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

Chow, Samuel Z; Speck, Madeleine; Yoganathan, Piriya; Nackiewicz, Dominika; Hansen, Ann Maria; Ladefoged, Mette; Rabe, Björn; Rose-John, Stefan; Voshol, Peter J; Lynn, Francis C; Herrera, Pedro Luis; Müller, Werner; Ellingsgaard, Helga; Ehses, Jan A

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Title		Glycoprotein 130 receptor signaling mediates α-cell dysfunction in a rodent model of type 2 diabetes
Authors		Chow, Samuel Z Speck, Madeleine Yoganathan, Piriya Nackiewicz, Dominika Hansen, Ann Maria Ladefoged, Mette Rabe, Björn Rose-John, Stefan Voshol, Peter J Lynn, Francis C Herrera, Pedro Luis Müller, Werner Ellingsgaard, Helga Ehses, Jan A show all authors [1 - 14]
Published in		Diabetes. 2014, vol. 63, no. 9, p. 2984-95
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
Identifiers		DOI: 10.2337/db13-1121 PMID: 24812426
Full text		Article (Published version) (2.1 MB) - Free access
Structures		Faculté de médecine / Section de médecine fondamentale / Département de médecine génétique et développement
Research group		Types cellulaires pancréatiques pendant l'ontogénèse (522)
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. 2984-95. https://archive-ouverte.unige.ch/unige:55460