Chow, Samuel Z2; Speck, Madeleine2; Yoganathan, Piriya2; Nackiewicz, Dominika2; Hansen, Ann Maria2; Ladefoged, Mette2; Rabe, Björn2; Rose-John, Stefan2; Voshol, Peter J2; Lynn, Francis C2; Herrera, Pedro L2; Müller, Werner2; Ellingsgaard, Helga3; Ehses, Jan A2
1 Infektionsmedicinsk Klinik, Finsencentret, Rigshospitalet, The Capital Region of Denmark2 unknown3 Center for Aktiv Sundhed (CFAS), Finsencentret, Rigshospitalet, The Capital Region of Denmark
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.