title: Syntaxin 4 heterozygous knockout mice develop muscle insulin resistance.
abstract: 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.
authors.affiliation: Department of Physiology and Biophysics, The University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: C
authors.initials: C
authors.lastname: Yang
authors.forename: K J
authors.initials: KJ
authors.lastname: Coker
authors.forename: J K
authors.initials: JK
authors.lastname: Kim
authors.forename: S
authors.initials: S
authors.lastname: Mora
authors.forename: D C
authors.initials: DC
authors.lastname: Thurmond
authors.forename: A C
authors.initials: AC
authors.lastname: Davis
authors.forename: B
authors.initials: B
authors.lastname: Yang
authors.forename: R A
authors.initials: RA
authors.lastname: Williamson
authors.forename: G I
authors.initials: GI
authors.lastname: Shulman
authors.forename: J E
authors.initials: JE
authors.lastname: Pessin
mesh_terms: D017667:Adipocytes / Q000502:physiology; D002001:Adipose Tissue, Brown; D000818:Animals; D001692:Biological Transport; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4; D006003:Glycogen / Q000378:metabolism; D006019:Glycolysis; D006579:Heterozygote; D007333:Insulin Resistance / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000502:physiology*; D050765:Qa-SNARE Proteins
chemical_list: D051275:Glucose Transporter Type 4; D008565:Membrane Proteins; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D050765:Qa-SNARE Proteins; C495693:Slc2a4 protein, mouse; D006003:Glycogen; D005947:Glucose