DOPAMINE AGONIST TREATMENT AMELIORATES HYPERGLYCEMIA, HYPERLIPIDEMIA,AND THE ELEVATED BASAL INSULIN RELEASE FROM ISLETS OF OBLOB MICE

One of the characteristics of obesity-associated diabetes is an elevat ed fasting plasma insulin concentration with a weak insulin secretory response to subsequent glucose stimulation. Evidence suggests that hyp erglycemia and hyperlipidemia may contribute to the initiation and pro gression of this disordered islet glucose sensing. It has been propose d that reducing hyperglycemia and hyperlipidemia per se may improve is let glucose sensing. Here we studied glucose-dependent insulin release in islets isolated from ob/ob mice treated with dopamine agonists (br omocriptine and SKF38393, BC/SKF) which significantly reduced circulat ing glucose and lipid levels of ob/ob mice. Islets from BC/SKF-treated mice showed a marked decrease of the elevated basal insulin release t o levels similar to lean mice. Such treatment also induced a higher se cretory response to glucose stimulation compared with that in ob/ob mi ce with sustained hyperglycemia and hyperlipidemia. Similarly, when is lets from untreated ob/ob mice were cultured for 7 days in II mM gluco se in the absence of free fatty acid, the basal insulin release was si gnificantly decreased and high glucose stimulated insulin release incr eased compared with that from islets cultured in medium containing 30 mM glucose and 2 mM oleate. The BC/SKF-induced reduction of elevated b asal insulin release was associated with decreased hexokinase activity and basal cyclic AMP content in islet tissue. Our results demonstrate that dopamine agonist treatment improves basal insulin release in ob/ ob mice and this effect may be mediated, in part, by a reduction of hy perglycemia and hyperlipidemia. (C) 1998 Published by Elsevier Science B.V. All rights reserved.