Munc18c heterozygous knockout mice display increased susceptibility for severe glucose intolerance

Eunjin Oh, Beth A. Spurlin, Jeffrey E. Pessin, Debbie C. Thurmond

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

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. Muac18c-/+ 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.

Original languageEnglish (US)
Pages (from-to)638-647
Number of pages10
JournalDiabetes
Volume54
Issue number3
DOIs
StatePublished - Mar 2005
Externally publishedYes

Fingerprint

Glucose Intolerance
Knockout Mice
Insulin
Glucose
Insulin Resistance
Munc18 Proteins
Fats
Qa-SNARE Proteins
Diet
Homologous Recombination
High Fat Diet
Glucose Tolerance Test
Adipocytes
Skeletal Muscle
Homeostasis
Carbohydrates

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Munc18c heterozygous knockout mice display increased susceptibility for severe glucose intolerance. / Oh, Eunjin; Spurlin, Beth A.; Pessin, Jeffrey E.; Thurmond, Debbie C.

In: Diabetes, Vol. 54, No. 3, 03.2005, p. 638-647.

Research output: Contribution to journalArticle

Oh, Eunjin ; Spurlin, Beth A. ; Pessin, Jeffrey E. ; Thurmond, Debbie C. / Munc18c heterozygous knockout mice display increased susceptibility for severe glucose intolerance. In: Diabetes. 2005 ; Vol. 54, No. 3. pp. 638-647.
@article{b2344b040eca4559ae00ed7c6a45fff7,
title = "Munc18c heterozygous knockout mice display increased susceptibility for severe glucose intolerance",
abstract = "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. Muac18c-/+ 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.",
author = "Eunjin Oh and Spurlin, {Beth A.} and Pessin, {Jeffrey E.} and Thurmond, {Debbie C.}",
year = "2005",
month = "3",
doi = "10.2337/diabetes.54.3.638",
language = "English (US)",
volume = "54",
pages = "638--647",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "3",

}

TY - JOUR

T1 - Munc18c heterozygous knockout mice display increased susceptibility for severe glucose intolerance

AU - Oh, Eunjin

AU - Spurlin, Beth A.

AU - Pessin, Jeffrey E.

AU - Thurmond, Debbie C.

PY - 2005/3

Y1 - 2005/3

N2 - 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. Muac18c-/+ 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.

AB - 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. Muac18c-/+ 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.

UR - http://www.scopus.com/inward/record.url?scp=14644408047&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=14644408047&partnerID=8YFLogxK

U2 - 10.2337/diabetes.54.3.638

DO - 10.2337/diabetes.54.3.638

M3 - Article

VL - 54

SP - 638

EP - 647

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 3

ER -