Alpha Parvin Promotes Glucose Uptake and Metabolism in Skeletal Muscle with Minimal Influence on Hepatic Insulin Sensitivity

Skeletal muscle and liver insulin resistance are early features in the sequelae of type 2 diabetes. Integrins are extracellular matrix receptors expressed on skeletal muscle cells and hepatocytes and have been implicated in modulating obesity-associated insulin resistance. Integrins regulate cell function through intracellular proteins including the ILK-PINCH-Parvin (IPP) complex. ILK promotes skeletal muscle and liver insulin resistance in diet-induced obesity in mice but the role of Parvin is unexplored. Here we demonstrate that hepatocyte specific deletion of -Parvin had only minimal influence on endogenous glucose production or whole-body insulin sensitivity. In contrast, deletion of -Parvin in skeletal muscle caused a striking reduction in muscle glucose uptake during an insulin clamp in lean mice which was not exacerbated by diet-induced obesity. Insulin-mediated GLUT4 membrane recruitment was impaired in mutant muscles which displayed significant morphological abnormalities due to actin cytoskeleton dysfunction. Consistent with severe muscular dysfunction, mitochondrial oxidative capacity and aerobic exercise capacity were blunted in muscle -Parvin-null mice. Thus, -Parvin has a minor role in liver insulin action but is required for insulin-stimulated glucose uptake in skeletal muscle due to its role in actin cytoskeleton regulation. These data suggest that individual IPP complex proteins link cell structure to metabolism via distinct mechanisms in a tissue-specific fashion.