Disruption of Adipose Rab10-Dependent Insulin Signaling Causes Hepatic Insulin Resistance.

Insulin controls glucose uptake into adipose and muscle cells by regulating the amount of the Glut4 glucose transporter in the plasma membrane. The effect of insulin is to promote translocation of intracellular Glut4 to the plasma membrane. The small Rab GTPase Rab10 is required for insulin-stimulated Glut4 translocation in cultured 3T3-L1 adipocytes. Here we demonstrate that both insulin-stimulated glucose uptake and Glut4 translocation to the plasma membrane are reduced by about half in adipocytes from adipose-specific Rab10 knockout mice. These data demonstrate that the full effect of insulin on adipose glucose uptake is the integrated effect of Rab10-dependent and Rab10-independent pathways, establishing a divergence in insulin signal transduction to the regulation of Glut4 trafficking. In adipose-specific Rab10 knockout female mice, the partial inhibition of stimulated glucose uptake in adipocytes induces insulin resistance independent of diet challenge. During euglycemic-hyperinsulinemic clamp, there is no suppression of hepatic glucose production despite normal insulin suppression of plasma free fatty acids. The impact of incomplete disruption of stimulated adipocyte Glut4 translocation on whole body glucose homeostasis is driven by a near complete failure of insulin to suppress hepatic glucose production rather than a significant inhibition in muscle glucose uptake. These data underscore the physiologic significance of precise control of insulin regulated trafficking in adipocytes.