Metformin therapy and clinical uses.

Metformin is now established as a first-line antidiabetic therapy for the management of type 2 diabetes. Its early use in treatment algorithms is supported by lack of weight gain, low risk of hypoglycaemia and its mode of action to counter insulin resistance. The drug's anti-atherosclerotic and cardioprotective effects have recently been confirmed in prospective and retrospective studies, and appear to reflect a collection of glucose-independent effects on the vascular endothelium, suppressant effects on glycation, oxidative stress and formation of adhesion molecules, stimulation of fibrinolysis and favourable effects on the lipid profile. Although avoidance of troublesome gastrointestinal tolerability issues requires careful dose titration, the risk of serious adverse events is considered low provided that contra-indications (especially with respect to renal function) are observed. As many of its actions go beyond glucose lowering, emerging evidence indicates potential benefits in other insulin-resistant states and possibly tumour suppression.

Expression and functional activity of PPARgamma in pancreatic beta cells.

Rosiglitazone is an agonist of peroxisome proliferator activated receptor-gamma (PPARgamma) and ameliorates insulin resistance in type II diabetes. In addition, it may also promote increased pancreatic beta-cell viability, although it is not known whether this effect is mediated by a direct action on the beta cell. We have investigated this possibility. Semiquantitative real-time reverse transcription-polymerase chain reaction analysis (Taqman) revealed that freshly isolated rat islets and the clonal beta-cell line, BRIN-BD11, express PPARgamma, as well as PPARalpha and PPARdelta. The levels of expression of PPARgamma were estimated by reference to adipose tissue and were found to represent approximately 60% (islets) and 30% (BRIN-BD11) of that found in freshly isolated visceral adipose tissue. Western blotting confirmed the presence of immunoreactive PPARgamma in rat (and human) islets and in BRIN-BD11 cells. Transfection of BRIN-BD11 cells with a PPARgamma-sensitive luciferase reporter construct was used to evaluate the functional competence of the endogenous PPARgamma. Luciferase activity was modestly increased by the putative endogenous ligand, 15-deoxy-Delta12,14 prostaglandin J2 (15dPGJ2). Rosiglitazone also caused activation of the luciferase reporter construct but this effect required concentrations of the drug (50-100 microm) that are beyond the expected therapeutic range. This suggests that PPARgamma is relatively insensitive to activation by rosiglitazone in BRIN-BD11 cells. Exposure of BRIN-BD11 cells to the lipotoxic effector, palmitate, caused a marked loss of viability. This was attenuated by treatment of the cells with either actinomycin D or cycloheximide suggesting that a pathway of programmed cell death was involved. Rosiglitazone failed to protect BRIN-BD11 cells from the toxic actions of palmitate at concentrations up to 50 microm. Similar results were obtained with a range of other PPARgamma agonists. Taken together, the present data suggest that, at least under in vitro conditions, thiazolidinediones do not exert direct protective effects against fatty acid-mediated cytotoxicity in pancreatic beta cells.

Mono-unsaturated fatty acids protect against beta-cell apoptosis induced by saturated fatty acids, serum withdrawal or cytokine exposure.

Long-chain saturated fatty acids are cytotoxic to pancreatic beta-cells while shorter-chain saturated and long-chain unsaturated molecules are better tolerated. Mono-unsaturated fatty acids are not, however, inert since they inhibit the pro-apoptotic effects of saturated molecules. In the present work we show that the mono-unsaturates palmitoleate (C16:1) or oleate (C18:1) also cause marked inhibition of apoptosis induced by exposure of clonal BRIN-BD11 beta-cells to serum withdrawal or a combination of interleukin-1beta plus interferon-gamma. This response was dose-dependent and not accompanied by changes in NO formation. Taken together, the results suggest that mono-unsaturated fatty acids regulate a distal step common to several apoptotic pathways in pancreatic beta-cells.