Insulin signaling in alpha cells modulates glucagon secretion in vivo.

Kawamori D, Kurpad AJ, Hu J, Liew CW, Shih JL, Ford EL, Herrera PL, Polonsky KS, McGuinness OP, Kulkarni RN
Cell Metab. 2009 9 (4): 350-61

PMID: 19356716 · PMCID: PMC2694613 · DOI:10.1016/j.cmet.2009.02.007

Glucagon plays an important role in glucose homeostasis by regulating hepatic glucose output in both normo- and 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 normo- and hypoglycemic conditions.

MeSH Terms (20)

Animals Arginine Diabetes Mellitus, Experimental Fasting Feeding Behavior Gene Expression Regulation Glucagon Glucagon-Secreting Cells Glucose Intolerance Hyperinsulinism Hypoglycemia Insulin Insulin-Secreting Cells Mice Mice, Knockout Organ Size Organ Specificity Receptor, Insulin Signal Transduction Streptozocin

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