Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

Insulin and Glucagon Secretion in vivo and its Neural Control

Gerald J. Taborsky

10.1002/cphy.cp070206

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 Anatomy of the Endocrine Pancreas
1.1 Islet Cell Types
1.2 Vascular Supply
1.3 Innervation
2 Acute Regulation of Secretion
2.1 Secretion During Feeding
2.2 Secretion During Hypoglycemia
3 Chronic Adaptation of Secretion
3.1 Fasting
3.2 Obesity
3.3 Pregnancy
3.4 Partial β‐Cell Loss or Dysfunction
3.5 Human Diabetes Mellitus
4 Summary and Conclusion
Figure 1. Figure 1.

Distribution of α, β, and δ cells in a typical islet from the splenic lobe of rat pancreas. Note the predominance of β cells and the peripheral distribution of the α and δ cells. In islets from the duodenal lobe, F cells would replace α cells in this diagram.

[From Orci (211) with permission.]
Figure 2. Figure 2.

a: Low magnification (15×) of dog pancreas immunostained for galanin to identify sympathetic nerves. Localized intense staining defines three large islets and one‐large blood vessel. b: High magnification (120×) of a single dog islet immunostained for galanin to identify sympathetic nerves. Note the dense sympathetic innervation of the islet compared to the surrounding acinar tissue.

(Photos courtesy of Drs. C. B. Verchere and D. G. Baskin, unpublished.)
Figure 3. Figure 3.

Potentiation of the insulin response to isoproterenol by increasing plasma glucose level in humans. As plasma glucose level is increased by infusion of glucose, both the baseline insulin level and the acute insulin response (AIR) above that baseline are increased.

From Halter et al. 69 with permission.
Figure 4. Figure 4.

Relationship between magnitude of acute insulin response (AIR) to arginine and the prestimulus glucose level in normal human subjects (•), and non‐insulin‐dependent diabetes meltitus (NIDDM) patients (○), illustrating calculation of the slope of glycemic potentiation, AIRmax, and PG 50.

From Ward et al. 196 with permission.
Figure 5. Figure 5.

Change of pancreatic norepinephrine (NE) output in response to deoxyglucose (2‐DG)‐induced neuroglucopenia, hemorrhagic hypotension, or hypoxia in halothane‐anesthetized dogs. Note the increase of pancreatic norepinephrine output after deoxyglucose suggesting glucopenia‐induced activation of pancreatic sympathetic nerves.

From Havel et al. 83 with permission.
Figure 6. Figure 6.

Arterial plasma immunoreactive glucagon (IRG) response to insulin‐induced hypoglycemia in control dogs (glucose nadir = 1.9 ± 0.2 mM) and in cord‐section (CORDX), vagotomized (VAGX) dogs (glucose nadir = 1.0 ± 0.1 mM). In the absence of autonomic activation, the glucagon response is markedly reduced.

From Havel et al. 84 with permission.
Figure 7. Figure 7.

Insulin secretion from isolated perfused pancreas of control rats and of 15‐day pregnant rats as a function of perfusate glucose. Note the decreased glucose threshold and larger maximal response in pancreas from 15‐day pregnant rats.

From Parsons et al. 143 with permission.
Figure 8. Figure 8.

Insulin and glucose levels and responses to arginine before and twice during intravenous infusion of an insulin‐selective analogue of somatostatin. Note the lowered insulin level and response to arginine early during analogue infusion and their restoration later, when plasma glucose levels have doubled.

From Taborsky et al. 178 with permission.
Figure 9. Figure 9.

Insulin and glucose levels and responses to isoproterenol in type II diabetic patients before and after infusion of insulin to reduce fasting hyperglycemia. Reduction of hyperglycemia reduces the acute insulin response to isoproterenol.

From Halter et al. 69 with permission.
Figure 10. Figure 10.

Plasma glucose during induction of insulin resistance by 20 days of intravenous infusion with nicotinic acid (NA) in control baboons (•) and in baboons treated with 200 mg/kg of the beta‐cell toxin streptozotocin (Δ). In control animals, nicotinic acid infusion does not affect glucose level. In streptozotocin‐treated baboons, glucose levels are normal both before and after infusion of nicotinic acid.

From McCulloch et al. 122 with permission.
Figure 11. Figure 11.

Glucagon response to insulin‐induced hypoglycemia in nondiabetics (○) compared to patients with type I diabetes (•) for less than 1 month (left panel), 1 to 5 years (middle panel), and 14 to 31 years (right panel). Note progressive loss of the glucagon response with duration of diabetes.

From Bolli et al. 21 with permission.
Figure 12. Figure 12.

Plasma epinephrine (EPI), norepinephrine (NE), pancreatic polypeptide (PP), and glucagon (IRG) response in normal humans to a first (○) and third (•) episode of hypoglycemia of 50 mg/dl. Note reduction in autonomic and glucagon responses caused by prior episodes of hypoglycemia.

From Heller and Cryer 85 with permission.


Figure 1.

Distribution of α, β, and δ cells in a typical islet from the splenic lobe of rat pancreas. Note the predominance of β cells and the peripheral distribution of the α and δ cells. In islets from the duodenal lobe, F cells would replace α cells in this diagram.

[From Orci (211) with permission.]


Figure 2.

a: Low magnification (15×) of dog pancreas immunostained for galanin to identify sympathetic nerves. Localized intense staining defines three large islets and one‐large blood vessel. b: High magnification (120×) of a single dog islet immunostained for galanin to identify sympathetic nerves. Note the dense sympathetic innervation of the islet compared to the surrounding acinar tissue.

(Photos courtesy of Drs. C. B. Verchere and D. G. Baskin, unpublished.)


Figure 3.

Potentiation of the insulin response to isoproterenol by increasing plasma glucose level in humans. As plasma glucose level is increased by infusion of glucose, both the baseline insulin level and the acute insulin response (AIR) above that baseline are increased.

From Halter et al. 69 with permission.


Figure 4.

Relationship between magnitude of acute insulin response (AIR) to arginine and the prestimulus glucose level in normal human subjects (•), and non‐insulin‐dependent diabetes meltitus (NIDDM) patients (○), illustrating calculation of the slope of glycemic potentiation, AIRmax, and PG 50.

From Ward et al. 196 with permission.


Figure 5.

Change of pancreatic norepinephrine (NE) output in response to deoxyglucose (2‐DG)‐induced neuroglucopenia, hemorrhagic hypotension, or hypoxia in halothane‐anesthetized dogs. Note the increase of pancreatic norepinephrine output after deoxyglucose suggesting glucopenia‐induced activation of pancreatic sympathetic nerves.

From Havel et al. 83 with permission.


Figure 6.

Arterial plasma immunoreactive glucagon (IRG) response to insulin‐induced hypoglycemia in control dogs (glucose nadir = 1.9 ± 0.2 mM) and in cord‐section (CORDX), vagotomized (VAGX) dogs (glucose nadir = 1.0 ± 0.1 mM). In the absence of autonomic activation, the glucagon response is markedly reduced.

From Havel et al. 84 with permission.


Figure 7.

Insulin secretion from isolated perfused pancreas of control rats and of 15‐day pregnant rats as a function of perfusate glucose. Note the decreased glucose threshold and larger maximal response in pancreas from 15‐day pregnant rats.

From Parsons et al. 143 with permission.


Figure 8.

Insulin and glucose levels and responses to arginine before and twice during intravenous infusion of an insulin‐selective analogue of somatostatin. Note the lowered insulin level and response to arginine early during analogue infusion and their restoration later, when plasma glucose levels have doubled.

From Taborsky et al. 178 with permission.


Figure 9.

Insulin and glucose levels and responses to isoproterenol in type II diabetic patients before and after infusion of insulin to reduce fasting hyperglycemia. Reduction of hyperglycemia reduces the acute insulin response to isoproterenol.

From Halter et al. 69 with permission.


Figure 10.

Plasma glucose during induction of insulin resistance by 20 days of intravenous infusion with nicotinic acid (NA) in control baboons (•) and in baboons treated with 200 mg/kg of the beta‐cell toxin streptozotocin (Δ). In control animals, nicotinic acid infusion does not affect glucose level. In streptozotocin‐treated baboons, glucose levels are normal both before and after infusion of nicotinic acid.

From McCulloch et al. 122 with permission.


Figure 11.

Glucagon response to insulin‐induced hypoglycemia in nondiabetics (○) compared to patients with type I diabetes (•) for less than 1 month (left panel), 1 to 5 years (middle panel), and 14 to 31 years (right panel). Note progressive loss of the glucagon response with duration of diabetes.

From Bolli et al. 21 with permission.


Figure 12.

Plasma epinephrine (EPI), norepinephrine (NE), pancreatic polypeptide (PP), and glucagon (IRG) response in normal humans to a first (○) and third (•) episode of hypoglycemia of 50 mg/dl. Note reduction in autonomic and glucagon responses caused by prior episodes of hypoglycemia.

From Heller and Cryer 85 with permission.
References
 1. 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.
 2. Ahren, R., G. J. Taborsky, Jr., and D. Porte, Jr.. Neuropeptidergic versus cholinergic and adrenergic regulation of islet hormone secretion. Diabetologia 29: 827–836, 1986.
 3. Albisser, A. M., R. S., Leibel, T. G. Ewart, Z. Davidovac, C. K. Rotz, and W. Zingg. An artificial endocrine pancreas. Diabetes 23: 389–396, 1974.
 4. Amiel, S. A., W. V., Tamborlane, D. C. Simonson, and R. S. Sherwin. Defective glucose counterregulation after strict glycemic control of insulin‐dependent diabetes mellitus. N. Engl. J. Med. 316: 1376–1383, 1987.
 5. Amiranoff, B., A.‐M., Lorinet, N. Yanaihara, and M. Laburthe. Structural requirement for galanin action in the pancreatic β cell line Rinm.5F. Eur. J. Pharmacol. 163: 205–207, 1989.
 6. Andersen, D. K., D., Elahi, J. C. Brown, J. D. Tobin, and R. Andres. Oral glucose augmentation of insulin secretion: interactions of gastric inhibitory polypeptide with ambient glucose and insulin levels. J. Clin. Invest. 62: 152–161, 1978.
 7. Araki, E., M. A., Lipes, M. E. Patti, J. C. Bruning, R. Haag, R. S. Johnson, and C. R. Kahn. Alternative pathway of insulin signaling in mice with targeted disruption of the IRS‐1 gene. Nature 372: 186–190, 1994.
 8. Arnush, M., D., Gu, C. Raugh, S. P. Sawyer, R. Mroczkowski, T. Krahl, and N. Sarvetnick. Growth factors in the regenerating pancreas of gamma‐interferon transgenic mice. Lab. Invest. 74: 985–990, 1996.
 9. 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.
 10. Rarseghian, G., and R. Levine. Effect of corticosterone on insulin and glucagon secretion by the isolated perfused rat pancreas. Endocrinology 106: 547–552, 1980.
 11. Rauer, F. E., L., Ginsberg, M. Venetikou, D. J. MacKay, J. M. Rurrin, and S. R. Rloom. Growth hormone release in man induced by galanin, a new hypothalamic peptide. Lancet 2: 192–195, 1986.
 12. Beard, J. C., W. K., Ward, J. B. Halter, B. J. Wallum, and D. Porte, Jr.. Relationship of islet function to insulin action in human obesity. J. Clin. Endocrinol. Metab. 65: 59–64, 1987.
 13. Rerthoud, H. R., and R. Jeanrenaud. Acute hyperinsulinemia and its reversal by vagotomy after lesions of the ventromedial hypothalamus in anesthetized rats. Endocrinology 105: 146–151, 1979.
 14. Berthoud, H.‐R., and T. L. Powley. Morphology and distribution of efferent vagal innervation of rat pancreas as revealed with anterograde transport of Dil. Brain Res. 553: 336–341, 1991.
 15. Biggers, D. W., S. R., Myers, D. Neal, R. Stinson, N. B. Cooper, J. B. Jaspan, P. E. Williams, A. D. Cherrington, and R. T. Fizzell. Role of brain in eounterregulation of insulin‐induced hypoglycemia in dogs. Diabetes 37: 7–16, 1989.
 16. 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.
 17. Block, M. B., M. E., Mako, D. F. Steiner, and A. H. Rubenstein. Circulating C‐peptide immunoreactivity. Studies in normals and diabetic patients. Diabetes 21: 1013–1026, 1972.
 18. 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.
 19. Boden, G.. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 46: 3–10, 1997.
 20. Boden, G., X., Chen, J. Rosner, and M. Barton. Effects of a 48‐h fat infusion on insulin secretion and glucose utilization. Diabetes 44: 1239–1242, 1995.
 21. Bolli, G., P. De Feo, P. Compagnucci, M. G. Cartechini, G. Angeletti, F. Santeusanio, P. Brunetti, and J. E. Gerich. Abnormal glucose eounterregulation in insulin‐dependent diabetes mellitus: interaction of anti‐insulin antibodies and impaired glucagon and epinephrine secretion. Diabetes 32: 134–141, 1983.
 22. Bonner‐Weir, S.. Morphological evidence for pancreatic polarity of beta‐cell within islets of Langerhans. Diabetes 37: 616–621, 1988.
 23. Bonner‐Weir, S., and L. Orci. New perspectives on the microvasculature of the islets of Langerhans in the rat. Diabetes 31: 883–889, 1982.
 24. Bonner‐Weir, S., D. F., Trent, and G. C. Weir. Partial pancreatectomy in the rat and subsequent defect in glucose‐induced insulin release. J. Clin. Invest. 71: 1544–1553, 1983.
 25. Brelje, T. C., D. W., Scharp, P. E. Lacy, L. Ogren, F. Talamantes, M. Robertson, H. G. Friesen, and R. L. Sorenson. Effect of homologous placental lactogens, prolactins, and growth hormones on islet B‐cell division and insulin secretion in rat, mouse, and human islets: implication for placental lactogen regulation of islet function during pregnancy. Endocrinology 132: 879–887, 1993.
 26. Brelje, T. C., D. W., Scharp, and R. L. Sorenson. Three‐dimensional imaging of intact isolated islets of Langerhans with confocal microscopy. Diabetes 38: 808–814, 1989.
 27. Brunicardi, F. C., J., Stagner, S. Bonner‐Weir, H. Wayland, R. Kleinman, E. Livingston, P. Guth, M. Menger, R. McCusky, M. Intaglietta, A. Charles, S. Ashley, A. Cheung, E. Ipp, S. Gilman, T. Howard, and E. Passaro, Jr.. Microcirculation of the islets of Langerhans. Diabetes 45: 385–392, 1996.
 28. Bruzzone, R., and P. Meda. The gap junction: a channel for multiple functions? Eur. J. Clin. Invest. 18: 444–453, 1988.
 29. Cahill, G. F., Jr., M. G. Herrera, A. P. Morgan, J. S. Soeldner, J. Steinke, P. L. Levy, G. A. Reichard, Jr., and D. M., Kipnis. Hormone‐fuel interrelationships during fasting. J. Clin. Invest. 45: 1751–1769, 1966.
 30. Cataland, S., S. E., Crockett, J. C. Brown, and E. L. Mazzaferri. Gastric inhibitory polypeptide (GIP) stimulation by oral glucose in man. J. Clin. Endocrinol. Metab. 39: 223–228, 1974.
 31. Chen, C., H., Hosokawa, L. M. Bumbalo, and J. L. Leahy. Mechanism of compensatory hyperinsulinemia in normoglycemic insulin‐resistant spontaneously hypertensive rats. Augmented enzymatic activity of glucokinase in beta‐cells. J. Clin. Invest. 94: 399–404, 1994.
 32. Cherrington, A. D., J. L., Chiasson, J. E. Liljenquist, A. S. Jennings, U. Keller, and W. W. Lacy. The role of insulin and glucagon in the regulation of basal glucose production in the postabsorptive dog. J. Clin. Invest. 58: 1407–1418, 1976.
 33. Clark, A., M. F., Saad, T. Nezzer, C. Uren, W. C. Knowler, P. H. Bennett, and R. C. Turner. Islet amyloid polypeptide in diabetic and non‐diabetic Pima Indians. Diabetologia 33: 285–289, 1990.
 34. Clark, A., C. A., Wells, I. D. Buley, J. K. Cruickshank, R. I. Vanhegan, D. R. Matthews, G. J. Cooper, R. R. Holman, and R. C. Turner. Islet amyloid, increased A‐cells, reduced B‐cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes. Diabetes Res. 9: 151–159, 1988.
 35. Coiro, V., M., Passeri, G. Rossi, L. Camellini, D. Davoli, M. Marchesi, P. Muzzetto, R. Minelli, L. Bianconi, C. Coscelli, and P. Chiodera. Effect of muscarinic and nicotinic–cholinergic blockade on the glucagon response to insulin‐induced hypoglycemia in normal men. Horm. Metab. Res. 21: 102–103, 1989.
 36. Cononie, C. C., A. P., Goldberg, E. Rogus, and J. M. Hagberg. Seven consecutive days of exercise lowers plasma insulin responses to an oral glucose challenge in sedentary elderly. J. Am. Geriatr. Soc. 42: 394–398, 1994.
 37. Creutzfeldt, W., and M. Nauck. Gut hormones and diabetes mellitus. Diabetes Metab Rev 8: 149–177, 1992.
 38. Cryer, P. E.. Hypoglycemia begets hypoglycemia in IDDM. Diabetes 42: 1691–1693, 1993.
 39. Curry, D. L., L. L., Bennett, and G. M. Grodsky. Dynamics of insulin secretion by the perfused rat pancreas. Endocrinology 83: 572–584, 1968.
 40. D'Alessio, D. A., C., Sieber, C. Beglinger, and J. W. Ensinck. A physiological role for somatostatin 28 as a regulator of insulin secretion. J. Clin. Invest. 84: 857–862, 1989.
 41. D'Alessio, D. A., C. B., Verchere, S. E. Kahn, V. Hoagland, D. G. Baskin, R. D. Palmiter, and J. W. Ensinck. Pancreatic expression and secretion of human islet amyloid polypeptide in a transgenic mouse. Diabetes 43: 1457–1461, 1994.
 42. D'Alessio, D. A., R., Vogel, R. Prigeon, E. Laschansky, D. Koerker, J. Eng, and J. W. Ensinck. Elimination of the action of glucagon‐like peptide 1 causes an impairment of glucose tolerance after nutrient ingestion by healthy baboons. J. Clin. Invest. 97: 133–138, 1996.
 43. Daniel, D., and D. R. Wegmann. Protection of nonobese diabetic mice from diabetes by intranasal or subcutaneous administration of insulin peptide B‐(9–23). Proc. Natl. Acad. Sci. U.S.A. 93: 956–960, 1996.
 44. Davis, S. N., C., Shavers, F. Costa, and R. Mosqueda‐Garcia. Role of Cortisol in the pathogenesis of deficient eounterregulation after antecedent hypoglycemia in normal humans. J. Clin. Invest. 98: 680–691, 1996.
 45. 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.
 46. Drucker, D. J.. Glucagon‐like peptides. Diabetes 47: 159–169, 1998.
 47. Dunning, B. E., B., Ahren, R. C. Veith, G. Bottcher, F. Sundler, and G. J. Taborsky, Jr.. Galanin: a novel pancreatic neuropeptide. Am. J. Physiol. 251 (Endocrinol. Metab. 14): E127–E133, 1986.
 48. Dunning, B. E., M. F., Scott, D. W. Neal, and A. D. Cherrington. Direct quantification of norepinephrine spillover and hormone output from the pancreas of the conscious dog. Am. J. Physiol. 272 (Endocrinol. Metab. 35): E746–E755, 1997.
 49. 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.
 50. Ebert, R.. Gut signals for islet hormone release. Eur. J. Clin. Invest. 20 (Suppl. 1): S20–S26, 1990.
 51. Eizirik, D. L., S., Sandler, and J. P. Palmer. Repair of pancreatic B‐cells: a relevant phenomenon in early IDDM? Diabetes 42: 1383–1391, 1993.
 52. Falko, J. M., S. E., Crockett, S. Cataland, and E. L. Mazzaferri. Gastric inhibitory polypeptide stimulated by fat ingestion in man. J. Clin. Endocrinol Metab. 41: 260–265, 1975.
 53. Fisher, 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: 1734–1739, 1976.
 54. Frier, B. M., R. J. M., Corrall, J. G. Ratcliffe, J. P. Ashby, and E. J. W. McClemont. Autonomic neural control mechanisms of substrate and hormonal responses to hypoglycemia in man. Clin. Endocrinol. (Oxf.) 14: 425–433, 1981.
 55. Fukuda, M., A., Tanaka, Y. Tahara, H. Ikegami, Y. Yamamoto, Y. Kumahara, and K. Shima. Correlation between minimal secretory capacity of pancreatic B‐cells and stability of diabetic control. Diabetes 37: 81–88, 1988.
 56. Ganda, O. P., S., Srikanta, S. J. Brink, M. A. Morris, R. E. Gleason, J. S. Soeldner, and G. S. Eisenbarth. Differential sensitivity to beta‐cell secretagogues in “early,” type I diabetes mellitus. Diabetes 33: 516–521, 1984.
 57. Gepts, W., and P. M. Lecompte. The pancreatic islets in diabetes. Am. J. Med. 70: 105–115, 1981.
 58. 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.
 59. Gerich, J. E.. Glucose in the control of glucagon secretion. In: Handbook of Experimental Pharmacology, edited by P. J. Lefebvre. Berlin: Springer‐Verlag, 1983, p. 3–18.
 60. Gold, G., H. D., Landahl, M. L. Gishizky, and G. M. Grodsky. Heterogeneity and compartmental properties of insulin storage and secretion in rat islets. J. Clin. Invest. 69: 554–563, 1982.
 61. Gotoh, M., M., Monden, J. Okamura, T. Mori, and K. Shima. Insulin and glucagon secretion after pancreatectomies; correlation of secretion and hormonal contents of remining pancreas. Diabetes 38: 861–867, 1989.
 62. Green, I., and K. W. Taylor. Effects of pregnancy in the rat on the size and insulin secretory response of the islets of Langerhans. J. Endocrinol. 54: 317–325, 1972.
 63. Greenbaum, C., 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.
 64. Grill, V.. Time and dose dependencies for priming effect of glucose on insulin secretion. Am. J. Physiol. 240 (Endocrinol. Metab. 3): E24–E31, 1981.
 65. Grill, V., U., Adamson, and E. Cerasi. Immediate and time‐dependent effects of glucose on insulin release from rat pancreatic‐tissue. Evidence for different mechanisms of action. J. Clin. Invest. 61: 1034–1043, 1978.
 66. Groger, G., and P. Layer. Exocrine pancreatic function in diabetes mellitus. Eur. J. Gastroenterol Hepatol 7: 740–746, 1995.
 67. Hagopian, W. A., C. B., Sanjeevi, I. Kockum, M. Landin‐Olsson, A. E. Karsen, G. Sundkvist, G. Dahlquist, J. Palmer, and A. Lernmark. Glutamate decarboxylase, insulin, and islet cell‐antibodies and HAL typing to detect diabetes in a general population‐based study of Swedish children. J. Clin. Invest. 95: 1505–1511, 1995.
 68. Halban, P. A.. Structural domains and molecular lifestyles of insulin and its precursors in the pancreatic beta cell. Diabetologia 34: 767–778, 1991.
 69. Halter, J. B., R. J. Graf, and D. Porte, Jr.. Potentiation of insulin secretory responses by plasma glucose levels in man: evidence that hyperglycemia in diabetes compensates for impaired glucose potentiation. J. Clin. Endocrinol. Metab. 48: 946–954, 1979.
 70. Hamilton‐Wessler, M., R. N., Bergman, J. B. Halter, R. M. Watanabe, and C. M. Donovan. The role of liver glucosensors in the integrated sympathetic response induced by deep hypoglycemia in dogs. Diabetes 43: 1052–1060, 1994.
 71. Havel, P., 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.
 72. 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.
 73. 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.
 74. Havel, P. J., D. E., Flatness, J. B. Halter, J. D. Best, R. C. Veith, and G. J. Taborsky, Jr.. Halothane anesthesia does not suppress sympathetic activation produced by neuroglucopenia. Am. J. Physiol. 252 (Endocrinol. Metab. 15): E667–E672, 1987.
 75. Havel, P. J., T. O. Mundinger, and G. J. Taborsky, Jr.. Pancreatic sympathetic nerves increase glucagon secretion during severe hypoglycemia in dogs. Am. J. Physiol. 270 (Endocrinol. Metab. 33): E20–E26, 1996.
 76. 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.
 77. Havel, P. J., T. L. Paquette, and G. J. Taborsky, Jr.. Halothane is less suppressive than pentobarbital on reflex and neural activation of pancreatic F‐cell. Am. J. Physiol. 251 (Endocrinol. Metab. 14): E111–E116, 1986.
 78. 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.
 79. 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.
 80. 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.
 81. 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. Monogr. 2: 201–204, 1994.
 82. Havel, P. J., and C. Valverde. Autonomic mediation of glucagon secretion during insulin‐induced hypoglycemia in rhesus monkeys. Diabetes 45: 960–966, 1996.
 83. Havel, P. J., R. C., Veith, B. E. Dunning, and G. J. Taborsky, Jr.. Pancreatic noradrenergic nerves are activated by neuroglucopenia but not 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.
 84. 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.
 85. Heller, S. R., and P. E. Cryer. Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after 1 episode of hypoglycemia in nondiabetic humans. Diabetes 40: 223–226, 1991.
 86. Herrmann, C., R., Goke, G. Richter, H. C. Fehmann, R. Arnold, and B. Goke. Glucagon‐like peptide‐1 and glucose‐dependent insulin‐releasing polypeptide plasma levels in response to nutrients. Digestion 56: 117–126, 1995.
 87. Hevener, A. L., R. N., Bergman, and C. M. Donovan. Portal vein afferents are critical for the sympathoadrenal response to hypoglycemia. Diabetes 49: 8–12, 2000.
 88. Hildebrand, P., J. W., Ensinck, S. Ketterer, F. Delco, S. Mossi, U. Bangerter, and C. Beglinger. Effect of a cholecystokinin antagonist on meal‐stimulated insulin and pancreatic polypeptide release in humans. J. Clin. Endocrinol. Metab. 72: 1123–1129, 1991.
 89. Hoeldtke, R. D., and G. Boden. Epinephrine secretion, hypoglycemia unawareness, and diabetic autonomic neuropathy. Ann. Intern. Med. 120: 512–517, 1994.
 90. Holst, J. J., M., Bersani, A. Hvidberg, U. Knigge, E. Christiansen, S. Madsbad, H. Harling, and H. Kofod. On the effects of human galanin in man. Diabetologia 36: 653–657, 1993.
 91. Holst, J. J., M., Bersani, A. H. Johnsen, H. Kofod, B. Hartmann, and C. Orskov. Proglucagon processing in porcine and human pancreas. J. Biol. Chem. 269: 18827–18833, 1994.
 92. 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.
 93. Holst, J. J., C., Orskov, O. V. Nielsen, and T. W. Schwartz. Truncated glucagon‐like peptide I, an insulin‐releasing hormone from the distal gut. FEBS Lett. 211: 169–174, 1987.
 94. Inoue, S., G. A., Bray, and Y. S. Mullen. Transplantation of pancreatic beta‐cells prevents development of hypothalamic obesity in rats. Am. J. Physiol. 235 (Endocrinol. Metab. Gastrointest. Physiol. 4): E266–E271, 1978.
 95. Jia, X., J. C., Brown, P. Ma, R. A. Pederson, and C. H. S. McIntosh. Effects of glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide‐I‐(7–36) on insulin secretion. Am. J. Phyiol. 268 (Endocrinol. Metab. 31): E645–E651, 1995.
 96. Johnston, C., P., Raghu, D. K. McCulloch, J. C. Beard, W. K. Ward, L. J. Klaff, B. McKnight, R. N. Bergman, and J. P. Palmer. Beta‐cell function and insulin sensitivity in nondiabetic HLA‐identical siblings of insulin‐dependent diabetics. Diabetes 36: 829–837, 1987.
 97. 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.
 98. Kahn, S.. Regulation of B‐cell function in vivo. Diabetes Rev. 4: 372–389, 1996.
 99. Kahn, S. E., J. C., Beard, M. W. Schwartz, W. K. Ward, H. L. Ding, R. N. Bergman, G. J. Taborsky, Jr., and D. Porte, Jr.. Increased beta‐cell secretory capacity as mechanism for islet adaptation to nicotinic acid‐induced insulin resistance. Diabetes 38: 562–568, 1989.
 100. Kahn, S. E., L. J., Klaff, M. W. Schwartz, J. C. Beard, R. N. Bergman, G. J. Taborsky, Jr., and D. Porte, Jr.. Treatment with a somatostatin analog decreases pancreatic B‐cell and whole body sensitivity to glucose. J. Clin. Endocrinol. Metab. 71: 994–1002, 1990.
 101. Kahn, S. E., V. G., Larson, J. C. Beard, K. C. Cain, G. W. Fellingham, R. S. Schwartz, R. C. Veith, J. R. Stratton, M. D. Cerqueria, and I. B. Abrass. Effect of exercise on insulin action, glucose tolerance, and insulin secretion in aging. Am. J. Physiol. 258 (Endocrinol. Metab. 21): E937–943, 1990.
 102. Kahn, S. E., D. K., McCulloch, M. W. Schwartz, J. P. Palmer, and D. Porte, Jr.. Effect of insulin resistance and hyperglycemia on proinsulin release in a primate model of diabetes mellitus. J. Clin. Endocrinol. Metab. 74: 192–197, 1992.
 103. Kahn, S. E., R. L., Prigeon, D. K. McCulloch, E. J. Boydo, R. N. Bergman, M. W. Schwartz, J. L. Neiflng, W. K. Ward, J. C. Beard, and J. P. Palmer. Quantification of the relationship between insulin sensitivity and beta‐cell function in human subjects. Evidence for a hyperbolic function. Diabetes 42: 1663–1672, 1993.
 104. Kampe, O., A., Andersson, E. Bjork, A. Hallberg, and F. A. Karlsson. High‐glucose stimulation of 64,000‐Mr islet cell autoantigen expression. Diabetes 38: 1326–1328, 1989.
 105. Keller, R. J., G. S., Eisenbarth, and R. A. Jackson. Insulin prophylaxis in individuals at high risk of type I diabetes. Lancet 34: 927–928, 1993.
 106. Kirchgessner, A. L., and M. D. Gershon. Presynaptic inhibition by serotonin of nerve‐mediated secretion of pancreatic amylase. Am. J. Physiol. 268 (Gastrointest. Liver Physiol. 31): G339–G345, 1995.
 107. Kolligs, F., H. C., Fehmann, R. Goke, and B. Goke. Reduction of the incretin effect in rats by the glucagon‐like peptide 1 receptor antagonist exendin (9–39) amide. Diabetes 44: 16–19, 1995.
 108. Komatsu, R., T., Matsuyama, M. Namba, N. Watanabe, H. Itoh, N. Kono, and S. Tarui. Glucagonostatic and insulinotropic action of glucagonlike peptide I‐(7–36)‐amide. Diabetes 38: 902–905, 1989.
 109. Koyama, K., G., Chen, M. Y. Wang, Y. Lee, M. Shimabukuro, C. B. Newgard, and R. H. Unger. Beta‐cell function in normal rats made chronically hyperleptinemic by adenovirus‐leptin gene therapy. Diabetes 46: 1276–1280, 1997.
 110. Krarup, T., T. W., Schwartz, J. Hilstead, S. Madsbad, O. Overlaege, and L. Sestoft. Impaired response of pancreatic polypeptide to hypoglycemia: an early sign of autonomic neuropathy in diabetics. BMJ 2: 1544–1546, 1979.
 111. Kreymann, B., M. A., Ghatei, G. Williams, and S. R. Bloom. Glucagon‐like peptide‐1 7–36: a physiological incretin in man. Lancet 2: 1300–1304, 1987.
 112. Larsson, L. I.. Innervation of the pancreas by substance P, enkephalin, vasoactive intestinal polypeptide and gastrin‐CCK immunoreactive nerves. J. Histochem. Cytochem. 27: 1283–1284, 1979.
 113. Lavine, R. L., N., Voyles, P. V. Perrino, and L. Recant. Functional abnormalities of islets of Langerhans of obese hyperglycemic mouse. Am. J. Physiol. 233 (Endocrinol. Metab. Gastrointest. Physiol. 2): E86–90, 1977.
 114. Leahy, J. L., S., Bonner‐Weir, and G. C. Weir. Abnormal insulin secretion in a streptozocin model of diabetes. Effects of insulin treatment. Diabetes 34: 660–666, 1985.
 115. Leahy, J. L., L. M., Bumbalo, and C. Chen. Beta‐cell hypersensitivity for glucose precedes loss of glucose‐induced insulin secretion in 90% pancreatectomized rats. Diabetologia 36: 1238–1244, 1993.
 116. Levin, B. E., J., Triscari, and A. C. Sullivan. Studies of origins of abnormal sympathetic function in obese Zucker rats. Am. J. Physiol. 245 (Endocrinol. Metab. 8): E87–93, 1983.
 117. Liddle, R. A., R. J., Rushakoff, E. T. Morita, L. Beccaria, J. D. Carter, and I. D. Goldfine. Physiological role for cholecystokinin in reducing postprandial hyperglycemia in humans. J. Clin. Invest. 81: 1675–1681, 1988.
 118. Lindkaer, S., J., Jensen, 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.
 119. Luiten, P. G. M., G. J. Ter Horst, and A. B. Steffens. The hypothalamus, intrinsic connections and outflow pathways to the endocrine system in relation to the control of feeding and metabolism. Prog. Neurobiol. 28: 1–54, 1987.
 120. Maruyama, H., A., Hisatomi, L. Orci, G. M. Grodsky, and R. H. Unger. Insulin within islets is a physiologic glucagon release inhibitor. J. Clin. Invest. 74: 2296–2299, 1984.
 121. Matschinsky, F. M.. Banting lecture 1995. A lession in metabolic regulation inspired by the glucokinase glucose sensor paradigm. Diabetes 45: 223–241, 1996.
 122. Matsumoto, K., H., Yamasaki, S. Akazawa, H. Sakamaki, M. Ishibashi, N. Abiru, S. Uotani, H. Matsuo, Y. Yamaguchi, K. Tokuyama, and S. Nagataki. High‐dose but not low‐dose dexamethasone impairs glucose tolerance by inducing compensatory failure of pancreatic beta‐cells in normal men. J. Clin. Endocrinol. Metab. 81: 2621–2626, 1996.
 123. McCulloch, D. K., S. E., Kahn, M. W. Schwartz, D. J. Koerker, and J. P. Palmer. Effect of nicotinic acid–induced insulin resistance on pancreatic B‐cell function in normal and streptozocin‐treated baboons. J. Clin. Invest. 87: 1395–1401, 1987.
 124. McCulloch, D. K., J. P., Palmer, and E. A. Benson. Beta cell function in the preclinical period of insulin‐dependent diabetes. Diabetes Metab. Rev. 3: 27–43, 1987.
 125. McCulloch, D. K., P. K., Raghu, C. Johnston, et al. Defects in beta‐cell function and insulin sensitivity in normoglycemic streptozocin‐treated baboons: a model of preclinical insulin‐dependent diabetes. J. Clin. Endocrinol. Metab. 67: 785–792, 1988.
 126. McDonald, T. J., J., Dupre, K. Tatemoto, G. R. Greenberg, J. Radziuk, and V. Mutt. Galanin inhibits insulin secretion and induces hyperglycemia in dogs. Diabetes 34: 192–196, 1985.
 127. McIntyre, N., C. D., Holdsworth, and D. S. Turner. New interpretation of oral glucose tolerance. Lancet II: 20–21, 1964.
 128. Mehta, V., W., Hao, B. M. Brooks‐Worrell, and J. P. Palmer. The functional state of the B cell modulates IL‐1 and TNF‐induced cytotoxicity. Lymphokine Cytokine Res. 12: 225–259, 1993.
 129. Meistas, M. T., S., Margolis, and A. A. Kowarski. Hyperinsulinemia of obesity is due to decreased clearance of insulin. Am. J. Physiol. 245: (Endocrinol. Metab. 8): E155–E159, 1983.
 130. Menchini, M., F., Meschi, R. Lambiase, M. Puzzovio, M. J. Del Guercio, and G. Chiumello. C‐peptide response to arginine stimulation in diabetic children. J. Pediatr. 96: 362–366, 1980.
 131. Miralles, P., E., Peiro, P. Degano, R. A. Silvestre, and J. Marco. Inhibition of insulin and somatostatin secretion and stimulation of glucagon release by homologous galanin in perfused rat pancreas. Diabetes 39: 996–1001, 1990.
 132. 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.
 133. Mulder, H., J. I., Finley, A. J. Coher, and C. Newgard. Overexpression of human malonyl‐CoA decarboxylase in an INS‐1 cell line with robust glucose sensing alleviates glucose inhibition of fatty acid oxidation without affecting insulin secretion. Diabetes 49: A248, 2000.
 134. Muller, W. A., G. R., Faloona, and R. H. Unger. Hyperglucogonemia in diabetic ketoacidosis. Its prevalence and significance. Am. J. Med. 54: 52–57, 1973.
 135. Murakami, T., T., Fujita, T. Miyake, A. Ohtsuka, T. Taguchi, and A. Kikuta. The insulo‐acinar portal and insulino‐venous drainage systems in the pancreas of the mouse, dog, monkey and certain other animals: a scanning electron microscopic study of corrosion casts. Arch. Histol. Cytol. 56: 127–147, 1993.
 136. Nakabayashi, H., M., Nishizawa, A. Nakagawa, R. Takeda, and A. Niijima. Vagal hepatopancreatic reflex effect evoked by intraportal appearance of tGLP‐1. Am. J. Physiol. 271 (Endocrinol. Metab. 34): E808–E813, 1996.
 137. Nakagawa, A., J. I., Stagner, and E. Samols. In situ binding of islet hormones in the isolated perfused rat pancreas: evidence for local high concentrations of islet hormones via the islet‐acinar axis. Diabetologia 38: 262–268, 1995.
 138. Nauck, M. A., E., Barrels, C. Orskov, 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.
 139. 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.
 140. Nolan, J. J., B., Ludvik, P. Beerdsen, M. Joyce, R. Olefsky, and J. Olefsky. Improvement glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N. Engl. J. Med. 3: 1188–1193, 1994.
 141. Okumura, T., T. N., Pappas, and I. L. Taylor. Pancreatic polypeptide microinjection into the dorsal motor nucleus inhibits pancreatic secretion in rats. Gastroenterology 108: 1517–1525, 1995.
 142. Orci, L., D., Baetens, C. Rufener, A. M. M. Ravazzola, P. Studer, F. A. U. Malaisse‐Lagae, and R. H. Unger. Hypertrophy and hyperplasia of somatostatin‐containing D‐cells in diabetes. Proc. Natl. Acad. Sci. U.S.A. 73: 1338–1342, 1976.
 143. Orci, L., and Unger, R. H.. Functional subdivision of islets of Langerhans and possible roll of D cells, Lancet 2: 1243–1244, 1975.
 144. Orskov, C., M., Bersan, 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.
 145. Owyang, C.. Physiological mechanisms of cholecystokinin action on pancreatic secretion. Am. J. Physiol. 271 (Gastrointest. Liver Physiol. 34): G1–G7, 1996.
 146. Parsons, J. A., T. C., Brelje, and R. L. Sorenson. Adaptation of islets of Langerhans to pregnancy: increased islet cell prolfieration and insulin secretion correlates with the onset of placental lactogen secretion. Endocrinology 130: 1459–1466, 1992.
 147. 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.
 148. Polonsky, K. S., B. D., Given, L. Hirsch, E. T. Shapiro, H. Tillil, C. Beebe, J. A. Galloway, B. H. Frank, T. Karrison, and E. Van Cauter. Quantitative study of insulin secretion and clearance in normal and obese subjects. J. Clin. Invest. 81: 435–141, 1988.
 149. Prentki, M., and B. E. Corkey. Are the B‐cell signaling molecules malonyl‐CoA and cytosolic long‐chain acyl‐CoA implicated in multiple tissue defects of obesity and NIDDM? Diabetes 45: 273–283, 1996.
 150. Roberge, J. N., and P. L. Brubaker. Secretion of proglucagon‐derived peptides in response to intestinal luminal nutrients. Endocrinology 128: 3169–3174, 1991.
 151. Rohner‐Jeanrenaud, F., A. C., Hochstrasser, and B. Jeanrenaud. Hyperinsulinemia of preobese and obese fa/fa rats is partly vagus nerve mediated. Am. J. Physiol. 244 (Endocrinol. Metab. 7): E317–E322, 1983.
 152. Rohner‐Jeanrenaud, F., and B. Jeanrenaud. Consequences of ventromedial hypothalamic lesions upon insulin and glucagon secretion by subsequently isolated perfused pancreases in the rat. J. Clin. Invest. 65: 902–910, 1980.
 153. Rushakoff, R. J., I. D., Goldfine, J. D. Carter, and R. A. Liddle. Physiological concentrations of cholecystokinin stimulate amino acid–induced release in humans. J. Clin. Endocrinol. Metab. 65: 395–101, 1987.
 154. Samols, E., and J. I. Stagner. Intra‐islet regulation. Am. J. Med. 85: 31–35, 1988.
 155. Samols, E., J., Tyler, and V. Marks. Glucagon‐insulin interrelationships. In: Glucagon. Molecular Physiology, Clinical and Therapeutic Implications, edited by P. Lefebvre and R. Unger. Oxford: Pergamon, 1972, p. 151–173.
 156. Schatz, D., J., Krischer, G. Horne, W. Riley, R. Spillar, J. Silverstein, W. Winter, A. Muir, D. Derovanesian, and S. Shah. Islet cell antibodies predict insulin‐dependent diabetes in United States school age children as powerfully as in unaffected relatives. J. Clin. Invest. 93: 2403–2407, 1994.
 157. Scheurink, A. J. W., T. O., Mundinger, B. E. Dunning, R. C. Veith, and G. J. Taborsky, Jr.. Alpha‐2 adrenergic regulation of galanin and norepinephrine release from canine pancreas. Am. J. Physiol. 262 (Regulatory Integrative Comp. Physiol. 31): R819–R825, 1992.
 158. Schwartz, G. J., and T. H. Moran. CCK elicits and modulates vagal afferent activity arising from gastric and duodenal sites. Ann. N.Y. Acad. Sci. 713: 121–128, 1994.
 159. Schwartz, T. W.. Pancreatic polypeptide: a hormone under vagal control. Gastroenterology 85: 1411–1425, 1983.
 160. 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 null mutation in the glucagon‐like peptide 1 receptor gene. Nat. Med. 2: 1254–1258, 1996.
 161. Seaquist, E. R., S. E., Kahn, P. M. Clark, C. N. Hales, D. Porte, Jr., and R. P., Robertson. Hyperproinsulinemia is associated with increased beta cell demand after hemipancreatectomy in humans. J. Clin. Invest. 97: 455–460, 1996.
 162. Seaquist, E. R., K., Pyzdrowski, A. Moran, A. U. Teuscher, and R. P. Robertson. Insulin‐mediated and glucose‐mediated glucose uptake following hemipancreatectomy in healthy human donors. Diabetologia 37: 1036–1043, 1994.
 163. Seaquist, E. R., and R. P. Robertson. Effects of hemipancreatectomy on pancreatic alpha and beta cell function in healthy human donors. J. Clin. Invest. 89: 1761–1766, 1992.
 164. Secchi, A., R., Caldara, A. Caumo, L. D. Monti, D. Bonfatti, V. Di Carlo, and G. Pozza. Cephalic‐phase insulin and glucagon release in normal subjects and in patients receiving pancreas transplantation. Metabolism 44: 1153–1158, 1995.
 165. Sheikh, S. P., J. J., Holst, T. Skak‐Nielsen, U. Knigge, J. Warberg, E. Theodorsson‐Norheim, T. Hokfelt, J. M. Lundberg, and T. W. Schwartz. Release of NPY in pig pancreas: dual parasympathetic and sympathetic regulation. Am. J. Physiol. 255 (Gastrointest. Liver Physiol. 18): G46–G54, 1988.
 166. Shimabukuro, M., Y. T., Zhou, M. Levi, and R. H. Unger. Fatty acid–induced beta cell apoptosis: a link between obesity and diabetes. Proc. Natl. Acad. Sci. U.S.A. 95: 2498–2502, 1998.
 167. Sorenson, R. L., and T. C. Brelje. Adaptation of islets of Langerhans to pregnancy: B‐cell growth, enhanced insulin secretion and the role of lactogenic hormones. Horm. Metab. Res. 29: 301–307, 1997.
 168. Sorenson, R. L., T. C., Brelje, and C. Roth. Effects of steroid and lactogenic hormones on islets of Langerhans: a new hypothesis for the role of pregnancy steroids in the adaptation of islets to pregnancy. Endocrinology 133: 2227–2234, 1993.
 169. Spellacy, W. N., and F. C. Goetz. Plasma insulin in normal late pregnancy. N. Engl J. Med. 268: 988–991, 1962.
 170. Stagner, J. I., and E. Samols. Retrograde perfusion as a method for testing the relative effects of glucose on the A cell. J. Clin. Invest. 77: 1034–1037, 1986.
 171. Stefan, Y., L., Orci, F. Malaisse‐Lagae, A. Perrelet, Y. Patel, and R. H. Unger. Quantitation of endocrine cell content in the pancreas of nondiabetic and diabetic humans. Diabetes 31: 694–700, 1982.
 172. Stein, D. T., V., Esser, B. E. Stevenson, K. E. Lane, J. H. Whiteside, M. B. Daniels, S. Chen, and J. D. McGarry. Essentiality of circulating fatty acids for glucose‐stimulated insulin secretion in the fasted rat. J. Clin. Invest. 97: 2728–2735, 1996.
 173. Stjarne, L.. Basic mechanisms and local modulation of nerve impulse–induced secretion of neurotransmitters from individual sympathetic nerve varicosities. Rev. Physiol. Biochem. Pharmacol. 112: 1–125, 1989.
 174. Strubbe, J. H.. Central nervous system and insulin secretion. Neth. J. Med. 34: 154–167, 1989.
 175. Strubbe, J. H., and A. B. Steffens. Rapid insulin release after ingestion of a meal in the unanesthetized rat. Am. J. Physiol. 229: 1019–1022, 1975.
 176. Strubbe, J. H., and P. van Wachem. Insulin secretion by the transplanted neonatal pancreas during food intake in fasted and fed rats. Diabetologia 20: 228–236, 1981.
 177. Taborsky, G. J., Jr.. Evidence of a paracrine role for pancreatic somatostatin in vivo. Am. J. Physiol. 245 (Endocrinol. Metab. 8): E598–E603, 1983.
 178. Taborsky, G. J., Jr., B. Ahren, and P. J. Havel. Autonomic mediation of glucagon secretion during hypoglycemia: implications for impaired α‐cell responses in type 1 diabetes. Diabetes 47: 995–1005, 1998.
 179. Taborsky, G. J., Jr., and J. W., Ensinck. The contribution of the pancreas to circulating somatostatin‐like immunoreactivity in the normal dog. J. Clin. Invest. 73: 216–223, 1984.
 180. Taborsky, G. J., Jr., T. L. Paquette, M. A. Pfeifer, and R. L. Gingerich. Pentobarbital suppresses basal and reflexive pancreatic polypeptide release in dogs. Am. J. Physiol. 249: E577–E583, 1985.
 181. Taborsky, G. J., Jr., and D. Porte, Jr.. Endogenous hyperglycemia restores the insulin release imapired by somatostatin analog. Am. J. Physiol. 240 (Endocrinol. Metab. 3): E407–E413, 1981.
 182. Tamemoto, H., T., Kadowaki, K. Tobe, et al. Insulin resistance and growth retardation in mice lacking insulin receptor substrate‐1. Nature 372: 182–186, 1994.
 183. Teff, K.. Oral sensory stimulation in men: effects on insulin, C‐peptide, and catecholamines. Am. J. Physiol. 265 (Regulatory Integrative Comp. Physiol. 34): R1223–R1230, 1993.
 184. Teff, K.. Oral sensory stimulation improves glucose tolerance in humans: effects on insulin, C‐peptide, and glucagon. Am. J. Physiol. 270 (Regulatory Integrative Comp. Physiol. 39): R1371–R1379, 1996.
 185. Teff, K., and R. Townsend. Effect of atropine and early insulin infusion on post‐prandial glucose, insulin and glucagon levels in obese and normal weight individuals. Diabetes 45 (Suppl. 2): 97A, 1996.
 186. Terauchi, Y., K., Iwamoto, H. Tamemoto, K. Komeda, C. Ishii, Y. Kanazawa, N. Asanuma, T. Aizawa, Y. Akanuma, K. Yasuda, T. Kodama, K. Tobe, Y. Yazaki, and T. Kadowaki. Development of non‐insulin‐dependent diabetes mellitus in the double knockout mice with disruption of insulin receptor substrate‐1 and β cell glucokinase genes. J. Clin. Invest. 99: 861–866, 1997.
 187. Terauchi, Y., H., Sakura, K. Yasuda, et al. Pancreatic‐B cell specific targeted disruption of glucokinase gene: diabetes mellitus due to defective insulin secretion to glucose. J. Biol. Chem. 268: 30253–30256, 1995.
 188. Thorens, B.. Expression cloning of the pancreatic b‐cell receptor for the gluco‐incretin hormone glucagon‐like peptide 1. Proc. Natl. Acad. Sci. U.S.A. 89: 8641–8645, 1992.
 189. Tseng, C. C., T. J., Kieffer, L. A. Jarboe, T. B. Usdin, and M. M. Wolfe. Postprandial stimulation of insulin release by glucose‐dependent insulinotropic polypeptide (GIP). J. Clin. Invest. 98: 2440–2445, 1996.
 190. Tsunehara, C. H., D. L., Leonetti, and W. Y. Fujimoto. Diet of second‐generation Japanese‐American men with and without noninsulin‐dependent diabetes. Am. J. Clin. Nutr. 52: 731–738, 1990.
 191. Unger, R. H.. Lipotoxicity in the pathogenesis of obesity‐dependent NIDDM. Diabetes 44: 863–870, 1995.
 192. Unger, R. H., and L. Orci. Physiology and pathophysiology of glucagon. Physiol. Rev. 56: 778–826, 1976.
 193. Unger, R. H., and L. Orci. Role of glucagon in diabetes. Arch. Intern. Med. 137: 482–491, 1977.
 194. Vardi, P., L., Crisa, and R. A. Jackson. Predictive value of intravenous glucose tolerance test insulin secretion less than or greater than the first percentile in islet cell antibody positive relatives of type 1 (insulin‐dependent) diabetic patients. Diabetologia 34: 93–102, 1991.
 195. Verchere, C. B., D. A., D'Alessio, R. D. Palmiter, G. C. Weir, S. Bonner‐Weir, D. G. Baskin, and S. E. Kahn. Islet amyloid formation associated with hyperglycemia in transgenic mice with pancreatic beta cell expression of human islet amyloid polypeptide. Proc. Natl. Acad. Sci. U.S.A. 93: 3492–3496, 1996.
 196. 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.
 197. Verchere, C. B., S., Kowalyk, G. H. Shen, M. R. Brown, 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.
 198. Wang, Z., R. M., Wang, A. A. Owji, D. M. Smith, M. A. Ghatei, and S. R. Bloom. Glucagon‐like peptide‐1 is a physiological incretin in rat. J. Clin. Invest. 95: 417–421, 1995.
 199. Ward, W. K., D. C., Bolgiano, B. McKnight, J. B. Halter, and D. Porte, Jr.. Diminished B cell secretory capacity in patients with noninsulin‐dependent diabetes mellitus. J. Clin. Invest. 74: 1318–28, 1984.
 200. Ward, W. K., E. C., LaCava, T. L. Paquette, J. C. Beard, B. J. Wallum, and D. Porte, Jr.. Disproportionate elevation of immunoreactive proinsulin in type 2 (non‐insulin‐dependent) diabetes mellitus and experimental insulin resistance. Diabetologia 30: 698–702, 1987.
 201. Ward, W. K., B. J., Wallum, J. C. Beard, G. J. Taborsky, Jr., and D. Porte, Jr.. Reduction of glycemic potentiation. Sensitive indicator of beta‐cell loss in partially pancreatectomized dogs. Diabetes 37: 723–729, 1988.
 202. Weir, G. C., S. D., Knowlton, R. F. Atkins, K. X. McKennan, and D. B. Martin. Glucagon secretion from the perfused pancreas of streptozotocin‐treated rats. Diabetes 25: 275–282, 1976.
 203. Westermark, G., M., Benig‐Arora, N. Fox, R. Carroll, S. J. Chan, P. Westerman, and D. F. Steiner. Amyloid formation in response to B‐cell stress occurs in vitro, but not in vivo, in islets of transgenic mice expressing human islet amyloid polypeptide. Mol. Med. 1: 542–553, 1995.
 204. Westermark, P.. Amyloid and polypeptide hormones: what is their relationship? Amyloid: Int. J. Exp. Clin. Invest. 1: 47–60, 1994.
 205. Williams, J. A., and I. D. Goldfine. The insulin–acinar relationship. In: The Pancreas: Biology, Pathobiology and Disease, edited by V. L. W. Go. New York: Raven, 1993, p. 789–802.
 206. Wisen, O., H., Bjorvell, P. Cantor, C. Johansson, and E. Theodorsson. Plasma concentrations of regulatory peptides in obesity following modified sham feeding (MSF) and a liquid test meal. Regul. Pept. 39: 43–54, 1992.
 207. Young, J. B., and L. Landsberg. Effect of diet and cold exposure on norepinephrine turnover in pancreas and liver. Am. J. Physiol. 236 (Endocrinol Metab Gastrointest. Physiol. 5): E524–E533, 1979.
 208. Zawalich, W. S.. Modulation of insulin secretion from beta‐cells by phosphoinositide‐derived second‐messenger molecules. Diabetes 37: 137–141, 1988.
 209. Zhou, Y. P., and V. E. Grill. Long‐term exposure of rat pancreatic islets to fatty acids inhibits glucose‐induced insulin secretion and biosynthesis through a glucose fatty acid cycle. J. Clin. Invest. 93: 870–876, 1994.
 210. Zhou, Y. P., and V. E. Grill. Palmitate‐induced beta‐cell insensitivity to glucose is coupled to decreased pyruvate dehydrogenase activity and enhanced kinase activity in rat pancreatic islets. Diabetes 44: 394–399, 1995.
 211. Zhou, Y.‐P., D. A., Priestman, P. J. Randle, and V. E. Grill. Fasting and decreased B cell sensitivity: important role for fatty acid–induced inhibition of PDH activity. Am. J. Physiol. 270 (Endocrinol. Metab. 33): E988–E994, 1996.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Insulin and Glucagon Secretion in vivo and its Neural Control
 

How to Cite

Gerald J. Taborsky. Insulin and Glucagon Secretion in vivo and its Neural Control. Compr Physiol 2011, Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism: 153-176. First published in print 2001. doi: 10.1002/cphy.cp070206