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Glycoprotein 130 receptor signaling mediates α-cell dysfunction in a rodent model of type 2 diabetes

Published inDiabetes, vol. 63, no. 9, p. 2984-2995
Publication date2014
Abstract

Dysregulated glucagon secretion accompanies islet inflammation in type 2 diabetes. We recently discovered that interleukin (IL)-6 stimulates glucagon secretion from human and rodent islets. IL-6 family cytokines require the glycoprotein 130 (gp130) receptor to signal. In this study, we elucidated the effects of α-cell gp130 receptor signaling on glycemic control in type 2 diabetes. IL-6 family cytokines were elevated in islets in rodent models of this disease. gp130 receptor activation increased STAT3 phosphorylation in primary α-cells and stimulated glucagon secretion. Pancreatic α-cell gp130 knockout (αgp130KO) mice showed no differences in glycemic control, α-cell function, or α-cell mass. However, when subjected to streptozotocin plus high-fat diet to induce islet inflammation and pathophysiology modeling type 2 diabetes, αgp130KO mice had reduced fasting glycemia, improved glucose tolerance, reduced fasting insulin, and improved α-cell function. Hyperinsulinemic-euglycemic clamps revealed no differences in insulin sensitivity. We conclude that in a setting of islet inflammation and pathophysiology modeling type 2 diabetes, activation of α-cell gp130 receptor signaling has deleterious effects on α-cell function, promoting hyperglycemia. Antagonism of α-cell gp130 receptor signaling may be useful for the treatment of type 2 diabetes.

Keywords
  • Animals
  • Cytokine Receptor gp130/antagonists & inhibitors/metabolism
  • Diabetes Mellitus, Experimental/physiopathology
  • Diabetes Mellitus, Type 2/physiopathology
  • Diet, High-Fat
  • Glucagon/secretion
  • Glucagon-Secreting Cells/metabolism
  • Interleukin-6/metabolism/pharmacology
  • Male
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Rats
  • STAT3 Transcription Factor/metabolism
Citation (ISO format)
CHOW, Samuel Z et al. Glycoprotein 130 receptor signaling mediates α-cell dysfunction in a rodent model of type 2 diabetes. In: Diabetes, 2014, vol. 63, n° 9, p. 2984–2995. doi: 10.2337/db13-1121
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Article (Published version)
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ISSN of the journal0012-1797
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