Syntaxin 4 heterozygous knockout mice develop muscle insulin resistance

To investigate the physiological function of syntaxin 4 in the regulation o f GLUT4 vesicle trafficking, we used homologous recombination to generate s yntaxin 4-knockout mice. Homozygotic disruption of the syntaxin 4 gene resu lts in early embryonic lethality, whereas heterozygous knockout mice, Syn4( +/-\), had normal viability with no significant impairment in growth, devel opment, or reproduction. However, the Syn4(+/-) mice manifested impaired gl ucose tolerance with a 50% reduction in whole-body glucose uptake. This def ect was attributed to a 50% reduction in skeletal muscle glucose transport determined by 2-deoxyglucose uptake during hyperinsulinemic-euglycemic clam p procedures. In parallel, insulin-stimulated GLUT4 translocation in skelet al 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 i n skeletal muscle. Furthermore, reduction in syntaxin 4 protein levels in t his tissue can account for the impairment in whole-body insulin-stimulated glucose metabolism in this animal model.