Uncoupling protein 2: A possible link between fatty acid excess and impaired glucose-induced insulin secretion?

The mechanism by which long-term exposure of the beta -cell to elevated con centrations of fatty acid alters glucose-induced insulin secretion has been examined. Exposure of INS-1 beta -cells to 0.4 mmol/l oleate for 72 h incr eased basal insulin secretion and decreased insulin release in response to high glucose, but not in response to agents acting at the level of the K+ c hannel (tolbutamide) or beyond (elevated KCI). This also suppressed the glu cose-induced increase in the cellular ATP-to-ADP ratio. The depolarization of the plasma membrane promoted by glucose was decreased after oleate expos ure, whereas the response to KCl was unchanged. Cells exposed to free fatty acids displayed a lower mitochondrial membrane potential and a decreased g lucose-induced hyperpolarization. The possible implication of uncoupling pr otein (UCP)-2 in the altered secretory response was examined by measuring U CP2 gene expression after chronic exposure of the cells to fatty acids. UCP 2 mRNA and protein were increased twofold by oleate. Palmitate and the nono xidizable fatty acid bromopalmitate had similar effects on UCP2 mRNA, sugge sting that UCP2 gene induction by fatty acids does not require their metabo lism. The data are compatible with a role of UCP2 and partial mitochondrial uncoupling in the decreased secretory response to glucose observed after c hronic exposure of the beta -cell to elevated fatty acids, and suggest that the expression and/or activity of the protein may modulate insulin secreti on in response to glucose.