Insulin resistance in tetracycline-repressible Munc18c transgenic mice

Beth A. Spurlin, Rhonda M. Thomas, Angela K. Nevins, Hyo Jeong Kim, Yoon Jung Kim, Hye Lim Noh, Gerald I. Shulman, Jason K. Kim, Debbie C. Thurmond

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

To investigate the physiological effects of modulating the abundance of Munc18c or syntaxin 4 (Syn4) proteins on the regulation of glucose homeostasis in vivo, we generated tetracycline-repressible transgenic mice that overexpress either Munc18c or Syn4 proteins in skeletal muscle, pancreas and adipose tissue seven-, five-, and threefold over endogenous protein, respectively. Munc18c transgenic mice displayed whole-body insulin resistance during hyperinsulinemic-euglycemic clamp resulting from >41% reductions in skeletal muscle and white adipose tissue glucose uptake, but without alteration of hepatic insulin action. Munc18c transgenic mice exhibited ∼40% decreases in whole-body glycogen/lipid synthesis, skeletal muscle glycogen synthesis, and glycolysis. Glucose intolerance in Munc18c transgenic mice was reversed by repression of transgene expression using tetracycline or by simultaneous overexpression of Syn4 protein. In addition, Munc18c transgenic mice had depressed serum insulin levels, reflecting a threefold reduction in insulin secretion from islets isolated therefrom, thus uncovering roles for Munc18c and/or Syn4 in insulin granule exocytosis. Taken together, these results indicate that balance, more than absolute abundance, of Munc18c and Syn4 proteins directly affects whole-body glucose homeostasis through alterations in insulin secretion and insulin action.

Original languageEnglish
Pages (from-to)1910-1917
Number of pages8
JournalDiabetes
Volume52
Issue number8
DOIs
StatePublished - Aug 1 2003

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Qa-SNARE Proteins
Tetracycline
Transgenic Mice
Insulin Resistance
Insulin
Skeletal Muscle
Glycogen
Glucose
Homeostasis
White Adipose Tissue
Glucose Clamp Technique
Glucose Intolerance
Exocytosis
Glycolysis
Transgenes
Adipose Tissue
Pancreas
Lipids
Muscles
Liver

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Spurlin, B. A., Thomas, R. M., Nevins, A. K., Kim, H. J., Kim, Y. J., Noh, H. L., ... Thurmond, D. C. (2003). Insulin resistance in tetracycline-repressible Munc18c transgenic mice. Diabetes, 52(8), 1910-1917. https://doi.org/10.2337/diabetes.52.8.1910

Insulin resistance in tetracycline-repressible Munc18c transgenic mice. / Spurlin, Beth A.; Thomas, Rhonda M.; Nevins, Angela K.; Kim, Hyo Jeong; Kim, Yoon Jung; Noh, Hye Lim; Shulman, Gerald I.; Kim, Jason K.; Thurmond, Debbie C.

In: Diabetes, Vol. 52, No. 8, 01.08.2003, p. 1910-1917.

Research output: Contribution to journalArticle

Spurlin, BA, Thomas, RM, Nevins, AK, Kim, HJ, Kim, YJ, Noh, HL, Shulman, GI, Kim, JK & Thurmond, DC 2003, 'Insulin resistance in tetracycline-repressible Munc18c transgenic mice', Diabetes, vol. 52, no. 8, pp. 1910-1917. https://doi.org/10.2337/diabetes.52.8.1910
Spurlin BA, Thomas RM, Nevins AK, Kim HJ, Kim YJ, Noh HL et al. Insulin resistance in tetracycline-repressible Munc18c transgenic mice. Diabetes. 2003 Aug 1;52(8):1910-1917. https://doi.org/10.2337/diabetes.52.8.1910
Spurlin, Beth A. ; Thomas, Rhonda M. ; Nevins, Angela K. ; Kim, Hyo Jeong ; Kim, Yoon Jung ; Noh, Hye Lim ; Shulman, Gerald I. ; Kim, Jason K. ; Thurmond, Debbie C. / Insulin resistance in tetracycline-repressible Munc18c transgenic mice. In: Diabetes. 2003 ; Vol. 52, No. 8. pp. 1910-1917.
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