It is well known that zinc (Zn2+) is required for the process of insulin biosynthesis and the maturation of insulin secretory granules in pancreatic beta (β)-cells, and that changes in Zn2+ levels in the pancreas have been found to be associated with diabetes. Glucose-stimulation causes a rapid co-secretion of Zn2+ and insulin with similar kinetics. However, we do not know whether Zn2+ regulates insulin availability and secretion. Here we investigated the effect of Zn2+ on glucose-stimulated insulin secretion (GSIS) in isolated mouse pancreatic islets. Whereas Zn2+ alone (control) had no effect on the basal secretion of insulin, it significantly inhibited GSIS. The application of CaEDTA, by removing the secreted Zn2+ from the extracellular milieu of the islets, resulted in significantly increased GSIS, suggesting an overall inhibitory role of secreted Zn2+ on GSIS. The inhibitory action of Zn2+ was mostly mediated through the activities of KATP/Ca2+ channels. Furthermore, during brief paired-pulse glucose-stimulated Zn2+ secretion (GSZS), Zn2+ secretion following the second pulse was significantly attenuated, probably by the secreted endogenous Zn2+ after the first pulse. Such an inhibition on Zn2+ secretion following the second pulse was completely reversed by Zn2+ chelation, suggesting a negative feedback mechanism, in which the initial glucose-stimulated Zn2+ release inhibits subsequent Zn2+ secretion, subsequently inhibiting insulin co-secretion as well. Taken together, these data suggest a negative feedback mechanism on GSZS and GSIS by Zn2+ secreted from β-cells, and the co-secreted Zn2+ may act as an autocrine inhibitory modulator.
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism