Development of Glucose Intolerance in Male Transgenic Mice Overexpressing Human Glycogen Synthase kinase-3beta on a Muscle-Specific Promoter

Metabolism. 2004 Oct;53(10):1322-30. doi: 10.1016/j.metabol.2004.05.008.


Glycogen synthase kinase-3 (GSK-3) protein levels and activity are elevated in skeletal muscle in type 2 diabetes, and inversely correlated with both glycogen synthase activity and insulin-stimulated glucose disposal. To explore this relationship, we have produced transgenic mice that overexpress human GSK-3beta in skeletal muscle. GSK-3beta transgenic mice were heavier, by up to 20% (P < .001), than their age-matched controls due to an increase in fat mass. The male GSK-3beta transgenic mice had significantly raised plasma insulin levels and by 24 weeks of age became glucose-intolerant as determined by a 50% increase in the area under their oral glucose tolerance curve (P < .001). They were also hyperlipidemic with significantly raised serum cholesterol (+90%), nonesterified fatty acids (NEFAs) (+55%), and triglycerides (+170%). At 29 weeks of age, GSK-3beta protein levels were 5-fold higher, and glycogen synthase activation (-27%), glycogen levels (-58%) and insulin receptor substrate-1 (IRS-1) protein levels (-67%) were significantly reduced in skeletal muscle. Hepatic glycogen levels were significantly increased 4-fold. Female GSK-3beta transgenic mice did not develop glucose intolerance despite 7-fold overexpression of GSK-3beta protein and a 20% reduction in glycogen synthase activation in skeletal muscle. However, plasma NEFAs and muscle IRS-1 protein levels were unchanged in females. We conclude that overexpression of human GSK-3beta in skeletal muscle of male mice resulted in impaired glucose tolerance despite raised insulin levels, consistent with the possibility that elevated levels of GSK-3 in type 2 diabetes are partly responsible for insulin resistance.

MeSH terms

  • Animals
  • Blotting, Western
  • Body Composition / physiology
  • Body Weight / physiology
  • DNA Primers
  • DNA, Complementary / biosynthesis
  • DNA, Complementary / genetics
  • Female
  • Glucose Intolerance / genetics*
  • Glucose Tolerance Test
  • Glycogen / metabolism
  • Glycogen Synthase Kinase 3 / biosynthesis*
  • Glycogen Synthase Kinase 3 / genetics*
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance / genetics
  • Insulin Resistance / physiology
  • Lipids / blood
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / physiology*
  • Phenotype
  • Phosphoproteins / biosynthesis
  • Phosphoproteins / genetics
  • Promoter Regions, Genetic / physiology*
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction


  • DNA Primers
  • DNA, Complementary
  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Lipids
  • Phosphoproteins
  • RNA, Messenger
  • Glycogen
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3