Adenovirus-mediated overexpression of uncoupling protein-2 in pancreatic islets of Zucker diabetic rats increases oxidative activity and improves beta-cell function

Diabetes. 1999 May;48(5):1020-5. doi: 10.2337/diabetes.48.5.1020.


The discovery of uncoupling protein (UCP)-2, a ubiquitously expressed protein homologous to UCP-1, has raised the possibility that energy balance of cells might be regulated in tissues other than brown adipocytes. In normal pancreatic islets, UCP-2 is upregulated by leptin and is low in leptin-resistant islets of ZDF rats. To determine whether UCP-2 does, in fact, have uncoupling activity and, if so, whether such activity would favorably influence the abnormalities in leptin-unresponsive UCP-2-underexpressing islets of diabetic ZDF rats, we transferred the UCP-2 gene to the islets of diabetic ZDF rats and lean (+/+) ZDF control rats. Although ATP was reduced by 23% in both groups of islets, the ATP:ADP ratio increased by 42 and 141%, respectively. [3H]palmitate oxidation was increased by 50%, and [3H]glucose oxidation was 42-63% higher. Preproinsulin mRNA was 2.9-fold above control levels, and glucose-stimulated insulin secretion, which was negligible in control ZDF rat islets, was improved in UCP-2-overexpressing islets. The high fat content of the islets was not reduced, however. We conclude that UCP-2 has uncoupling function when overexpressed in leptin-insensitive islets and that its overexpression corrects the underexpression of the insulin gene and ameliorates glucose-stimulated insulin secretion, possibly by increasing the ATP:ADP ratio.

MeSH terms

  • Adenosine Diphosphate / metabolism
  • Adenosine Triphosphate / metabolism
  • Adenoviridae / genetics*
  • Animals
  • Diabetes Mellitus / physiopathology*
  • Gene Expression*
  • Gene Transfer Techniques
  • Glucose / metabolism
  • Humans
  • Insulin
  • Ion Channels
  • Islets of Langerhans / physiology*
  • Male
  • Membrane Transport Proteins*
  • Mitochondrial Proteins*
  • Oxidation-Reduction
  • Palmitic Acid / metabolism
  • Proinsulin / genetics
  • Protein Precursors / genetics
  • Proteins / genetics*
  • Rats
  • Rats, Zucker
  • Triglycerides / metabolism
  • Uncoupling Agents
  • Uncoupling Protein 2


  • Insulin
  • Ion Channels
  • Membrane Transport Proteins
  • Mitochondrial Proteins
  • Protein Precursors
  • Proteins
  • Triglycerides
  • UCP2 protein, human
  • Ucp2 protein, rat
  • Uncoupling Agents
  • Uncoupling Protein 2
  • Palmitic Acid
  • preproinsulin
  • Adenosine Diphosphate
  • Adenosine Triphosphate
  • Proinsulin
  • Glucose