Munc18c heterozygous knockout mice display increased susceptibility for severe glucose intolerance.
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.
Oh
Eunjin
E
Department of Biochemistry and Molecular Biology, Center for Diabetes Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Spurlin
Beth A
BA
Pessin
Jeffrey E
JE
Thurmond
Debbie C
DC
D000818:Animals; D001786:Blood Glucose; D001835:Body Weight; D004032:Diet; D004041:Dietary Fats; D005247:Feeding Behavior; D020022:Genetic Predisposition to Disease; D018149:Glucose Intolerance / Q000235:genetics*; D051275:Glucose Transporter Type 4; D006579:Heterozygote; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D051938:Munc18 Proteins; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000502:physiology*
D001786:Blood Glucose; D004041:Dietary Fats; D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D051938:Munc18 Proteins; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; C495693:Slc2a4 protein, mouse; C497943:Stxbp3 protein, mouse; D033921:Vesicular Transport Proteins