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Substrate Control of Insulin Release

Christopher B. Newgard, Franz M. Matschinsky

10.1002/cphy.cp070205

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 Cellular Architecture of Pancreatic Islets
2 General Aspects of Nutrient Sensing
3 The Glucose‐Sensing System: A Basic Model
4 Adenine Nucleotides and the Adenosine Triphosphate–Sensitive Potassium Channel
5 Regulation of Glucose Metabolism in Islet β Cells
6 Molecular Manipulations of Glucose‐Phosphorylating Activity in Islet Cells
7 Similarities and Differences in the Metabolic Environment of β Cells and Hepatocytes
8 Role of Lipids in Regulation of Insulin Secretion
9 Fundamentals of Amino Acid‐Stimulated Insulin Release
10 Mitochondria as Metabolic Signal Generators of Fuel‐Stimulated β Cells
11 Outlook
Figure 1. Figure 1.

A: Hierarchy of metabolic signaling pathways in pancreatic β cells. Four aspects of stimulus–secretion coupling in pancreatic β cells are highlighted in A–D. A: Role of adenine nucleotides as metabolic coupling factors in glucose‐stimulated insulin release. Three sites are critical in this process: site 1 is located at the lower end of the glycolytic pathway, leading to the net generation of two ATP's for every glucose molecule; site 2 is associated with the transfer of cytosolic reducing equivalents to mitochondria via hydrogen shuttles using the glycero‐P shuttle as an example; site 3 refers to the generation of GTP and reducing equivalents NADH and FADH2 by the citric acid cycle. Electron transport and oxidative phosphorylation are quantitatively more important for total ATP production of the cell than substrate phosphorylation in glycolysis. However, this does not preclude a special role of glycolytic ATP for glucose‐induced insulin release. The potassium channel and processes involved in exocytosis are important targets of this signaling pathway.

B: Putative role of lipid‐related metabolic coupling factors proposed to complement adenine nucleotides. Citrate and, secondarily, malonyl CoA are examples of mitochondrial coupling factors other than ATP. Protein kinase C and exocytosis per se are plausible targets of this signaling pathway.

C: Glucose regulation of glutaminolysis and insulin secretion. The interaction between glucose metabolism and glutaminolysis is depicted. The adenosine nucleotide–sensitive K+ channel and the voltage–sensitive Ca+ channel are indicated. ATP, Acyl‐CoA, and Ca2+ converge as signals to increase insulin release.

D: Interplay of neuroendocrine regulation and drug actions with fundamental processes of fuel‐stimulated insulin release (for further discussion, see ref. 83). Neural and endocrine factors may act by enhancing, rather than initiating, intracellular signaling pathways involved in substrate‐controlled insulin release as expression of the basic secretory competence of β cells. Glucose per se activates the adenylate cyclase–protein kinase A, phospholipase C–protein kinase C, and Ca2+–calmodulin‐dependent protein kinase signaling pathways. The effect of glucose on cytosolic Ca2+ is central for understanding this three‐pronged activation process. The glucose‐induced rise of cAMP is Ca2+‐dependent, as is the glucose‐induced elevation of diacylglycerol and inositol triphosphate. The detailed mechanisms by which elevated cytosolic Ca2+ activates adenylate cyclase or phospholipase C are not understood. It is, for example, not known whether specific isoforms of these two enzymes are involved or whether trimeric G proteins participate in the activation process initiated by an intracellular Ca2+ signal. Acetycholine and glucagon‐like peptide 1, through activation of their respective receptors, greatly augment the cAMP, inositol triphosphate, and diacylglycerol responses but do not initiate insulin release in the absence of glucose because substrate‐induced ATP provision is an absolute requirement for initiation of secretion. Other mitochondrial coupling factors may be needed (B). AC, adenylate cyclase; ACL, acetylcholine; Ca2+/PKC, protein kinase C; CPT, carnitine palmityl CoA transferase; DAG, diacylglycerol; Δψ, cell membrane potential; Δp, mitochondrial proton motive force, a function of ΔpH and Δψ across the mitochondrial membrane; DHAP, dihydroxyacetone‐phosphate; 1,3DPGA, 1,3‐glycerate bisphosphate; F1,6P2, fructose‐1,6‐bisphosphate; FFA, free fatty acids; GAP, glyceraldehyde‐3‐phosphate; Gi, Gq, and Gs, trimeric G proteins; GK, glucokinase; GLP‐1, glucagon‐like peptide 1; Glut‐2, glucose transporter 2; G6P, glucose‐6‐phosphate; GOP, α‐glycerophosphate; IP3, inositol triphosphate; OAA, oxalacetate; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; Pi, inorganic phosphate; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; PKCaCM, calcium–calmodulin‐dependent protein kinase; PL, phospholipids; SUR, sulfonylurea receptor; TG, triglycerides.
Figure 2. Figure 2.

A: Hierarchy of metabolic signaling pathways in pancreatic β cells. Four aspects of stimulus–secretion coupling in pancreatic β cells are highlighted in A–D. A: Role of adenine nucleotides as metabolic coupling factors in glucose‐stimulated insulin release. Three sites are critical in this process: site 1 is located at the lower end of the glycolytic pathway, leading to the net generation of two ATP's for every glucose molecule; site 2 is associated with the transfer of cytosolic reducing equivalents to mitochondria via hydrogen shuttles using the glycero‐P shuttle as an example; site 3 refers to the generation of GTP and reducing equivalents NADH and FADH2 by the citric acid cycle. Electron transport and oxidative phosphorylation are quantitatively more important for total ATP production of the cell than substrate phosphorylation in glycolysis. However, this does not preclude a special role of glycolytic ATP for glucose‐induced insulin release. The potassium channel and processes involved in exocytosis are important targets of this signaling pathway.

B: Putative role of lipid‐related metabolic coupling factors proposed to complement adenine nucleotides. Citrate and, secondarily, malonyl CoA are examples of mitochondrial coupling factors other than ATP. Protein kinase C and exocytosis per se are plausible targets of this signaling pathway.

C: Glucose regulation of glutaminolysis and insulin secretion. The interaction between glucose metabolism and glutaminolysis is depicted. The adenosine nucleotide–sensitive K+ channel and the voltage–sensitive Ca+ channel are indicated. ATP, Acyl‐CoA, and Ca2+ converge as signals to increase insulin release.

D: Interplay of neuroendocrine regulation and drug actions with fundamental processes of fuel‐stimulated insulin release (for further discussion, see ref. 83). Neural and endocrine factors may act by enhancing, rather than initiating, intracellular signaling pathways involved in substrate‐controlled insulin release as expression of the basic secretory competence of β cells. Glucose per se activates the adenylate cyclase–protein kinase A, phospholipase C–protein kinase C, and Ca2+–calmodulin‐dependent protein kinase signaling pathways. The effect of glucose on cytosolic Ca2+ is central for understanding this three‐pronged activation process. The glucose‐induced rise of cAMP is Ca2+‐dependent, as is the glucose‐induced elevation of diacylglycerol and inositol triphosphate. The detailed mechanisms by which elevated cytosolic Ca2+ activates adenylate cyclase or phospholipase C are not understood. It is, for example, not known whether specific isoforms of these two enzymes are involved or whether trimeric G proteins participate in the activation process initiated by an intracellular Ca2+ signal. Acetycholine and glucagon‐like peptide 1, through activation of their respective receptors, greatly augment the cAMP, inositol triphosphate, and diacylglycerol responses but do not initiate insulin release in the absence of glucose because substrate‐induced ATP provision is an absolute requirement for initiation of secretion. Other mitochondrial coupling factors may be needed (B). AC, adenylate cyclase; ACL, acetylcholine; Ca2+/PKC, protein kinase C; CPT, carnitine palmityl CoA transferase; DAG, diacylglycerol; Δψ, cell membrane potential; Δp, mitochondrial proton motive force, a function of ΔpH and Δψ across the mitochondrial membrane; DHAP, dihydroxyacetone‐phosphate; 1,3DPGA, 1,3‐glycerate bisphosphate; F1,6P2, fructose‐1,6‐bisphosphate; FFA, free fatty acids; GAP, glyceraldehyde‐3‐phosphate; Gi, Gq, and Gs, trimeric G proteins; GK, glucokinase; GLP‐1, glucagon‐like peptide 1; Glut‐2, glucose transporter 2; G6P, glucose‐6‐phosphate; GOP, α‐glycerophosphate; IP3, inositol triphosphate; OAA, oxalacetate; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; Pi, inorganic phosphate; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; PKCaCM, calcium–calmodulin‐dependent protein kinase; PL, phospholipids; SUR, sulfonylurea receptor; TG, triglycerides.
Figure 3. Figure 3.

A: Hierarchy of metabolic signaling pathways in pancreatic β cells. Four aspects of stimulus–secretion coupling in pancreatic β cells are highlighted in A–D. A: Role of adenine nucleotides as metabolic coupling factors in glucose‐stimulated insulin release. Three sites are critical in this process: site 1 is located at the lower end of the glycolytic pathway, leading to the net generation of two ATP's for every glucose molecule; site 2 is associated with the transfer of cytosolic reducing equivalents to mitochondria via hydrogen shuttles using the glycero‐P shuttle as an example; site 3 refers to the generation of GTP and reducing equivalents NADH and FADH2 by the citric acid cycle. Electron transport and oxidative phosphorylation are quantitatively more important for total ATP production of the cell than substrate phosphorylation in glycolysis. However, this does not preclude a special role of glycolytic ATP for glucose‐induced insulin release. The potassium channel and processes involved in exocytosis are important targets of this signaling pathway.

B: Putative role of lipid‐related metabolic coupling factors proposed to complement adenine nucleotides. Citrate and, secondarily, malonyl CoA are examples of mitochondrial coupling factors other than ATP. Protein kinase C and exocytosis per se are plausible targets of this signaling pathway.

C: Glucose regulation of glutaminolysis and insulin secretion. The interaction between glucose metabolism and glutaminolysis is depicted. The adenosine nucleotide–sensitive K+ channel and the voltage–sensitive Ca+ channel are indicated. ATP, Acyl‐CoA, and Ca2+ converge as signals to increase insulin release.

D: Interplay of neuroendocrine regulation and drug actions with fundamental processes of fuel‐stimulated insulin release (for further discussion, see ref. 83). Neural and endocrine factors may act by enhancing, rather than initiating, intracellular signaling pathways involved in substrate‐controlled insulin release as expression of the basic secretory competence of β cells. Glucose per se activates the adenylate cyclase–protein kinase A, phospholipase C–protein kinase C, and Ca2+–calmodulin‐dependent protein kinase signaling pathways. The effect of glucose on cytosolic Ca2+ is central for understanding this three‐pronged activation process. The glucose‐induced rise of cAMP is Ca2+‐dependent, as is the glucose‐induced elevation of diacylglycerol and inositol triphosphate. The detailed mechanisms by which elevated cytosolic Ca2+ activates adenylate cyclase or phospholipase C are not understood. It is, for example, not known whether specific isoforms of these two enzymes are involved or whether trimeric G proteins participate in the activation process initiated by an intracellular Ca2+ signal. Acetycholine and glucagon‐like peptide 1, through activation of their respective receptors, greatly augment the cAMP, inositol triphosphate, and diacylglycerol responses but do not initiate insulin release in the absence of glucose because substrate‐induced ATP provision is an absolute requirement for initiation of secretion. Other mitochondrial coupling factors may be needed (B). AC, adenylate cyclase; ACL, acetylcholine; Ca2+/PKC, protein kinase C; CPT, carnitine palmityl CoA transferase; DAG, diacylglycerol; Δψ, cell membrane potential; Δp, mitochondrial proton motive force, a function of ΔpH and Δψ across the mitochondrial membrane; DHAP, dihydroxyacetone‐phosphate; 1,3DPGA, 1,3‐glycerate bisphosphate; F1,6P2, fructose‐1,6‐bisphosphate; FFA, free fatty acids; GAP, glyceraldehyde‐3‐phosphate; Gi, Gq, and Gs, trimeric G proteins; GK, glucokinase; GLP‐1, glucagon‐like peptide 1; Glut‐2, glucose transporter 2; G6P, glucose‐6‐phosphate; GOP, α‐glycerophosphate; IP3, inositol triphosphate; OAA, oxalacetate; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; Pi, inorganic phosphate; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; PKCaCM, calcium–calmodulin‐dependent protein kinase; PL, phospholipids; SUR, sulfonylurea receptor; TG, triglycerides.
Figure 4. Figure 4.

A: Hierarchy of metabolic signaling pathways in pancreatic β cells. Four aspects of stimulus–secretion coupling in pancreatic β cells are highlighted in A–D. A: Role of adenine nucleotides as metabolic coupling factors in glucose‐stimulated insulin release. Three sites are critical in this process: site 1 is located at the lower end of the glycolytic pathway, leading to the net generation of two ATP's for every glucose molecule; site 2 is associated with the transfer of cytosolic reducing equivalents to mitochondria via hydrogen shuttles using the glycero‐P shuttle as an example; site 3 refers to the generation of GTP and reducing equivalents NADH and FADH2 by the citric acid cycle. Electron transport and oxidative phosphorylation are quantitatively more important for total ATP production of the cell than substrate phosphorylation in glycolysis. However, this does not preclude a special role of glycolytic ATP for glucose‐induced insulin release. The potassium channel and processes involved in exocytosis are important targets of this signaling pathway.

B: Putative role of lipid‐related metabolic coupling factors proposed to complement adenine nucleotides. Citrate and, secondarily, malonyl CoA are examples of mitochondrial coupling factors other than ATP. Protein kinase C and exocytosis per se are plausible targets of this signaling pathway.

C: Glucose regulation of glutaminolysis and insulin secretion. The interaction between glucose metabolism and glutaminolysis is depicted. The adenosine nucleotide–sensitive K+ channel and the voltage–sensitive Ca+ channel are indicated. ATP, Acyl‐CoA, and Ca2+ converge as signals to increase insulin release.

D: Interplay of neuroendocrine regulation and drug actions with fundamental processes of fuel‐stimulated insulin release (for further discussion, see ref. 83). Neural and endocrine factors may act by enhancing, rather than initiating, intracellular signaling pathways involved in substrate‐controlled insulin release as expression of the basic secretory competence of β cells. Glucose per se activates the adenylate cyclase–protein kinase A, phospholipase C–protein kinase C, and Ca2+–calmodulin‐dependent protein kinase signaling pathways. The effect of glucose on cytosolic Ca2+ is central for understanding this three‐pronged activation process. The glucose‐induced rise of cAMP is Ca2+‐dependent, as is the glucose‐induced elevation of diacylglycerol and inositol triphosphate. The detailed mechanisms by which elevated cytosolic Ca2+ activates adenylate cyclase or phospholipase C are not understood. It is, for example, not known whether specific isoforms of these two enzymes are involved or whether trimeric G proteins participate in the activation process initiated by an intracellular Ca2+ signal. Acetycholine and glucagon‐like peptide 1, through activation of their respective receptors, greatly augment the cAMP, inositol triphosphate, and diacylglycerol responses but do not initiate insulin release in the absence of glucose because substrate‐induced ATP provision is an absolute requirement for initiation of secretion. Other mitochondrial coupling factors may be needed (B). AC, adenylate cyclase; ACL, acetylcholine; Ca2+/PKC, protein kinase C; CPT, carnitine palmityl CoA transferase; DAG, diacylglycerol; Δψ, cell membrane potential; Δp, mitochondrial proton motive force, a function of ΔpH and Δψ across the mitochondrial membrane; DHAP, dihydroxyacetone‐phosphate; 1,3DPGA, 1,3‐glycerate bisphosphate; F1,6P2, fructose‐1,6‐bisphosphate; FFA, free fatty acids; GAP, glyceraldehyde‐3‐phosphate; Gi, Gq, and Gs, trimeric G proteins; GK, glucokinase; GLP‐1, glucagon‐like peptide 1; Glut‐2, glucose transporter 2; G6P, glucose‐6‐phosphate; GOP, α‐glycerophosphate; IP3, inositol triphosphate; OAA, oxalacetate; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; Pi, inorganic phosphate; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; PKCaCM, calcium–calmodulin‐dependent protein kinase; PL, phospholipids; SUR, sulfonylurea receptor; TG, triglycerides.


Figure 1.

A: Hierarchy of metabolic signaling pathways in pancreatic β cells. Four aspects of stimulus–secretion coupling in pancreatic β cells are highlighted in A–D. A: Role of adenine nucleotides as metabolic coupling factors in glucose‐stimulated insulin release. Three sites are critical in this process: site 1 is located at the lower end of the glycolytic pathway, leading to the net generation of two ATP's for every glucose molecule; site 2 is associated with the transfer of cytosolic reducing equivalents to mitochondria via hydrogen shuttles using the glycero‐P shuttle as an example; site 3 refers to the generation of GTP and reducing equivalents NADH and FADH2 by the citric acid cycle. Electron transport and oxidative phosphorylation are quantitatively more important for total ATP production of the cell than substrate phosphorylation in glycolysis. However, this does not preclude a special role of glycolytic ATP for glucose‐induced insulin release. The potassium channel and processes involved in exocytosis are important targets of this signaling pathway.

B: Putative role of lipid‐related metabolic coupling factors proposed to complement adenine nucleotides. Citrate and, secondarily, malonyl CoA are examples of mitochondrial coupling factors other than ATP. Protein kinase C and exocytosis per se are plausible targets of this signaling pathway.

C: Glucose regulation of glutaminolysis and insulin secretion. The interaction between glucose metabolism and glutaminolysis is depicted. The adenosine nucleotide–sensitive K+ channel and the voltage–sensitive Ca+ channel are indicated. ATP, Acyl‐CoA, and Ca2+ converge as signals to increase insulin release.

D: Interplay of neuroendocrine regulation and drug actions with fundamental processes of fuel‐stimulated insulin release (for further discussion, see ref. 83). Neural and endocrine factors may act by enhancing, rather than initiating, intracellular signaling pathways involved in substrate‐controlled insulin release as expression of the basic secretory competence of β cells. Glucose per se activates the adenylate cyclase–protein kinase A, phospholipase C–protein kinase C, and Ca2+–calmodulin‐dependent protein kinase signaling pathways. The effect of glucose on cytosolic Ca2+ is central for understanding this three‐pronged activation process. The glucose‐induced rise of cAMP is Ca2+‐dependent, as is the glucose‐induced elevation of diacylglycerol and inositol triphosphate. The detailed mechanisms by which elevated cytosolic Ca2+ activates adenylate cyclase or phospholipase C are not understood. It is, for example, not known whether specific isoforms of these two enzymes are involved or whether trimeric G proteins participate in the activation process initiated by an intracellular Ca2+ signal. Acetycholine and glucagon‐like peptide 1, through activation of their respective receptors, greatly augment the cAMP, inositol triphosphate, and diacylglycerol responses but do not initiate insulin release in the absence of glucose because substrate‐induced ATP provision is an absolute requirement for initiation of secretion. Other mitochondrial coupling factors may be needed (B). AC, adenylate cyclase; ACL, acetylcholine; Ca2+/PKC, protein kinase C; CPT, carnitine palmityl CoA transferase; DAG, diacylglycerol; Δψ, cell membrane potential; Δp, mitochondrial proton motive force, a function of ΔpH and Δψ across the mitochondrial membrane; DHAP, dihydroxyacetone‐phosphate; 1,3DPGA, 1,3‐glycerate bisphosphate; F1,6P2, fructose‐1,6‐bisphosphate; FFA, free fatty acids; GAP, glyceraldehyde‐3‐phosphate; Gi, Gq, and Gs, trimeric G proteins; GK, glucokinase; GLP‐1, glucagon‐like peptide 1; Glut‐2, glucose transporter 2; G6P, glucose‐6‐phosphate; GOP, α‐glycerophosphate; IP3, inositol triphosphate; OAA, oxalacetate; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; Pi, inorganic phosphate; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; PKCaCM, calcium–calmodulin‐dependent protein kinase; PL, phospholipids; SUR, sulfonylurea receptor; TG, triglycerides.



Figure 2.

A: Hierarchy of metabolic signaling pathways in pancreatic β cells. Four aspects of stimulus–secretion coupling in pancreatic β cells are highlighted in A–D. A: Role of adenine nucleotides as metabolic coupling factors in glucose‐stimulated insulin release. Three sites are critical in this process: site 1 is located at the lower end of the glycolytic pathway, leading to the net generation of two ATP's for every glucose molecule; site 2 is associated with the transfer of cytosolic reducing equivalents to mitochondria via hydrogen shuttles using the glycero‐P shuttle as an example; site 3 refers to the generation of GTP and reducing equivalents NADH and FADH2 by the citric acid cycle. Electron transport and oxidative phosphorylation are quantitatively more important for total ATP production of the cell than substrate phosphorylation in glycolysis. However, this does not preclude a special role of glycolytic ATP for glucose‐induced insulin release. The potassium channel and processes involved in exocytosis are important targets of this signaling pathway.

B: Putative role of lipid‐related metabolic coupling factors proposed to complement adenine nucleotides. Citrate and, secondarily, malonyl CoA are examples of mitochondrial coupling factors other than ATP. Protein kinase C and exocytosis per se are plausible targets of this signaling pathway.

C: Glucose regulation of glutaminolysis and insulin secretion. The interaction between glucose metabolism and glutaminolysis is depicted. The adenosine nucleotide–sensitive K+ channel and the voltage–sensitive Ca+ channel are indicated. ATP, Acyl‐CoA, and Ca2+ converge as signals to increase insulin release.

D: Interplay of neuroendocrine regulation and drug actions with fundamental processes of fuel‐stimulated insulin release (for further discussion, see ref. 83). Neural and endocrine factors may act by enhancing, rather than initiating, intracellular signaling pathways involved in substrate‐controlled insulin release as expression of the basic secretory competence of β cells. Glucose per se activates the adenylate cyclase–protein kinase A, phospholipase C–protein kinase C, and Ca2+–calmodulin‐dependent protein kinase signaling pathways. The effect of glucose on cytosolic Ca2+ is central for understanding this three‐pronged activation process. The glucose‐induced rise of cAMP is Ca2+‐dependent, as is the glucose‐induced elevation of diacylglycerol and inositol triphosphate. The detailed mechanisms by which elevated cytosolic Ca2+ activates adenylate cyclase or phospholipase C are not understood. It is, for example, not known whether specific isoforms of these two enzymes are involved or whether trimeric G proteins participate in the activation process initiated by an intracellular Ca2+ signal. Acetycholine and glucagon‐like peptide 1, through activation of their respective receptors, greatly augment the cAMP, inositol triphosphate, and diacylglycerol responses but do not initiate insulin release in the absence of glucose because substrate‐induced ATP provision is an absolute requirement for initiation of secretion. Other mitochondrial coupling factors may be needed (B). AC, adenylate cyclase; ACL, acetylcholine; Ca2+/PKC, protein kinase C; CPT, carnitine palmityl CoA transferase; DAG, diacylglycerol; Δψ, cell membrane potential; Δp, mitochondrial proton motive force, a function of ΔpH and Δψ across the mitochondrial membrane; DHAP, dihydroxyacetone‐phosphate; 1,3DPGA, 1,3‐glycerate bisphosphate; F1,6P2, fructose‐1,6‐bisphosphate; FFA, free fatty acids; GAP, glyceraldehyde‐3‐phosphate; Gi, Gq, and Gs, trimeric G proteins; GK, glucokinase; GLP‐1, glucagon‐like peptide 1; Glut‐2, glucose transporter 2; G6P, glucose‐6‐phosphate; GOP, α‐glycerophosphate; IP3, inositol triphosphate; OAA, oxalacetate; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; Pi, inorganic phosphate; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; PKCaCM, calcium–calmodulin‐dependent protein kinase; PL, phospholipids; SUR, sulfonylurea receptor; TG, triglycerides.



Figure 3.

A: Hierarchy of metabolic signaling pathways in pancreatic β cells. Four aspects of stimulus–secretion coupling in pancreatic β cells are highlighted in A–D. A: Role of adenine nucleotides as metabolic coupling factors in glucose‐stimulated insulin release. Three sites are critical in this process: site 1 is located at the lower end of the glycolytic pathway, leading to the net generation of two ATP's for every glucose molecule; site 2 is associated with the transfer of cytosolic reducing equivalents to mitochondria via hydrogen shuttles using the glycero‐P shuttle as an example; site 3 refers to the generation of GTP and reducing equivalents NADH and FADH2 by the citric acid cycle. Electron transport and oxidative phosphorylation are quantitatively more important for total ATP production of the cell than substrate phosphorylation in glycolysis. However, this does not preclude a special role of glycolytic ATP for glucose‐induced insulin release. The potassium channel and processes involved in exocytosis are important targets of this signaling pathway.

B: Putative role of lipid‐related metabolic coupling factors proposed to complement adenine nucleotides. Citrate and, secondarily, malonyl CoA are examples of mitochondrial coupling factors other than ATP. Protein kinase C and exocytosis per se are plausible targets of this signaling pathway.

C: Glucose regulation of glutaminolysis and insulin secretion. The interaction between glucose metabolism and glutaminolysis is depicted. The adenosine nucleotide–sensitive K+ channel and the voltage–sensitive Ca+ channel are indicated. ATP, Acyl‐CoA, and Ca2+ converge as signals to increase insulin release.

D: Interplay of neuroendocrine regulation and drug actions with fundamental processes of fuel‐stimulated insulin release (for further discussion, see ref. 83). Neural and endocrine factors may act by enhancing, rather than initiating, intracellular signaling pathways involved in substrate‐controlled insulin release as expression of the basic secretory competence of β cells. Glucose per se activates the adenylate cyclase–protein kinase A, phospholipase C–protein kinase C, and Ca2+–calmodulin‐dependent protein kinase signaling pathways. The effect of glucose on cytosolic Ca2+ is central for understanding this three‐pronged activation process. The glucose‐induced rise of cAMP is Ca2+‐dependent, as is the glucose‐induced elevation of diacylglycerol and inositol triphosphate. The detailed mechanisms by which elevated cytosolic Ca2+ activates adenylate cyclase or phospholipase C are not understood. It is, for example, not known whether specific isoforms of these two enzymes are involved or whether trimeric G proteins participate in the activation process initiated by an intracellular Ca2+ signal. Acetycholine and glucagon‐like peptide 1, through activation of their respective receptors, greatly augment the cAMP, inositol triphosphate, and diacylglycerol responses but do not initiate insulin release in the absence of glucose because substrate‐induced ATP provision is an absolute requirement for initiation of secretion. Other mitochondrial coupling factors may be needed (B). AC, adenylate cyclase; ACL, acetylcholine; Ca2+/PKC, protein kinase C; CPT, carnitine palmityl CoA transferase; DAG, diacylglycerol; Δψ, cell membrane potential; Δp, mitochondrial proton motive force, a function of ΔpH and Δψ across the mitochondrial membrane; DHAP, dihydroxyacetone‐phosphate; 1,3DPGA, 1,3‐glycerate bisphosphate; F1,6P2, fructose‐1,6‐bisphosphate; FFA, free fatty acids; GAP, glyceraldehyde‐3‐phosphate; Gi, Gq, and Gs, trimeric G proteins; GK, glucokinase; GLP‐1, glucagon‐like peptide 1; Glut‐2, glucose transporter 2; G6P, glucose‐6‐phosphate; GOP, α‐glycerophosphate; IP3, inositol triphosphate; OAA, oxalacetate; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; Pi, inorganic phosphate; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; PKCaCM, calcium–calmodulin‐dependent protein kinase; PL, phospholipids; SUR, sulfonylurea receptor; TG, triglycerides.



Figure 4.

A: Hierarchy of metabolic signaling pathways in pancreatic β cells. Four aspects of stimulus–secretion coupling in pancreatic β cells are highlighted in A–D. A: Role of adenine nucleotides as metabolic coupling factors in glucose‐stimulated insulin release. Three sites are critical in this process: site 1 is located at the lower end of the glycolytic pathway, leading to the net generation of two ATP's for every glucose molecule; site 2 is associated with the transfer of cytosolic reducing equivalents to mitochondria via hydrogen shuttles using the glycero‐P shuttle as an example; site 3 refers to the generation of GTP and reducing equivalents NADH and FADH2 by the citric acid cycle. Electron transport and oxidative phosphorylation are quantitatively more important for total ATP production of the cell than substrate phosphorylation in glycolysis. However, this does not preclude a special role of glycolytic ATP for glucose‐induced insulin release. The potassium channel and processes involved in exocytosis are important targets of this signaling pathway.

B: Putative role of lipid‐related metabolic coupling factors proposed to complement adenine nucleotides. Citrate and, secondarily, malonyl CoA are examples of mitochondrial coupling factors other than ATP. Protein kinase C and exocytosis per se are plausible targets of this signaling pathway.

C: Glucose regulation of glutaminolysis and insulin secretion. The interaction between glucose metabolism and glutaminolysis is depicted. The adenosine nucleotide–sensitive K+ channel and the voltage–sensitive Ca+ channel are indicated. ATP, Acyl‐CoA, and Ca2+ converge as signals to increase insulin release.

D: Interplay of neuroendocrine regulation and drug actions with fundamental processes of fuel‐stimulated insulin release (for further discussion, see ref. 83). Neural and endocrine factors may act by enhancing, rather than initiating, intracellular signaling pathways involved in substrate‐controlled insulin release as expression of the basic secretory competence of β cells. Glucose per se activates the adenylate cyclase–protein kinase A, phospholipase C–protein kinase C, and Ca2+–calmodulin‐dependent protein kinase signaling pathways. The effect of glucose on cytosolic Ca2+ is central for understanding this three‐pronged activation process. The glucose‐induced rise of cAMP is Ca2+‐dependent, as is the glucose‐induced elevation of diacylglycerol and inositol triphosphate. The detailed mechanisms by which elevated cytosolic Ca2+ activates adenylate cyclase or phospholipase C are not understood. It is, for example, not known whether specific isoforms of these two enzymes are involved or whether trimeric G proteins participate in the activation process initiated by an intracellular Ca2+ signal. Acetycholine and glucagon‐like peptide 1, through activation of their respective receptors, greatly augment the cAMP, inositol triphosphate, and diacylglycerol responses but do not initiate insulin release in the absence of glucose because substrate‐induced ATP provision is an absolute requirement for initiation of secretion. Other mitochondrial coupling factors may be needed (B). AC, adenylate cyclase; ACL, acetylcholine; Ca2+/PKC, protein kinase C; CPT, carnitine palmityl CoA transferase; DAG, diacylglycerol; Δψ, cell membrane potential; Δp, mitochondrial proton motive force, a function of ΔpH and Δψ across the mitochondrial membrane; DHAP, dihydroxyacetone‐phosphate; 1,3DPGA, 1,3‐glycerate bisphosphate; F1,6P2, fructose‐1,6‐bisphosphate; FFA, free fatty acids; GAP, glyceraldehyde‐3‐phosphate; Gi, Gq, and Gs, trimeric G proteins; GK, glucokinase; GLP‐1, glucagon‐like peptide 1; Glut‐2, glucose transporter 2; G6P, glucose‐6‐phosphate; GOP, α‐glycerophosphate; IP3, inositol triphosphate; OAA, oxalacetate; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; Pi, inorganic phosphate; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; PKCaCM, calcium–calmodulin‐dependent protein kinase; PL, phospholipids; SUR, sulfonylurea receptor; TG, triglycerides.

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Article Title: Substrate Control of Insulin Release
 

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Christopher B. Newgard, Franz M. Matschinsky. Substrate Control of Insulin Release. Compr Physiol 2011, Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism: 125-151. First published in print 2001. doi: 10.1002/cphy.cp070205