Postprandial suppression of glucagon secretion depends on intact pulsatile insulin secretion: further evidence for the intraislet insulin hypothesis.

Type 2 diabetes is characterized by an approximately 60% loss of beta-cell mass, a marked defect in postprandial insulin secretion, and a failure to suppress postprandial glucagon concentrations. It is possible that postprandial hyperglucagonemia in type 2 diabetes is due to impaired postprandial insulin secretion. To address this, we studied eight adult Goettingen minipigs before and after an approximately 60% reduction in beta-cell mass induced by alloxan. Pigs were studied fasting and after ingestion of a mixed meal. Insulin and glucagon secretion were determined by deconvolution of blood hormone concentrations measured at 1-min intervals. The relationship between insulin and glucagon release was analyzed using cross-correlation and forward versus reverse cross-approximate entropy. We report that glucagon and insulin were secreted in approximately 4-min pulses. Prealloxan, postprandial insulin secretion drove an approximately 20% suppression of glucagon concentrations (P < 0.01), through inhibition of glucagon pulse mass. The alloxan-induced approximately 60% deficit in beta-cell mass lead to an approximately 70% deficit in postprandial insulin secretion and loss of the postprandial insulin-driven suppression of glucagon secretion. We conclude that postprandial hyperglucagonemia in type 2 diabetes is likely due to loss of intraislet postprandial suppression of glucagon secretion by insulin.

[1]  R. Sherwin,et al.  Hyperglucagonemia and blood glucose regulation in normal, obese and diabetic subjects. , 1976, The New England journal of medicine.

[2]  N. Porksen,et al.  Effects of Glucose Ingestion Versus Infusion on Pulsatile Insulin Secretion: The Incretin Effect Is Achieved by Amplification of Insulin Secretory Burst Mass , 1996, Diabetes.

[3]  W. Gepts.  Pathologic Anatomy of the Pancreas in Juvenile Diabetes Mellitus , 1965, Diabetes.

[4]  P. Cryer,et al.  Intraislet hyperinsulinemia prevents the glucagon response to hypoglycemia despite an intact autonomic response. , 2002, Diabetes.

[5]  R. Rizza,et al.  Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration? , 2005, Diabetologia.

[6]  R. Robertson,et al.  Regulation of α-Cell Function by the β-Cell During Hypoglycemia in Wistar Rats: the “Switch-off” Hypothesis , 2004 .

[7]  Robert A. Rizza,et al.  β-Cell Deficit and Increased β-Cell Apoptosis in Humans With Type 2 Diabetes , 2003, Diabetes.

[8]  P. Cryer,et al.  Hypoglycemia-associated autonomic failure in advanced type 2 diabetes. , 2002, Diabetes.

[9]  P. Lefèbvre,et al.  GLUCAGON AND DIABETES , 1996 .

[10]  M. Straume,et al.  Decrease in beta-cell mass leads to impaired pulsatile insulin secretion, reduced postprandial hepatic insulin clearance, and relative hyperglucagonemia in the minipig. , 2001, Diabetes.

[11]  P. Raskin,et al.  Effect of insulin-glucose infusions on plasma glucagon levels in fasting diabetics and nondiabetics. , 1975, The Journal of clinical investigation.

[12]  M. Ravier,et al.  Glucose or Insulin, but not Zinc Ions, Inhibit Glucagon Secretion From Mouse Pancreatic α-Cells , 2005 .

[13]  G. Paolisso,et al.  Pulsatile insulin delivery is more efficient than continuous infusion in modulating islet cell function in normal subjects and patients with type 1 diabetes. , 1988, The Journal of clinical endocrinology and metabolism.

[14]  P. Lefèbvre.  Glucagon and its Family Revisited , 1995, Diabetes Care.

[15]  J D Veldhuis,et al.  Direct measurement of pulsatile insulin secretion from the portal vein in human subjects. , 2000, The Journal of clinical endocrinology and metabolism.

[16]  M. Löhr,et al.  Residual insulin positivity and pancreatic atrophy in relation to duration of chronic Type 1 (insulin-dependent) diabetes mellitus and microangiopathy , 1987, Diabetologia.

[17]  Steven M. Pincus,et al.  Joint synchrony of reciprocal hormonal signaling in human paradigms of both ACTH excess and cortisol depletion. , 2005, American journal of physiology. Endocrinology and metabolism.

[18]  N. Porksen,et al.  Mechanisms of Sulfonylurea's Stimulation of Insulin Secretion In Vivo: Selective Amplification of Insulin Secretory Burst Mass , 1996, Diabetes.

[19]  D. Pipeleers,et al.  Pancreatic beta cells in insulin-dependent diabetes. , 1992, Diabetes/metabolism reviews.

[20]  V. Marks,et al.  The order of islet microvascular cellular perfusion is B----A----D in the perfused rat pancreas. , 1988, The Journal of clinical investigation.

[21]  J. Holst,et al.  Differential regional metabolism of glucagon in anesthetized pigs. , 2003, American journal of physiology. Endocrinology and metabolism.

[22]  N. Porksen,et al.  Effects of somatostatin on pulsatile insulin secretion: elective inhibition of insulin burst mass. , 1996, The American journal of physiology.

[23]  D. Kelley,et al.  Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. , 1992, The New England journal of medicine.

[24]  Ferdinand Roelfsema,et al.  Analysis of bidirectional pattern synchrony of concentration-secretion pairs: implementation in the human testicular and adrenal axes. , 2005, American journal of physiology. Regulatory, integrative and comparative physiology.

[25]  C. Christiansen,et al.  Prevalence of Residual Beta-cell Function in Insulin-Dependent Diabetics in Relation to Age at Onset and Duration of Diabetes , 1978, Diabetes.

[26]  P. Cryer,et al.  Loss of the decrement in intraislet insulin plausibly explains loss of the glucagon response to hypoglycemia in insulin-deficient diabetes: documentation of the intraislet insulin hypothesis in humans. , 2005, Diabetes.

[27]  Y. Seino,et al.  The Novel Insulinotropic Mechanism of Pimobendan: Direct Enhancement of the Exocytotic Process of Insulin Secretory Granules by Increased Ca2+ Sensitivity inβ -Cells. , 1998, Endocrinology.

[28]  M L Johnson,et al.  Deconvolution analysis of hormone data. , 1992, Methods in enzymology.

[29]  S M Pincus,et al.  Approximate entropy as a measure of system complexity. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[30]  C. J. Goodner,et al.  Decreased Insulin- and Glucagon-Pulse Amplitude Accompanying β-Cell Deficiency Induced by Streptozocin in Baboons , 1989, Diabetes.

[31]  Robert L. Hazelwood,et al.  The endocrine pancreas , 1989 .

[32]  Catherine B. Chan,et al.  Glucose-regulated glucagon secretion requires insulin receptor expression in pancreatic alpha-cells. , 2005, The Journal of biological chemistry.

[33]  R. Robertson,et al.  Regulation of α-Cell Function by the β-Cell in Isolated Human and Rat Islets Deprived of Glucose: the “Switch-off” Hypothesis , 2004 .

[34]  C. J. Goodner,et al.  Insulin, glucagon, and glucose exhibit synchronous, sustained oscillations in fasting monkeys. , 1977, Science.

[35]  K. Polonsky,et al.  Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus. , 1988, The New England journal of medicine.

[36]  N. Porksen,et al.  In humans at least 75% of insulin secretion arises from punctuated insulin secretory bursts. , 1997, American journal of physiology. Endocrinology and metabolism.

[37]  W. A. Müller,et al.  Studies of pancreatic alpha cell function in normal and diabetic subjects. , 1970, The Journal of clinical investigation.

[38]  J. Gerich,et al.  Lack of Glucagon Response to Hypoglycemia in Diabetes: Evidence for an Intrinsic Pancreatic Alpha Cell Defect , 1973, Science.

[39]  G. Paolisso,et al.  Pulsatility of insulin and glucagon release: physiological significance and pharmacological implications , 1987, Diabetologia.

[40]  Catherine B. Chan,et al.  Glucose-regulated Glucagon Secretion Requires Insulin Receptor Expression in Pancreatic α-Cells* , 2005, Journal of Biological Chemistry.

[41]  L. Orci,et al.  Role of glucagon in diabetes. , 1977, Archives of internal medicine.

[42]  P. Raskin,et al.  Hyperglucagonemia and its suppression. Importance in the metabolic control of diabetes. , 1978, The New England journal of medicine.

[43]  N. Porksen,et al.  Pulsatile insulin secretion accounts for 70% of total insulin secretion during fasting. , 1995, The American journal of physiology.