Mitogen‐inducible gene 6 haploinsufficiency protects mice against streptozotocin‐induced diabetes (1108.11)

Abstract

Epidermal growth factor (EGF) and gastrin co‐administration is effective in correcting hyperglycemia and pancreatic beta cell mass deficiencies in various type 1 diabetes (T1D) rodent models, yet the failure in clinical translation of this treatment implies that EGF‐mediated tissue repair is a complicated process warranting further investigation. In this study, we aimed to determine if EGF receptor feedback inhibition by Mitogen‐inducible Gene 6 (Mig6) contributes to the development of T1D. We hypothesized that Mig6 haploinsufficiency, and hence heightened EGFR signaling, would abrogate T1D development in mice. To this end, we treated Mig6 haploinsufficient mice (Mig6+/‐) and their wild‐type littermates (Mig6+/+) with multiple low doses of streptozotocin (STZ) to induce beta cell death and diabetes. We found that whereas STZ‐treated Mig6+/+ mice became diabetic, STZ‐treated Mig6+/‐ mice remained fully glucose tolerant. Concurrently, STZ‐treated Mig6+/‐ mice exhibited preserved levels of circulating insulin following a glucose challenge. As insulin sensitivity was similar between Mig6+/‐ and Mig6+/+ mice, the preserved glucose tolerance in STZ‐treated Mig6+/‐ mice is likely the result of preserved beta cell function. Conversely, Mig6 overexpression in isolated islets compromises glucose‐stimulated insulin secretion. In vitro studies in 832/13 INS‐1 beta cells suggested that Mig6 hinders EGF receptor activation, thereby inhibiting EGF‐mediated DNA damage repair. Finally, STZ‐treated Mig6+/‐ mice have greater beta cell mass recovery at 20 days post‐STZ. These data demonstrate that a reduction in Mig6 promotes beta cell damage repair, thus abating the progression of T1D. Our work suggests that Mig6 may be a novel therapeutic target for T1D.Grant Funding Source: Supported by NIH grant DK078732 and a DeVault Fellowship from IUSM