Insulin resistance of glucose transport and metabolism in insulin-sensitive tissues is a primary defect leading to the development of type 2 diabetes. While the etiology of insulin resistance is multifactorial, one factor associated with reduced insulin action is enhanced activity of the serine/threonine kinase glycogen synthase kinase-3 (GSK-3) in skeletal muscle, liver, and adipose tissue. GSK-3 is involved in numerous cellular functions, including glycogen synthesis, protein synthesis, gene transcription, and cell differentiation. Evidence from muscle and fat cell lines and in skeletal muscle from a variety of obese rodent models and from type 2 diabetic humans supports a role of GSK-3 overactivity in the development of insulin resistance of glucose transport and glycogenesis. Studies utilizing highly selective GSK-3 inhibitors indicate that GSK-3 overactivity in obesity is associated with enhanced IRS-1 serine phosphorylation and defective IRS-1- dependent signaling, ultimately resulting in reduced GLUT-4 translocation and glucose transport activity in skeletal muscle. A role of GSK-3 overactivity in the exaggerated hepatic glucose production of type 2 diabetes has also been reported. Recent studies have demonstrated that oxidative stress, resulting from enhanced exposure to oxidants, causes impaired insulin signaling and insulin resistance of skeletal muscle glucose transport, in part due to reduced suppression of GSK-3 activity and increased IRS-1 Ser307 phosphorylation. The evidence to date supports an important role of GSK-3 dysfunction in the multifactorial etiology of insulin resistance in skeletal muscle. GSK-3 remains an important target for interventions designed to improve insulin action in obesity-associated insulin resistance and type 2 diabetes.
Keywords: GSK-3, Insulin resistance, Skeletal muscle, Inhibitors, Zucker rat, Oxidative stress, Type 2 Diabetes, Etiology, HYPERGLYCEMIA, High Fat-Fed Lean Zucker Rat, cardiometabolic syndrome, cardiac hypertrophy, serine kinases, JNK, p38 MAPK, IKKβ, GSK-3β, ZDF, 3T3-L1 adipocytes, C2C12 myocytes, adipokines