Dysregulated glucagon secretion accompanies islet inflammation in type 2 diabetes. We recently discovered that IL-6 stimulates glucagon secretion from human and rodent islets. IL-6 family cytokines require the 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 knock out (αgp130KO) mice showed no differences in glycemic control, α cell function or α cell mass. However, when subjected to streptozotocin (STZ) plus high fat diet (HFD) to induce islet inflammation and pathophysiology modelling 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.
- Received July 19, 2013.
- Accepted April 7, 2014.
- © 2014 by the American Diabetes Association.
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