Syntaxin 4 heterozygous knockout mice develop muscle insulin resistance

J Clin Invest. 2001 May;107(10):1311-8. doi: 10.1172/JCI12274.


To investigate the physiological function of syntaxin 4 in the regulation of GLUT4 vesicle trafficking, we used homologous recombination to generate syntaxin 4-knockout mice. Homozygotic disruption of the syntaxin 4 gene results in early embryonic lethality, whereas heterozygous knockout mice, Syn4(+/-), had normal viability with no significant impairment in growth, development, or reproduction. However, the Syn4(+/-) mice manifested impaired glucose tolerance with a 50% reduction in whole-body glucose uptake. This defect was attributed to a 50% reduction in skeletal muscle glucose transport determined by 2-deoxyglucose uptake during hyperinsulinemic-euglycemic clamp procedures. In parallel, insulin-stimulated GLUT4 translocation in skeletal muscle was also significantly reduced in these mice. In contrast, Syn4(+/-) mice displayed normal insulin-stimulated glucose uptake and metabolism in adipose tissue and liver. Together, these data demonstrate that syntaxin 4 plays a critical physiological role in insulin-stimulated glucose uptake in skeletal muscle. Furthermore, reduction in syntaxin 4 protein levels in this tissue can account for the impairment in whole-body insulin-stimulated glucose metabolism in this animal model.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adipocytes / physiology
  • Adipose Tissue, Brown
  • Animals
  • Biological Transport
  • Glucose / metabolism*
  • Glucose Clamp Technique
  • Glucose Tolerance Test
  • Glucose Transporter Type 4
  • Glycogen / metabolism
  • Glycolysis
  • Heterozygote
  • Insulin Resistance / genetics*
  • Liver / metabolism
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Knockout
  • Monosaccharide Transport Proteins / metabolism*
  • Muscle Proteins*
  • Muscle, Skeletal / physiology*
  • Qa-SNARE Proteins


  • Glucose Transporter Type 4
  • Membrane Proteins
  • Monosaccharide Transport Proteins
  • Muscle Proteins
  • Qa-SNARE Proteins
  • Slc2a4 protein, mouse
  • Glycogen
  • Glucose