The disruption of Munc18c binding to
syntaxin 4 impairs
insulin-stimulated GLUT4 vesicle translocation in 3T3L1 adipocytes. To investigate the physiological function and requirement for Munc18c in the regulation of GLUT4 translocation and
glucose homeostasis in vivo, we used homologous recombination to generate Munc18c-knockout (KO) mice. Homozygotic disruption of the Munc18c gene resulted in early embryonic lethality, whereas heterozygous KO mice (Munc18c(-/+)) had normal viability. Munc18c(-/+) mice displayed significantly decreased
insulin sensitivity in an
insulin tolerance test and a >50% reduction in skeletal muscle
insulin-stimulated GLUT4 translocation when compared with wild-type (WT) mice. Furthermore,
glucose-stimulated insulin secretion was significantly reduced in islets isolated from Munc18c(-/+) mice compared with those from WT mice. Despite the defects in
insulin action and secretion, Munc18c(-/+) mice demonstrated the ability to clear
glucose to the same level as WT mice in a
glucose tolerance test when fed a normal diet. However, after consuming a high-fat diet for only 5 weeks, the Munc18c(-/+) mice manifested severely
impaired glucose tolerance compared with high-fat-fed WT mice. Taken together, these data suggest that the reduction of
Munc18c protein in the Munc18c(-/+) mice results in impaired
insulin sensitivity with a latent increased susceptibility for developing severe
glucose intolerance in response to environmental perturbations such as intake of a high-calorie diet rich in fat and
carbohydrate.