ASPECTS OF NOVEL SITES OF REGULATION OF THE INSULIN STIMULUS-SECRETION COUPLING IN NORMAL AND DIABETIC PANCREATIC-ISLETS

Noninsulin-dependent diabetes mellitus (NIDDM), a major health care pr oblem in the Western world, is a disease typified by a relative defici ency of insulin, leading to vast derangements in glucose and lipid hom eostasis with disastrous vascular complications. Despite immense resea rch efforts aimed at a clear understanding of the etiology of this com plex disease, the molecular mechanisms causing the disorder still rema in elusive. This article reviews extant data from recent publications implicating novel signal transduction pathways as important regulators of the insulin stimulus-secretion coupling in the pancreatic beta-cel l. The significance of nitric oxide and serine/threonine protein phosp hatases, and their inactivation by insulin secretagogues, glucose meta bolites, ATP, GTP, glutamate, and inositol hexaphosphate in this arena is scrutinized. Additionally, also presented is the growing concept t hat an important signal for insulin secretion may reside in the inextr icable interplay between glucose and lipid metabolism, specifically th e generation of malonyl-CoA, which inhibits carnitine palmitoyltransfe rase 1 with the attendant accumulation of long-chain acyl CoA esters. Moreover, attention is directed towards novel intracellular actions of hypoglycemic sulfonylureas in the beta-cell. Finally, the importance of ''lipotoxicity'' and aberrations in glucose uptake and metabolism i n beta-cell dysfunction is given consideration. Future research effort s should aim at further characterization of effects of second messenge rs on protein phosphorylation elements in beta-cells. Additionally, lo ng-term regulation by glucose and the diabetic state (e.g., fatty acid s and ketones) on beta-cell protein phosphatases, pyruvate dehydrogena se, and carnitine palmitoyltransferase 1 needs to be explored in great er depth. Clearly, the detrimental impact of diabetic hyperlipidemia o n beta-cell function has been a relatively neglected area, but future pharmacological approaches directed at preventing lipotoxicity may pro ve beneficial in the treatment of diabetes.