Effect of the new imidazoline derivative S-22068 (PMS 847) on insulin secretion in vitro and glucose turnover in vivo in rats

We have investigated the possible mechanisms underlying the antihyperglycaemic effect of the imidazoline derivative S-22068. In vitro, in the presence of 5 mmol/l glucose, S-22068 (100 mu mol/l) induced a significant and sustained increase in insulin secretion from isolated, perifused, rat islets and a marked sensitization to a subsequent glucose challenge (10 mmol/l). S-22068 (100 mu mol/l was able to antagonize the stimulatory effect of diazoxide on Rb-86 efflux from preloaded islets incubated in the presence of 20 mmol/l glucose. Experiments were also performed to investigate whether S-22068 can alter glucose turnover and peripheral insulin sensitivity in vivo in mildly diabetic rats and obese, insulin resistant, Zucker rats. Neither glucose production nor individual tissue glucose utilization was modified by S-22068 in either group of rats. Similar results were obtained whether the studies were performed under basal conditions or during euglycaemic/hyperinsulinemic clamps. The results suggest that S-22068 exerts part of its antihyperglycaemic effect by promoting insulin secretion without alteration of peripheral insulin sensitivity. (C) 1999 Elsevier Science B.V. All rights reserved.