Mitogen‐inducible Gene 6 Accelerates the Progression to Diabetes by Inhibiting EGFR‐Mediated Repair Mechanisms

Type 1 diabetes (T1D) is caused by autoimmune‐mediated beta cell destruction. Following beta cell injury, the pancreas initiates a cellular repair or regeneration program, which includes epidermal growth factor receptor (EGFR) signaling. However, upon irreparable beta cell damage, EGFR signaling is dampened, disrupting attempts to restore functional beta cell mass and maintain normoglycemia. We have previously demonstrated that the negative feedback inhibitor of EGFR, Mitogen‐inducible gene 6 (Mig6), is induced by the pro‐inflammatory cytokines central to the autoimmune‐mediated beta cell destruction. We also established that pro‐inflammatory cytokines suppress EGFR activation, and siRNA‐mediated suppression of Mig6 restores EGFR signaling. Thus, we hypothesized that a loss of pancreatic Mig6 would protect mice from a chemically‐induced form of diabetes by enhancing EGFR signaling and promoting cellular repair. To this end, we treated mice lacking pancreatic Mig6 (PKO) and their wild‐type littermates (WT) with multiple low doses of streptozotocin (STZ) to induce beta cell death and diabetes or with saline as a control. Whereas STZ‐treated WT mice became hyperglycemic and had reduced beta cell mass, STZ‐treated PKO mice remained euglycemic and glucose tolerant, due to preserved beta cell mass. In addition, nitric oxide (NO) synthase inhibition blocks both the induction of Mig6 and cytokine‐impaired EGFR signaling, and treatment with an NO donor alone induces Mig6. Thus, we conclude that Mig6 ablation promotes beta cell damage repair, hence abating the progression to T1D. Our work suggests that Mig6 may be a novel therapeutic target for preserving beta cell mass in T1D. Support or Funding Information This work was supported by NIH grant DK099311 (PTF)