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 Ser(307) 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.