Transgenic mice overexpressing nuclear SREBP-1c in pancreatic beta-cells

Diabetes. 2005 Feb;54(2):492-9. doi: 10.2337/diabetes.54.2.492.

Abstract

Influx of excess fatty acids and the resultant accumulation of intracellular triglycerides are linked to impaired insulin secretion and action in the pathogenesis of type 2 diabetes. Sterol regulatory element-binding protein (SREBP)-1c is a transcription factor that controls cellular synthesis of fatty acids and triglycerides. SREBP-1c is highly expressed in high-energy and insulin-resistant states. To investigate effects of this synthetic lipid regulator on insulin secretion, we generated transgenic mice overexpressing nuclear SREBP-1c under the insulin promoter. beta-Cell-specific expression of SREBP-1c caused reduction in islet mass and impaired glucose-stimulated insulin secretion and was associated with accumulation of triglycerides, suppression of pancreas duodenal homeobox-1, and upregulation of uncoupling protein 2 gene expression. The mice presented with impaired glucose tolerance that was exacerbated by a high-energy diet. Taken together with enhanced insulin secretion from SREBP-1-null islets, these data suggest that SREBP-1c and endogenous lipogenesis could be involved in beta-cell dysfunction and diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • CCAAT-Enhancer-Binding Proteins / genetics*
  • CCAAT-Enhancer-Binding Proteins / physiology
  • Cell Nucleus / physiology*
  • DNA Primers
  • DNA, Complementary / genetics
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / physiology
  • Diet
  • Energy Metabolism
  • Gene Expression Regulation
  • Glucose Intolerance / genetics*
  • Helix-Loop-Helix Motifs
  • Homeodomain Proteins / genetics
  • Humans
  • Hyperinsulinism / prevention & control
  • Insulin / genetics
  • Insulin / metabolism
  • Insulin Secretion
  • Ion Channels
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / physiology*
  • Membrane Transport Proteins / genetics
  • Mice
  • Mice, Transgenic
  • Mitochondrial Proteins / genetics
  • Promoter Regions, Genetic
  • Rats
  • Sterol Regulatory Element Binding Protein 1
  • Trans-Activators / genetics
  • Transcription Factors / genetics*
  • Transcription Factors / physiology
  • Uncoupling Protein 2

Substances

  • CCAAT-Enhancer-Binding Proteins
  • DNA Primers
  • DNA, Complementary
  • DNA-Binding Proteins
  • Homeodomain Proteins
  • Insulin
  • Ion Channels
  • Membrane Transport Proteins
  • Mitochondrial Proteins
  • SREBF1 protein, human
  • Srebf1 protein, mouse
  • Srebf1 protein, rat
  • Sterol Regulatory Element Binding Protein 1
  • Trans-Activators
  • Transcription Factors
  • UCP2 protein, human
  • Ucp2 protein, mouse
  • Ucp2 protein, rat
  • Uncoupling Protein 2
  • pancreatic and duodenal homeobox 1 protein