α-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, which have been implicated in modulating obesity-associated insulin resistance. Integrins regulate cell function through intracellular proteins including the ILK-PINCH-Parvin (IPP) complex. ILK signaling amplifies skeletal muscle and liver insulin resistance in diet-induced obesity in mice but the role of α-Parvin is unexplored. The hyperinsulinemic-euglycemic clamp was used to assess hepatic and muscle insulin action. We demonstrate that deletion of hepatocyte-specific α-Parvin had only minimal influence on obesity-induced liver or whole-body insulin resistance. In contrast, deletion of α-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. The decrease in muscle glucose uptake in lean mice was due to a decrease in insulin-mediated GLUT4 membrane recruitment, which was associated with significant morphological abnormalities including actin cytoskeleton dysfunction. In addition, severe muscular dysfunction, blunted mitochondrial oxidative capacity and reduced aerobic exercise capacity were manifest in muscle α-Parvin KO mice. Thus, α-Parvin has a minor role in liver insulin action but is required for insulin-stimulated glucose uptake in skeletal muscle in lean mice 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.