Long-Term Actions of Sulfonylureas on (Pro-) Insulin Biosynthesis and Secretion - I. Lack of Evidence for a Compensatory Increase in (Pro-) Insulin Biosynthesis After Exposure of Isolated Pancreatic Rat Islets to Tolbutamide and Glibenclamide in Vitro

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Abstract
It was the aim of this study to elucidate (1) how long the inhibitory action of sulfonylureas on (pro-) insulin biosynthesis in vitro persists and (2) whether a compensatory increase of hormone synthesis occurs following exposure of isolated islets to sulfonylureas. Collagenase-isolated pancreatic rat islets were preexposed for a long (2 hours, scheme A) or short period (30 min, scheme B) to tolbutamide or glibenclamide. The washed islets were then labelled with 3H-leucine for 2 hours. In experiments of type B, an intermediate incubation was carried out for 90 min in the presence of glucose only prior to labelling. (Pro-) Insulin biosynthesis was estimated from incorporation data for 3H-leucine. Preexposure of islets for 2 hours, but not for 30 min, to tolbutamide at low glucose markedly reduced subsequent 3H-leucine incorporation into proinsulin and insulin. Preexposure to glibenclamide did not influence subsequent 3H-leucine incorporation (protocol A) whereas, when tested after longer time periods, hormone biosynthesis was found slightly reduced (protocol B). Long prestimulation with high - instead of low - glucose increased the following 3H-leucine incorporation into (pro-) insulin. The stimulatory action on insulin release persisted for several hours following preexposure to glibenclamide. After a high glucose stimulus for 2 hours an elevated insulin secretion rate was observed too. Conclusions: (1) Sulfonylureas reduce insulin biosynthesis in vitro also several hours after withdrawal of the drug. (2) No rebound of hormone biosynthesis is apparent after sulfonylureas. A feedback of the insulin storage pool on insulin biosynthesis could not be demonstrated. 1 This part of the studies was included in the thesis of D.S. 2 Supported by Deutsche Forschungsgemeinschaft, Bonn - Bad Godesberg

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