Involvement of Elevated Intracellular and Extracellular ATP in the Regulation of Insulin Secretion: Therapeutic Targets in Non-Insulin-Dependent Diabetes Mellitus.

Abstract

Non-insulin-dependent diabetes mellitus (NIDDM) is a heterogeneous disease resulting primarily from a variety of pancreatic beta-cell disorders and insulin resistance. Whereas insulin resistance, which constitutes a defect in insulin action, increases the risk of developing NIDDM and, as such, is a predictor of the onset of this disease, it is mostly the beta-cell dysfunction in regulating insulin secretion which yields the chronic hyperglycemia with all its associated clinical complications. The individual steps in the secretory pathway of insulin which is induced primarily by blood plasma glucose have now been identified. The transport of the sugar into the beta-cell is followed by its phosphorylation as the rate-determining step. The glycolytic metabolism of glucose-6-phosphate leads to the generation of ATP resulting in increases in beta-cell ATP pools (steady-state-levels) as well as ATP/ADP ratios, which, in turn, produce the closure of ATP-sensitive K(+) channels, thus depolarizing the beta-cell membrane and opening of Ca(2+) channels. The resulting influx of extracellular Ca(2+) and the increase in recruitment of Ca(2+) from intracellular stores in response to extracellular signals yield an increase in total [Ca(2+)](i) which activates the granular insulin secretory machinery. The intracellular beta-cell ATP pools have a key role in transducing the signals of the stimulus-secretion coupling pathway and toxins such as alloxan and streptozotocin which produce experimental diabetes in animals act by damaging mitochondrial oxidative phosphorylation, leading to permanent decreases in cellular ATP pools which, due to the sensitivity of beta-cell function to these pools, manifest itself as a form of diabetes. In addition to the major effects of blood plasma glucose in the regulation of insulin secretion, a variety of hormonal and neural factors producing endocrine and paracrine effects modulate and fine-tune beta-cell insulin secretion. The enteroinsular axis provides a linkage between the gastrointestinal tract and pancreatic beta-cells stimulus-secretion pathway. Although a powerful effect of ATP on insulin secretion was demonstrated more than 30 years ago, only recently has it been shown that beta-cells possess P(2)-purinoceptors. Extracellular ATP and its synthetic agonists are insulin secretagogues by virtue of their activation of membrane purinergic receptors which is coupled to increases in extracellular Ca(2+) influx and mobilization of Ca(2+) from internal stores resulting in insulin release from beta-cell granules. The physiological significance of extracellular ATP regulation of insulin secretion as well as the physiological source of these ATP pools have not yet been established. It has been recently demonstrated that the administration of adenine nucleotides in vivo can yield significant increases in tissue, blood (red blood cell), and blood plasma ATP pools. Increasing pancreatic beta-cell intracellular and blood plasma (extracellular) pools of ATP is a new therapeutic modality in non-insulin-dependent diabetes mellitus.