Adenovirus-mediated overexpression of uncoupling protein-2 in pancreatic islets of Zucker diabetic rats increases oxidative activity and improves beta-cell function.
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.
Wang
M Y
MY
Department of Internal Medicine, University of Texas Southwestern Medical Center, and the Veterans Administration Medical Center, Dallas 75235-8854, USA.
Shimabukuro
M
M
Lee
Y
Y
Trinh
K Y
KY
Chen
J L
JL
Newgard
C B
CB
Unger
R H
RH
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D003920:Diabetes Mellitus / Q000503:physiopathology*; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin; D007473:Ion Channels; D007515:Islets of Langerhans / Q000502:physiology*; D008297:Male; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D010084:Oxidation-Reduction; D019308:Palmitic Acid / Q000378:metabolism; D011384:Proinsulin / Q000235:genetics; D011498:Protein Precursors / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D051381:Rats; D011924:Rats, Zucker; D014280:Triglycerides / Q000378:metabolism; D014475:Uncoupling Agents; D000071246:Uncoupling Protein 2
D007328:Insulin; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D011498:Protein Precursors; D011506:Proteins; D014280:Triglycerides; C000604389:UCP2 protein, human; C000604391:Ucp2 protein, rat; D014475:Uncoupling Agents; D000071246:Uncoupling Protein 2; D019308:Palmitic Acid; C013737:preproinsulin; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D011384:Proinsulin; D005947:Glucose