Insulin resistance in tetracycline-repressible Munc18c transgenic mice.
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 approximately 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.
Spurlin
Beth A
BA
Department of Biochemistry and Molecular Biology, Center for Diabetes Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Thomas
Rhonda M
RM
Nevins
Angela K
AK
Kim
Hyo-Jeong
HJ
Kim
Yoon-Jung
YJ
Noh
Hye-Lim
HL
Shulman
Gerald I
GI
Kim
Jason K
JK
Thurmond
Debbie C
DC
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000493:pharmacokinetics; D018149:Glucose Intolerance / Q000378:metabolism / Q000503:physiopathology*; D006706:Homeostasis / Q000502:physiology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D000078790:Insulin Secretion; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D051938:Munc18 Proteins; D018482:Muscle, Skeletal / Q000378:metabolism; D009419:Nerve Tissue Proteins; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D050765:Qa-SNARE Proteins; D013752:Tetracycline; D033921:Vesicular Transport Proteins
D000900:Anti-Bacterial Agents; D007328:Insulin; D008565:Membrane Proteins; D051938:Munc18 Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D050765:Qa-SNARE Proteins; C497943:Stxbp3 protein, mouse; D033921:Vesicular Transport Proteins; D013752:Tetracycline; D005947:Glucose