Restoration of Insulin-Receptor Expression in Adulthood Reverses Diabetic Phenotype in Type 2 Diabetes Models

Type 2 diabetes mellitus (T2DM) is characterized by ineffective insulin action due to adult onset insulin resistance. Insulin receptor (IR) tissue content reduction in diabetes is one key contributor to the defective insulin signaling and diabetes progression. Rescuing IR levels by transgenic complementation attained beneficial effects. However, such an approach has not been considered as a treatment option since it did not always match physiological expression level or tissue selectivity and was accompanied with developmental defects as reported. In the current study, we showed that expression of human IR (hIR) via a single adeno-associated virus (AAV) administration in adult ob/ob mice normalized blood glucose and plasma triglyceride (TG) to the levels of healthy control mice and significantly lowered liver TG level with long-lasting improvement in insulin sensitivity. To further examine if this approach is applicable for treating adult onset diabetes, we generated inducible whole body IR knockout (iIRKO) mice and successfully induced hyperglycemia, hyperinsulinemia and abnormal liver TG level at 3 months of age. Injection of AAV-hIR reversed tamoxifen-induced diabetic phenotype in iIRKO mice. Western blot analysis showed that while ob/ob and iIRKO mice had IR reduction detected in all metabolic tissues, their diabetic phenotypes were largely rescued by liver tropic IR expression via AAV delivery. More interestingly, the current method had no significant effect on IR expression or metabolism in healthy animals, suggesting that the approach restores IR level only as “needed” to maintain normal energy metabolism so it does not increase the risk of excessive insulin action, such as hypoglycemia. The approach described here effectively restores IR expression and insulin signaling with long lasting efficacy and low risk, which supports its therapeutic utility in the treatment of T2DM and metabolic disorders. Disclosure Y. Wang: None. H. Zhou: Employee; Self; Merck & Co., Inc.. J. Mu: None.