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 elevated fasting plasma insulin concentration with a weak insulin secretory response to subsequent glucose stimulation. Evidence suggests that hyperglycemia and hyperlipidemia may contribute to the initiation and progression of this disordered islet glucose sensing. It has been proposed that reducing hyperglycemia and hyperlipidemia per se may improve islet glucose sensing. Here we studied glucose-dependent insulin release in islets isolated from ob/ob mice treated with dopamine agonists (bromocriptine and SKF38393, BC/SKF) which significantly reduced circulating glucose and lipid levels of ob/ob mice. Islets from BC/SKF-treated mice showed a marked decrease of the elevated basal insulin release to levels similar to lean mice. Such treatment also induced a higher secretory response to glucose stimulation compared with that in ob/ob mice with sustained hyperglycemia and hyperlipidemia. Similarly, when islets from untreated ob/ob mice were cultured for 7 days in II mM glucose in the absence of free fatty acid, the basal insulin release was significantly decreased and high glucose stimulated insulin release increased compared with that from islets cultured in medium containing 30 mM glucose and 2 mM oleate. The BC/SKF-induced reduction of elevated basal 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 hyperglycemia and hyperlipidemia. (C) 1998 Published by Elsevier Science B.V. All rights reserved.