The Role of Glycogen Synthase Kinase-3 in Insulin-resistant Skeletal Muscle

The metabolic syndrome is a multifaceted condition characterized by a clustering of metabolic and cardiovascular abnormalities, including insulin resistance in skeletal muscle, adipose tissue and liver, visceral adiposity, hyperinsulinemia, glucose intolerance, dyslipidemia, and essential hypertension. Those affected by this syndrome are at very high risk for developing type 2 diabetes and all of the related sequelae. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that contributes to the multi-factorial etiology of insulin resistance by attenuating insulin signaling in skeletal muscle, thereby decreasing glucose uptake. GSK- 3 is overactive in humans with type 2 diabetes, and in animal models of both type 2 diabetes and the metabolic syndrome (pre-diabetes). Selective GSK-3 inhibition reversed several facets of insulin resistance in the obese Zucker (fa/fa) rat, a model of pre-diabetes and the metabolic syndrome. Acute GSK-3 inhibition in skeletal muscle improved insulin-stimulated glucose uptake and glycogen synthase activity, and enhanced the functionality of key components of the insulin signaling pathway. In addition, GSK-3-β activity was decreased. Chronic selective GSK-3 inhibition improved whole-body insulin-sensitivity, reduced plasma free fatty acids, increased insulin-stimulated glucose uptake into isolated skeletal muscle, and enhanced insulin signaling in skeletal muscle. Oxidative stress is another etiologic component of insulin resistance, and type 2 diabetes is associated with higher levels of oxidant stress. Oxidant stress was induced in isolated muscle of insulin-sensitive lean Zucker rats, a model of normal glucose metabolism. Oxidant stress reduced insulin-stimulated glucose transport, glycogen synthesis, and glycogen synthase activity by ~50%, and reduced the ability of insulin to de-activate GSK-3ß. In the presence of oxidant stress, the GSK-3 inhibitor improved insulin-stimulated glucose transport, insulin stimulated glycogen synthesis, glycogen synthase activity and insulin signaling. Selective GSK-3 inhibition, therefore, partially ameliorated the skeletal muscle insulin resistance caused by oxidative stress. The results of the current study suggest that GSK-3 overactivity contributes to the multi-factorial etiology of obesity-associated insulin resistance as well as insulin resistance related to oxidative stress. Taken together, these findings support the potential of selective GSK-3 inhibition to ameliorate, in part, the insulin resistance associated with the metabolic syndrome and type 2 diabetes, and worsened by oxidative stress