Overexpression of uncoupling protein 2 inhibits glucose-stimulated insulinsecretion from rat islets

Uncoupling protein 2 (UCP-8) mRNA expression has been shown to be altered b y metabolic conditions such as obesity in humans, but its functional signif icance is unknown. The expression of UCP-8 mRNA and protein in normal rat i slets was established by reverse transcriptase-polymerase chain reaction an d immunocytochemistry in pancreatic islets and tissue, respectively. Intens e immunostaining of UCP-2 correlated with insulin-positive p-cells. Overexp ression of UCP-2 in normal rat islets was accomplished by infection with an adenovirus (AdEGI-UCP-2) containing the full-length human UCP-2 coding seq uence. Induction of the AdEGI-UCP-2 gene resulted in severe blunting of glu cose-stimulated insulin secretion (GSIS) without affecting islet insulin co ntent or the ability of the calcium ionophore A23187 to increase insulin se cretion from AdEGI-UCP-2-expressing islets. Therefore, UCP-2 overexpression affects signal transduction proximal to Ca2+-mediated steps, including exo cytosis. Insulin secretion from single beta-cells to 16.5 mmol/l glucose ex amined by reverse hemolytic plaque assay was nearly ablated if UCP-2 was ov erexpressed. Thus, a direct, causal relationship between overexpression of UCP-2 and inhibition of GSIS in normal islets has been established. These d ata suggest that increased expression of UCP-2 has the potential to cause t he lack of a glucose effect on insulin secretion in type 2 diabetes.