Mig6 haploinsufficiency protects mice against streptozotocin-induced diabetes

Aims/hypothesis EGF and gastrin co-administration reverses type 1 diabetes in rodent models. However, the failure of this to translate into a clinical treatment suggests that EGF-mediated tissue repair is a complicated process and warrants further investigation. Thus, we aimed to determine whether EGF receptor (EGFR) feedback inhibition by mitogen-inducible gene 6 protein (MIG6) limits the effectiveness of EGF therapy and promotes type 1 diabetes development. Methods We treated Mig6 (also known as Errfi1) haploinsufficient mice (Mig6(+/-)) and their wild-type littermates (Mig6(+/+)) with multiple low doses of streptozotocin (STZ), and monitored diabetes development via glucose homeostasis tests and histological analyses. We also investigated MIG6-mediated cytokine-induced desensitisation of EGFR signalling and the DNA damage repair response in 832/13 INS-1 beta cells. Results Whereas STZ-treated Mig6(+/+) mice became diabetic, STZ-treated Mig6(+/-) mice remained glucose tolerant. In addition, STZ-treated Mig6(+/-) mice exhibited preserved circulating insulin levels following a glucose challenge. As insulin sensitivity was similar between Mig6(+/-) and Mig6(+/+) mice, the preserved glucose tolerance in STZ-treated Mig6(+/-) mice probably results from preserved beta cell function. This is supported by elevated Pdx1 and Irs2 mRNA levels in islets isolated from STZ-treated Mig6(+/-) mice. Conversely, MIG6 overexpression in isolated islets compromises glucose-stimulated insulin secretion. Studies in 832/13 cells suggested that cytokine-induced MIG6 hinders EGFR activation and inhibits DNA damage repair. STZ-treated Mig6(+/-) mice also have increased beta cell mass recovery. Conclusions/interpretation Reducing Mig6 expression promotes beta cell repair and abates the development of experimental diabetes, suggesting that MIG6 may be a novel therapeutic target for preserving beta cells.