Munc18c heterozygous knockout mice display increased susceptibility for severe glucose intolerance

The disruption of Muncl8c binding to syntaxin 4 impairs insulin-stimulated GLUT4 vesicle translocation in 3T3L1 adipocytes. To investigate the physiological function and requirement for Muncl8c in the regulation of GLUT4 translocation and glucose homeostasis in vivo, we used homologous recombination to generate Muncl8c-knockout (KO) mice. Homozygotic disruption of the Muncl8c gene resulted in early embryonic lethality, whereas heterozygous KO mice (Muncl8c(-/+)) had normal viability. Muncl8c(-/+) mice displayed significantly decreased insulin sensitivity in an insulin tolerance test and a >50% reduction in skeletal muscle insulinstimulated GLUT4 translocation when compared with wild-type (WT) mice. Furthermore, glucose-stimulated insulin secretion was significantly reduced in islets isolated from Muncl8c(-/+) mice compared with those from WT mice. Despite the defects in insulin action and secretion, Muncl8c(-/+) 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 Muncl8c(-/+) mice manifested severely impaired glucose tolerance compared with high-fat-fed WT mice. Taken together, these data suggest that the reduction of Muncl8c protein in the Muncl8c(-/+) 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.