Insulin Signaling in α-cells Modulates Glucagon Secretion in vivo

Glucagon plays an important role in glucose homeostasis by regulating hepatic glucose output in both normoand hypoglycemic conditions. In this study, we created and characterized alpha cell-specific insulin receptor knockout (alphaIRKO) mice to directly explore the role of insulin signaling in the regulation of glucagon secretion in vivo. Adult male alphaIRKO mice exhibited mild glucose intolerance, hyperglycemia, and hyperglucagonemia in the fed state and enhanced glucagon secretion in response to L-arginine stimulation. Hyperinsulinemic-hypoglycemic clamp studies revealed an enhanced glucagon secretory response and an abnormal norepinephrine response to hypoglycemia in alphaIRKO mice. The mutants also exhibited an age-dependent increase in beta cell mass. Furthermore, siRNA-mediated knockdown of insulin receptor in glucagon-secreting InR1G cells promoted enhanced glucagon secretion and complemented our in vivo findings. Together, these data indicate a significant role for intraislet insulin signaling in the regulation of alpha cell function in both normoand hypoglycemic conditions. KAWAMORI, Dan, et al. Insulin signaling in alpha cells modulates glucagon secretion in vivo. Cell Metabolism, 2009, vol. 9, no. 4, p. 350-361 DOI : 10.1016/j.cmet.2009.02.007

[1]  E. Oetjen,et al.  Loss of insulin-induced inhibition of glucagon gene transcription in hamster pancreatic islet alpha cells by long-term insulin exposure , 2008, Diabetologia.

[2]  Hui Li,et al.  Disruption of leptin receptor expression in the pancreas directly affects beta cell growth and function in mice. , 2007, The Journal of clinical investigation.

[3]  J. Gromada,et al.  Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains. , 2007, Endocrine reviews.

[4]  J. Bryan,et al.  Zinc, not insulin, regulates the rat alpha-cell response to hypoglycemia in vivo. , 2007, Diabetes.

[5]  A. Salehi,et al.  Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells , 2007, Diabetologia.

[6]  M. J. Charron,et al.  Ablation of the glucagon receptor gene increases fetal lethality and produces alterations in islet development and maturation. , 2006, Endocrinology.

[7]  A. Salehi,et al.  Paradoxical Stimulation of Glucagon Secretion by High Glucose Concentrations , 2006, Diabetes.

[8]  N. Diamant,et al.  Insulin regulates islet alpha-cell function by reducing KATP channel sensitivity to adenosine 5'-triphosphate inhibition. , 2006, Endocrinology.

[9]  Tasneem S. Ansari,et al.  Counterregulatory deficits occur within 24 h of a single hypoglycemic episode in conscious, unrestrained, chronically cannulated mice. , 2006, American journal of physiology. Endocrinology and metabolism.

[10]  Johannes D Veldhuis,et al.  Postprandial suppression of glucagon secretion depends on intact pulsatile insulin secretion: further evidence for the intraislet insulin hypothesis. , 2006, Diabetes.

[11]  H. Kaneto,et al.  The Forkhead Transcription Factor Foxo1 Bridges the JNK Pathway and the Transcription Factor PDX-1 through Its Intracellular Translocation* , 2006, Journal of Biological Chemistry.

[12]  Y. Zhang,et al.  Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system. , 2006, Cell metabolism.

[13]  M. Foretz,et al.  Regulation of glucagon secretion by glucose transporter type 2 (glut2) and astrocyte-dependent glucose sensors. , 2005, The Journal of clinical investigation.

[14]  O. Gavrilova,et al.  Increased glucose tolerance and reduced adiposity in the absence of fasting hypoglycemia in mice with liver-specific Gs alpha deficiency. , 2005, The Journal of clinical investigation.

[15]  R. Sherwin,et al.  Activation of ATP-sensitive K+ channels in the ventromedial hypothalamus amplifies counterregulatory hormone responses to hypoglycemia in normal and recurrently hypoglycemic rats. , 2005, Diabetes.

[16]  S. Theander,et al.  Beta-cell secretory products activate alpha-cell ATP-dependent potassium channels to inhibit glucagon release. , 2005, Diabetes.

[17]  M. Ravier,et al.  Glucose or insulin, but not zinc ions, inhibit glucagon secretion from mouse pancreatic alpha-cells. , 2005, Diabetes.

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

[19]  R. Sherwin,et al.  Hypothalamic ATP-sensitive K + channels play a key role in sensing hypoglycemia and triggering counterregulatory epinephrine and glucagon responses. , 2004, Diabetes.

[20]  R. Robertson,et al.  Regulation of alpha-cell function by the beta-cell during hypoglycemia in Wistar rats: the "switch-off" hypothesis. , 2004, Diabetes.

[21]  R. Robertson,et al.  Regulation of alpha-cell function by the beta-cell in isolated human and rat islets deprived of glucose: the "switch-off" hypothesis. , 2004, Diabetes.

[22]  Ahmed Mansouri,et al.  Opposing actions of Arx and Pax4 in endocrine pancreas development. , 2003, Genes & development.

[23]  A. Barthel,et al.  Novel concepts in insulin regulation of hepatic gluconeogenesis. , 2003, American journal of physiology. Endocrinology and metabolism.

[24]  J. Holst,et al.  Lower blood glucose, hyperglucagonemia, and pancreatic α cell hyperplasia in glucagon receptor knockout mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[25]  C. Wollheim,et al.  Islet beta-cell secretion determines glucagon release from neighbouring alpha-cells. , 2003, Nature cell biology.

[26]  In Kyu Lee,et al.  Selective beta-cell loss and alpha-cell expansion in patients with type 2 diabetes mellitus in Korea. , 2003, The Journal of clinical endocrinology and metabolism.

[27]  K. Prasadan,et al.  Glucagon is required for early insulin-positive differentiation in the developing mouse pancreas. , 2002, Diabetes.

[28]  Angel Pizarro,et al.  Functional genomics of the endocrine pancreas: the pancreas clone set and PancChip, new resources for diabetes research. , 2002, Diabetes.

[29]  M. Stoffel,et al.  beta-cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass. , 2002, Nature genetics.

[30]  L Raeymaekers,et al.  Basic principles of quantitative PCR , 2000, Molecular biotechnology.

[31]  P. Herrera,et al.  Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages. , 2000, Development.

[32]  B. AhrØn,et al.  Autonomic regulation of islet hormone secretion ± Implications for health and disease , 2000 .

[33]  D. Hanahan,et al.  Altered function of insulin receptor substrate-1-deficient mouse islets and cultured beta-cell lines. , 1999, The Journal of clinical investigation.

[34]  J. Habener,et al.  The glucagon-like peptides. , 1999, Endocrine reviews.

[35]  C. Kahn,et al.  Tissue-Specific Knockout of the Insulin Receptor in Pancreatic β Cells Creates an Insulin Secretory Defect Similar to that in Type 2 Diabetes , 1999, Cell.

[36]  Philippe Soriano.  Generalized lacZ expression with the ROSA26 Cre reporter strain , 1999, Nature Genetics.

[37]  P. Froguel,et al.  Defective insulin secretion in hepatocyte nuclear factor 1alpha-deficient mice. , 1998, The Journal of clinical investigation.

[38]  A. Scheen,et al.  Assessment of residual insulin secretion in diabetic patients using the intravenous glucagon stimulatory test: methodological aspects and clinical applications. , 1996, Diabetes & metabolism.

[39]  P. Cryer.  Hypoglycemia: The Limiting Factor in the Management of IDDM , 1994, Diabetes.

[40]  P. Cryer.  Hypoglycemia Unawareness in IDDM , 1993, Diabetes Care.

[41]  G. Shulman,et al.  Impaired hormonal responses to hypoglycemia in spontaneously diabetic and recurrently hypoglycemic rats. Reversibility and stimulus specificity of the deficits. , 1993, The Journal of clinical investigation.

[42]  C. Greenbaum,et al.  Intra-islet insulin permits glucose to directly suppress pancreatic A cell function. , 1991, The Journal of clinical investigation.

[43]  P. Cryer,et al.  Reduced Neuroendocrine and Symptomatic Responses to Subsequent Hypoglycemia After 1 Episode of Hypoglycemia in Nondiabetic Humans , 1991, Diabetes.

[44]  P. Rorsman,et al.  Glucose-inhibition of glucagon secretion involves activation of GABAA-receptor chloride channels , 1989, Nature.

[45]  J. Philippe.  Glucagon gene transcription is negatively regulated by insulin in a hamster islet cell line. , 1989, The Journal of clinical investigation.

[46]  E. Samols,et al.  Intra-islet regulation. , 1988, The American journal of medicine.

[47]  D. Drucker,et al.  Proglucagon gene expression and posttranslational processing in a hamster islet cell line. , 1988, Endocrinology.

[48]  W. Tamborlane,et al.  Effect of Intensive Insulin Therapy on Glycemic Thresholds for Counterregulatory Hormone Release , 1988, Diabetes.

[49]  E. Samols,et al.  Retrograde perfusion as a model for testing the relative effects of glucose versus insulin on the A cell. , 1986, The Journal of clinical investigation.

[50]  L. Orci,et al.  Insulin within islets is a physiologic glucagon release inhibitor. , 1984, The Journal of clinical investigation.

[51]  L. Orci,et al.  New Perspectives on the Microvasculature of the Islets of Langerhans in the Rat , 1982, Diabetes.

[52]  J. Palmer,et al.  In vivo inhibition of glucagon secretion by paracrine beta cell activity in man. , 1981, The Journal of clinical investigation.

[53]  R. Unger,et al.  Role of glucagon in the pathogenesis of diabetes: the status of the controversy. , 1978, Metabolism: clinical and experimental.

[54]  L. Orci,et al.  The role of glucagon in the endogenous hyperglycemia of diabetes mellitus. , 1977, Annual review of medicine.

[55]  L. Orci,et al.  Hypertrophy and hyperplasia of somatostatin-containing D-cells in diabetes. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[56]  G. Weir,et al.  Glucagon Secretion from the Perfused Pancreas of Streptozotocin-treated Rats , 1976, Diabetes.

[57]  E. Tsalikian,et al.  Normalization of fasting hyperglucagonemia and excessive glucagon responses to intravenous arginine in human diabetes mellitus by prolonged infusion of insulin. , 1975, The Journal of clinical endocrinology and metabolism.

[58]  R. Guillemin,et al.  Inhibition of Pancreatic Glucagon Responses to Arginine by Somatostatin in Normal Man and in Insulin-Dependent Diabetics , 1974, Diabetes.

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

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

[61]  R. Butcher,et al.  Gluconeogenesis in the perfused liver. The effects of fasting, alloxan diabetes, glucagon, epinephrine, adenosine 3',5'-monophosphate and insulin. , 1966, The American journal of medicine.