Uncoupling Protein 2: A Possible Link Between Fatty Acid Excess and Impaired Glucose-Induced Insulin Secretion?

Abstract

The mechanism by which long-term exposure of the ␤-cell to elevated concentrations of fatty acid alters glucose-induced insulin secretion has been examined. Exposure of INS-1 ␤-cells to 0.4 mmol/l oleate for 72 h increased 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 ATP channel (tolbutamide) or beyond (elevated KCl). This also suppressed the glucose-induced increase in the cellular ATP-to-ADP ratio. The depolarization of the plasma membrane promoted by glucose was decreased after oleate exposure, whereas the response to KCl was unchanged. Cells exposed to free fatty acids displayed a lower mitochondrial membrane potential and a decreased glucose-induced hyperpolarization. The possible implication of uncoupling protein (UCP)-2 in the altered secretory response was examined by measuring UCP2 gene expression after chronic exposure of the cells to fatty acids. UCP2 mRNA and protein were increased twofold by oleate. Palmitate and the nonoxidizable fatty acid bromopalmitate had similar effects on UCP2 mRNA, suggesting that UCP2 gene induction by fatty acids does not require their metabolism. The data are compatible with a role of UCP2 and partial mitochondrial uncoupling in the decreased secretory response to glucose observed after chronic exposure of the ␤-cell to elevated fatty acids, and suggest that the expression and/or activity of the protein may modulate insulin secretion in response to glucose. Diabetes 50:803-809, 2001

Increasing uncoupling protein-2 in pancreatic beta cells does not alter glucose-induced insulin secretion but decreases production of reactive oxygen species

“…After 24 h of culture, islets were hand-picked again, preincubated and incubated in KRBH containing 0.5% fatty-acid-free BSA or BSA-oleate prepared as described [9], and used for measurement of insulin secretion and content, or ATP/ADP levels. Islet insulin was extracted with cold acid-ethanol (1.5% HCl, 75% ethanol) and measured by radioimmunoassay.…”

“…Cell culture Cells were plated (10 5 cells per well) into 24-well plates and cultured under standard cell culture conditions [9]. After 2-3 days, doxycycline (Sigma Chemical, St Louis, MO, USA) was added for 48 h to induce UCP2 production.…”

“…Glucose oxidation was measured as 14 CO 2 production from [U-14 C]glucose (0.1 μCi/μmol) (Amersham). Carbon dioxide was trapped and measured as described [9].…”

“…Indeed, several studies have associated an increase in UCP2 with inhibition of GSIS and indications of mitochondrial uncoupling [6][7][8]. An increase in UCP2 protein levels has been measured after long-term exposure of beta cells to high concentrations of fatty acids [9][10][11][12], with indications of mitochondrial uncoupling. Exposure of human islets to high glucose increases UCP2 expression, and alters GSIS [13].…”

Uncoupling protein-2: evidence for its function as a metabolic regulator

“…Both leptin [16] and PPAR-g ligands [108] are reported to induce UCP2 mRNA, implying that UCP2 could be regulated by NEFA [16] as described for other tissues. Indeed, chronic exposure of clonal beta cells to oleic acid impairs GSIS, lowers mitochondrial membrane potential and reduces the ATP:ADP ratio, correlating with increased UCP2 mRNA and protein [113]. Glucose metabolism is also implicated in the regulation of UCP2 transcription (Fig.…”