Redistribution of substrates to adipose tissue promotes obesity in mice with selective insulin resistance in muscle

Obesity and insulin resistance in skeletal muscle are two major factors in the pathogenesis of type 2 diabetes. Mice with muscle-specific inactivation of the insulin receptor gene (MIRKO) are normo-glycemic but have increased fat mass. To identify the potential mechanism for this important associati on, we examined insulin action in specific tissues of MIRKO and control mic e under hyperinsulinemic-euglycemic conditions. We found that insulin-stimu lated muscle glucose transport and glycogen synthesis were decreased by abo ut 80% in MIRKO mice, whereas insulin-stimulated fat glucose transport was increased threefold in MIRKO mice. These data demonstrate that selective in sulin resistance in muscle promotes redistribution of substrates to adipose tissue thereby contributing to increased adiposity and development of the prediabetic syndrome.