Da Costa, L.; Saint-Beat, C.; Bron, C.; Lang, A.; Duchampt, A.; Micoud, M.; Evrard, F.; Mithieux, G.; Stein, A. G.

Targeting hepatic gluconeogenesis is an efficient strategy to counteract the development of type 2 diabetes. Hepatic glucose production into the bloodstream is controlled by the GLUT2 transporter and a vesicular pathway dependent on Caveolin-1 (CAV1) involving G6PC1 location at the plasma membrane. We hypothesized that decreasing hepatic gluconeogenesis by targeting CAV1 specifically in the liver (L.Cav1-/- mice) improves energy and glucose metabolism in diabetic mice. Here we show that the absence of hepatic CAV1 increases insulin sensitivity, glucose tolerance and decreases fasting hyperglycemia and hyperinsulinemia in mice feeding a high fat high sucrose diet (HFHS diet). The decrease in insulin sensitivity takes place also in L.Cav1-/- mice feeding a standard diet (STD diet). Moreover, we demonstrated an improvement of glycemic control when hepatic Cav1 is deleted in previously prediabetic mice. In parallel, the absence of CAV1 in the liver reduces body weight gain and lipid intestinal absorption. Together these findings highlight that the vesicular pathway of glucose production represents a promising therapeutic target in the prevention of type 2 diabetes.