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Regulation of alpha cell function by gp130 receptor signalling in a rodent model of type 2 diabetes

University of British Columbia

Dysregulated α cell glucagon secretion contributes to post-meal hyperglycemia in pre-diabetes and to hyperglycemia in type 2 diabetes (T2D). Islets in T2D are characterized by chronic inflammation, and recent human data showed increased IL-6 family cytokine expression in T2D islets in a global gene expression study (IL6 mRNA increased 2.75-fold, IL11 mRNA increased 1.61-fold). We recently discovered that IL-6 stimulates glucagon secretion from human and rodent islets. Cytokines of the IL-6 family all require the gp130 receptor to signal. Therefore, we were interested in elucidating the effects of α cell gp130 receptor signalling on glycemic control in T2D. IL-6 family cytokines were elevated in islets in rodent models of T2D. IL-6 induced STAT3 activation in primary α cells and stimulated glucagon secretion in a gp130 receptor-dependent manner. Pancreatic α cell specific gp130 knockout (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 T2D, αgp130KO mice had reduced fasting glycemia, improved glucose tolerance, and improved α cell function. Hyperinsulinemic-euglycemic clamps revealed no differences in insulin sensitivity. Our data strongly suggest that reduced glycemia and improved glucose tolerance in our αgp130KO mice is due to improved α cell function, however further studies are required to elucidate the mechanism of action of gp130 receptor signalling in α cells. We conclude that in a setting of increased islet inflammation such as observed in T2D, activation of α cell gp130 receptor signalling has long-lasting deleterious effects on α cell function, promoting hyperglycemia. Antagonism of α cell gp130 receptor signalling may be useful for the treatment of T2D.

Text

2014-12-23

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/51699

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/