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

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

    21 Citationer (Scopus)

    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.

    OriginalsprogEngelsk
    TidsskriftDiabetes
    Vol/bind63
    Udgave nummer9
    Sider (fra-til)2984-95
    Antal sider12
    ISSN0012-1797
    DOI
    StatusUdgivet - sep. 2014

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