Role of Glycogen Synthase Kinase-3α in Insulin Action in Cultured Human Skeletal Muscle Cells

An association between glycogen synthase kinase-3 (GSK3) in skeletal muscle and insulin resistance has been demonstrated in type 2 diabetic patients. In addition, inhibition of GSK3 improves insulin action. The aim of the present study was to elucidate the role of the α-isoform of GSK3 in insulin resistance in human skeletal muscle cells from nondiabetic subjects maintained in culture. Transfection of muscle cells with specific antisense oligonucleotides resulted in a 30–50% decrease of GSK3α protein expression (P < 0.05). Whereas neither the basal fractional velocity of glycogen synthase (GS FV) (an indicator of the activation state of the enzyme) nor glucose uptake (GU) were altered, reducing GSK3α expression resulted in increases in insulin stimulation of both GS FV and GU. GSK3α overexpression (60–100% increase over control) did not alter basal GS FV or GU but impaired insulin stimulation of both responses. Knockdown of GSKα also led to an increase in insulin receptor substrate-1 protein expression bu...