Loss of Pancreatic Mitogen‐inducible Gene 6 Protects Mice Against Streptozotocin‐induced Diabetes

Abstract

Type 1 diabetes (T1D) is caused by autoimmune‐mediated beta cell destruction. Following destruction, the pancreas attempts to mount a cellular repair/regenerative program, although this response is unable to fully restore functional beta cell mass. Epidermal growth factor receptor signaling (EGFR) is one component of the regenerative program. We previously demonstrated that a negative feedback inhibitor of EGFR, Mitogen‐inducible gene 6 (Mig6), is induced by pro‐inflammatory cytokines thought to participate in T1D‐mediated beta cell destruction, which may explain the inability to mount successful beta cell restoration in T1D. Thus, we hypothesized that a loss of Mig6 in the pancreas would confer resistance to a chemically‐induced form of diabetes. To this end, wetreated 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. We found that whereas STZ‐treated WT mice became hyperglycemic and glucose intolerant, STZ‐treated PKO mice remained euglycemic and fully glucose tolerant. We also demonstrated that pro‐inflammatory cytokines suppress EGFR activation, which can be partially corrected by siRNA‐mediated suppression of Mig6. Further, nitric oxide itself, the downstream toxic component of cytokines, induces Mig6, and nitric oxide synthase inhibition blocks the induction of Mig6 and EGFR signaling impairment mediated by cytokines. These data demonstrate that ablation of Mig6 promotes beta cell damage repair, thus abating the progression to T1D. Our work suggests that Mig6 may be a novel therapeutic target for T1D.