A stepped intravenous metformin infusion was used in conjunction with the hyperglycaemic clamp technique to study the dose-response relationship of plasma metformin concentration with hepatic glucose production and peripheral glucose disposal in nine patients with Type 2 diabetes. The study was of double-blind crossover design, using NaCl infusion as control. Plasma metformin concentrations spanning the therapeutic range (1.64 +/- 0.13 mg l-1 and 6.57 +/- 0.61 mg l-1) were achieved. No differences in peripheral glucose disposal were demonstrated when compared with NaCl infusion (3.4 +/- 0.1 vs 3.6 +/- 0.2 (+/- SE) mg kg-1 min-1 and 3.4 +/- 0.2 vs 3.3 +/- 0.2 mg kg-1 min-1, respectively). There was also no difference in basal hepatic glucose production during metformin and NaCl infusion (2.7 +/- 0.3 vs 2.8 +/- 0.2 mg kg-1 min-1). No acute effect of metformin on hepatic glucose production or peripheral glucose disposal was observed, implying that a chronic persistent effect is more important in these respects than immediate effects consequent upon changes in plasma drug level.

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The dose response effect of a new adenosine analogue, GR79236 (N-[1S trans-2-hydroxycyclopentyl] adenosine) upon insulin sensitivity was examined in human adipocytes. The influence of adenosine upon insulin sensitivity for suppression of lipolysis and stimulation of glucose transport was examined. Removal of adenosine by use of adenosine deaminase stimulated lipolysis to the same extent as did 10(-9) M noradrenaline. GR79236 brought about dose dependent inhibition of lipolysis with half-maximal effect at 11.3 +/- 7.8 x 10(-9) M. When lipolysis was stimulated by noradrenaline alone the subsequent inhibition of lipolysis brought about by GR79236 was significantly greater than that of insulin. To examine adenosine effects on the insulin signalling pathway separately from those on lipolysis, the insulin sensitivity of glucose transport was examined. Removal of adenosine brought about a small but significant increase in the concentration of insulin required for half-maximal stimulation of glucose transport. Adenosine agonists offer promise as new agents for the modulation of metabolism in diabetes and other states of insulin resistance.

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The dose-response effects of a new adenosine agonist, GR79236, were examined in isolated rat soleus muscle strips and human rectus abdominus muscle strips. Effects on the insulin sensitivity of carbohydrate metabolism were examined, in particular upon insulin stimulated glycogen synthesis and glycolytic flux. In the presence of adenosine deaminase (ADA), GR79236 increased insulin sensitivity of pyruvate release from rat soleus muscle strips by 24% from 82.5 +/- 10.0 to 102.5 +/- 10.0 (P < 0.01), by 27% to 105.0 +/- 12.5 (P < 0.01) and by 24% to 102.5 +/- 10.0 (P < 0.01) nmol/25 mg per h at 0.1 and 10 microM GR79236, respectively. Rates of lactate release followed a similar but non-significant trend. Addition of GR79236 in the presence of ADA had no effect on rates of glycogen synthesis. Insulin stimulated rates of pyruvate or lactate release or of glycogen synthesis were unaffected by the addition of adenosine deaminase or GR79236 in human rectus abdominus muscle strips. Adenosine agonists may act indirectly to modulate insulin sensitivity of carbohydrate metabolism.