in man. Scand. J. Gastroenterol. 29: 501–505, 1994.
 943. Wettergren, A., B., Schjoldager, P. E Mortensen, J. Myhre, J. Christiansen, and J. J. Holst. Truncated GLP‐1 (proglucagon 78–107 amide) inhibits gastric and pancreatic functions in man. Dig. Dis. Sci. 38: 665–673, 1993.
 944. Wettergren, A., M., Wojdemann, S. Meisner, F. Stadil, and J. J. Holst. The inhibitory effect of glucagon‐like peptide‐1 (GLP‐1) 7–36 amide on gastric acid secretion in humans depends on an intact vagal innervation. Gut 40: 597–601, 1997.
 945. Wheeler, M. B., M., Lu, J. S. Dillon, X. H. Leng, C. Chen, and A. E. Boyd III.. Functional expression of the rat glucagon‐like peptide‐1 (GLP‐1) receptor. Evidence for coupling to adenylyl cyclase and phospholipase. Endocrinology 133: 57–62, 1993.
 946. Wider, M. D., T., Matsuyama, and J. C. Dunbar. Elevated gut glucagon‐like immunoreactive material in human and experimental diabetes and its suppression by somatostatin. Metabolism 25 (Suppl. 1): 1487–1489, 1976.
 947. Widmann, C., W., Dolci, and B. Thorens. Internalization and homologous desensitization of the GLP‐1 receptor depend upon phosphorylation of the receptor carboxy tail at the same three sites. Mol. Endocrinol. 11: 1094–1102, 1997.
 948. Wilkinson, D. S.. Necrolytic migratory erythema with carcinoma of the pancreas. Trans St. John's Hosp. Dermatol. Soc. 59: 244–248, 1973.
 949. Willms, B., J., Werner, J. J. Holst, C. Orskov, W. Creutzfeld, and M. A. Nauck. Gastric emptying, glucose responses and insulin secretion after a liquid test meal: effects of exogenous glucagon‐like peptide‐1 (GLP‐1) (7–36)amide in type 2 (non‐insulin‐dependent) diabetic patients. J. Clin. Endocrinol. Metab. 81: 327–332, 1996.
 950. Wilmen, A., R., Göke, and B. Göke. The isolated N‐terminal extracellular domain of the glucagon‐like peptide‐1 (GLP‐1) receptor has intrinsic binding activity. FEBS Lett. 398: 43–47, 1996.
 951. Wise, J. K., R., Hendler, and P. Felig. Influence of glucocorticoids on glucagon secretion and plasma amino acid concentrations in man. J. Clin. Invest. 52: 2774–2782, 1973.
 952. Wojcikowski, C., V., Maier, R. Fussganger, and E. F. Pfeiffer. Release of glucagon‐like immunoreactive material (GLI) from the isolated perfused jejunum of normal and diabetic rats. Horm. Metab. Res. 17: 105–106, 1985.
 953. Wolfe, M. M., M. O., Boylan, T. J. Kieffer, and C.‐C. Tseng. Glucose‐dependent insulinotropic polypeptide (GIP): incretin vs. enterogastrone. In: Gastrointestinal Endo, edited by G. H. Greeley, Jr. Totowa, NJ: Humana, 1999, p. 439–466.
 954. Wollheim, C. B., B., Blondel, A. E. Renold, and G. W. Sharp. Calcium induced glucagon release in monolayer culture of the endocrine pancreas. Studies with inophore A23187. Diabetologia 12: 287–294, 1976.
 955. Wollheim, C. B., B., Blondel, A. E Renold, and G. W. Sharp. Stimulatory and inhibitory effects of cyclic AMP on pancreatic glucagon release from monolayer cultures and the controlling role of calcium. Diabetologia 12: 269–277, 1976.
 956. Wollheim, C. B., B., Blondel, A. E Renold, and G. W. Sharp. Somatostatin inhibition of pancreatic glucagon release from monolayer cultures and interactions with calcium. Endocrinology 101: 911–919, 1977.
 957. Woods, S. C., and D. Porte. Neural control of the endocrine pancreas. Physiol. Rev. 54: 596–619, 1974.
 958. Wright, D. E., and M. Rodbell. Glucagon 1–6 binds to the glucagon receptor and activates hepatic adenylate cyclase. J. Biol. Chem. 254: 268–269, 1979.
 959. Wünsch, E.. Totalsynthese des pankreas‐hormons glucagon. Z. Naturforsch. [C] 22: 1269–1276, 1967.
 960. Wünsch, E., E., Jaeger, and R. Scharf. Zur Synthese des Glucagons. [Pure Preparation of synthetic glucagon]. XIX. Reindarstellung des synthetischen Glucagons. Chem. Ber. 101: 3664–3670, 1968.
 961. Yalow, R. S., and S. A. Berson. Immunoassay of endogenous plasma insulin in man. J. Clin. Invest. 39: 1157–1165, 1960.
 962. Yamada, T., and T. Chiba. Somatostatin. In: Handbook of Physiology. The Gastrointestinal System, Neural and Endocrine Biology, edited by S. G. Schultz and G. M. Makhlouf. Washington D.C. Am. Physiol. Soc., 1989, sect. 6, vol. II, p. 431–453.
 963. Yamada, Y., S. R., Post, K. Wang, H. S. Tager, G. I. Bell, and S. Seino. Cloning and functional characterization of a family of human and mouse somatostatin receptors expressed in brain, gastrointestinal tract, and kidney. Proc. Natl. Acad. Sci. U.S.A. 89: 251–255, 1992.
 964. Yamaguchi, N., R., Briand, and R. Gaspo. Effect of functional adrenalectomy on glucagon secretion and circulating catecholamines during insulin hypoglycemia in the dog. Can. J. Physiol. Pharmacol. 68: 1183–1188, 1990.
 965. Yamato, E., H., Ikegami, K. Takekawa, T. Fujisawa, Y. Nakagawa, Y. Hamada, H. Ueda, and T. Ogihara. Tissue‐specific and glucose‐dependent expression of receptor genes for glucagon and glucagon‐like peptide‐1 (GLP‐1). Horm. Metab. Res. 29: 56–59, 1997.
 966. Yokota, C., K., Kawai, S. Ohashi, Y. Watanabe, S. Suzuki, and K. Yamashita. Stimulatory effects of pituitary adenylate cyclase–activating polypeptide (PACAP) on insulin and glucagon release from the isolated perfused rat pancreas. Acta Endocrinol. (Copenh.) 129: 473–479, 1993.
 967. Yoo‐Warren, H., A. G., Willse, N. Hancock, J. Hull, M. McCaleb, and J. M. Livingston. Regulation of rat glucagon receptor receptor expression. Biochem. Biophys. Res. Commun. 205: 347–353, 1994.
 968. Zechel, C., D., Trivedi, and V. J. Hruby. Synthetic glucagon antagonists and partial agonists. Int. J. Pept. Prot. Res. 38: 131–138, 1991.
 969. Zhang, Y., I. T. E., Cook, A. T. Hattersly, R. Firt, P. I. Saker, M. Warren‐Perry, M. Stoffer, and R. C. Turner. Non‐linkage of the glucagon‐like peptide receptor gene with maturity onset diabetes of the young. Diabetologia 37: 721–724, 1994.
 970. Zunz, E., and J. LaBarre. Contributions a l'étude des variations physiologiques de la secretion interne du pancreas: relations entre les secretions externe et interne du pancreas. Arch. Int. Physiol. Biochim. 31: 20–44, 1929.

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Article Title: Glucagon and Glucagon‐like Peptide Production and Degradation
 

How to Cite

Timothy J. Kieffer, Mehboob A. Hussain, Joel F. Habener. Glucagon and Glucagon‐like Peptide Production and Degradation. Compr Physiol 2011, Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism: 197-265. First published in print 2001. doi: 10.1002/cphy.cp070208