203-LB: Boosted Beta-Cell Function with Selective Deletion of the Adaptor Protein Mig6

Abstract

Type 1 and type 2 diabetes (T1D and T2D) are characterized by absolute and relative insulin deficiency, respectively. Thus, fortifying functional beta cell mass is essential for preventing or reversing either form of diabetes. We have investigated the impact of the adaptor protein mitogen inducible gene 6 (Mig6), a feedback inhibitor of epidermal growth factor receptor (EGFR) signaling induced in the diabetic milieu, on functional beta cell mass in the context of T1D and T2D. Given the importance of EGFR signaling in establishing and maintaining functional beta cell mass, we hypothesized that a selective loss of Mig6 in beta cells would increase functional beta cell mass. To this end, we generated mice lacking Mig6 in beta cells (BKO) using Mig6 floxed and Ins1-Cre knock-in mice and conducted extensive phenotyping, including quantifying beta cell function in vivo with hyperglycemic clamps. Compared to control littermates (CON), BKO mice had comparable beta cell mass, glucose tolerance, and post-prandial blood glucose or insulin concentrations when fed a standard chow diet. Mice underwent surgical catheterization of a carotid artery and jugular vein, and were allowed to recover for 4 days. Following a 5-h fast, mice were administered a primed and subsequent variable glucose infusion designed to clamp blood glucose at 15 mM (270 mg/dl). Target glycemia was achieved by 60 min and remained constant for the duration of the experiment. During the clamp, blood glucose or glucose infusion rates were not different between groups. Whereas beta cell mass was not different between groups, BKO had enhanced beta cell function in vivo, as exhibited by increased insulin secretion; compared to CON, the cumulative circulating insulin during the clamp in BKO was substantially larger (AUC: 340 ± 24 vs. 545 ± 70 ng/ml*120 min). Thus, a loss of Mig6 in beta cells enhances functional beta cell mass by increasing beta cell insulin secretory capacity in vivo. Therefore, Mig6 should be considered as a therapeutic target for diabetes. Disclosure B. M. Bauer: None. E. A. Bloom-saldana: None. J. M. Irimia-dominguez: None. P. T. Fueger: Consultant; Self; Protomer Technologies. Funding National Institutes of Health (R01DK099311)