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.

No abstract

Long-chain saturated fatty acids are cytotoxic to pancreatic L L-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 proapoptotic e¡ects 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 L L-cells to serum withdrawal or a combination of interleukin-1L L plus interferon-Q Q. 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 L L-cells.

IDDM results from a progressive loss of pancreatic beta-cells that, in humans, may be triggered by a combination of genetic and environmental factors. Recently, attention has been focused on the hypothesis that the loss of beta-cells is initiated by inappropriate induction of apoptosis. We now demonstrate that human islets of Langerhans undergo apoptosis upon exposure to interleukin-1beta. The cytokine also sharply increases the number of cells that enter apoptosis on treatment with a stimulatory anti-Fas antibody. Western blotting and immunocytochemistry clearly show for the first time that human pancreatic beta-cells normally express Fas ligand. The results suggest that human islet cells are primed to undergo apoptosis by interleukin-1beta and that this involves the close association between cell-surface Fas and its ligand.

Venous PO2 was measured in the feet and hands of four subject groups: 14 diabetics with neuropathy and foot ulceration; 12 diabetics with neuropathy but no ulceration; 11 diabetics with no evidence of microvascular complications; and 10 non-diabetic controls. Neither patients nor controls had clinical evidence of peripheral vascular disease. The mean venous PO2 in the feet of subjects with neuropathy and foot ulceration was significantly higher than in controls or the other two diabetic groups. Venous PO2 in the feet of the subjects with ulcers was also significantly higher than in their hands or in the hands of the other groups. These results provide further evidence of abnormal blood flow in the diabetic neuropathic foot and are compatible with arteriovenous shunting.

Experiments were carried out in human volunteers to investigate the mechanism by which guar gum improves glucose tolerance. Guar reduced both plasma glucose and insulin responses to an oral glucose load, and delayed gastric emptying. However, there was no correlation between changes in individual blood glucose responses and changes in gastric emptying rates induced by guar. With a steady-state perfusion technique, glucose absorption was found to be significantly reduced during perfusion of the jejunum with solutions containing guar, but returned to control values during subsequent guar-free perfusions. Preperfusing the intestine with guar did not affect electrical measurements of unstirred layer thickness in the human jejunum in vivo. Experiments in vitro established that glucose diffusion out of a guar/glucose mixture was delayed under conditions of constant stirring. We conclude that guar improves glucose tolerance predominantly by reducing glucose absorption in the small intestine. It probably does this by inhibiting the effects of intestinal motility on fluid convection.

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Intracellular production of nitric oxide (NO) is thought to mediate the pancreatic B-cell-directed cytotoxicity of cytokines in insulin-dependent diabetes mellitus, and recent evidence has indicated that this may involve induction of apoptosis. A primary effect of NO is to activate soluble guanylyl cyclase leading to increased cGMP levels and this effect has been demonstrated in pancreatic B-cells, although no intracellular function has been defined for islet cGMP. Here we demonstrate that the NO donor, GSNO, induces apoptosis in the pancreatic B-celliine HIT-TI5 in a dose-and time-dependent manner. This response was significantly attenuated by micromolar concentrations of a specific inhibitor of soluble guanylyl cyclase, ODQ, and both 8-bromo cGMP (100 ~) and dibutyryl cGMP (300 ~) were able to fully relieve this inhibition. In addition, incubation of HIT -T15 cells with each cGMP analogue directly promoted cell death in the absence of ODQ. KT5823, a potent and highly selective inhibitor of cGMP-dependent protein kinase (PKG), abolished the induction of cell death in fiT cells in response to either GSNO or cGMP analogues. This effect was dose-dependent over the concentration range of 10--250 nM. Overall, these data provide evidence that the activation of apoptosis in HIT-TI5 cells by NO donors is secondary to a rise in cGMP and suggest that the pathway controlling cell death involves activation of PKG.