Dysregulation of glycogen synthase kinase-3 in skeletal muscle and the etiology of insulin resistance and type 2 diabetes.

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)285-293
Number of pages9
JournalCurrent Diabetes Reviews
Volume6
Issue number5
StatePublished - Sep 1 2010

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Glycogen Synthase Kinase 3
Type 2 Diabetes Mellitus
Insulin Resistance
Skeletal Muscle
Glucose
Insulin
Obesity
Phosphorylation
Protein-Serine-Threonine Kinases
Liver
Glycogen
Adipocytes
Oxidants
Muscle Cells
Serine
Adipose Tissue
Cell Differentiation
Rodentia
Oxidative Stress
Cell Line

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

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abstract = "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.",
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