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Glycoprotein 130 Receptor Signaling Mediates α-Cell Dysfunction in a Rodent Model of Type 2 Diabetes

2014; American Diabetes Association; Volume: 63; Issue: 9 Linguagem: Inglês

10.2337/db13-1121

1939-327X

Samuel Chow, Madeleine Speck, Piriya Yoganathan, Dominika Nąckiewicz, Ann Maria Kruse Hansen, Mette Ladefoged, Björn Rabe, Stefan Rose‐John, Peter J. Voshol, Francis C. Lynn, Pedro L. Herrera, Werner Müller, Helga Ellingsgaard, Jan A. Ehses,

Diabetes and associated disorders

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.