Autocrine effect of Zn super(2+) on the glucose-stimulated insulin secretion

• Published in: Endocrine Vol. 50; no. 1; pp. 110 - 122
• Main Authors: Slepchenko, Kira G, Daniels, Nigel A, Guo, Aili, Li, Yang V
• Format: Journal Article
• Language: English
• Published: 01.09.2015
• ISSN: 1355-008X; 1559-0100
• DOI: 10.1007/s12020-015-0568-z

It is well known that zinc (Zn super(2+)) is required for the process of insulin biosynthesis and the maturation of insulin secretory granules in pancreatic beta ( beta )-cells, and that changes in Zn super(2+) levels in the pancreas have been found to be associated with diabetes. Glucose-stimulation causes a rapid co-secretion of Zn super(2+) and insulin with similar kinetics. However, we do not know whether Zn super(2+) regulates insulin availability and secretion. Here we investigated the effect of Zn super(2+) on glucose-stimulated insulin secretion (GSIS) in isolated mouse pancreatic islets. Whereas Zn super(2+) alone (control) had no effect on the basal secretion of insulin, it significantly inhibited GSIS. The application of CaEDTA, by removing the secreted Zn super(2+) from the extracellular milieu of the islets, resulted in significantly increased GSIS, suggesting an overall inhibitory role of secreted Zn super(2+) on GSIS. The inhibitory action of Zn super(2+) was mostly mediated through the activities of K sub(ATP)/Ca super(2+) channels. Furthermore, during brief paired-pulse glucose-stimulated Zn super(2+) secretion (GSZS), Zn super(2+) secretion following the second pulse was significantly attenuated, probably by the secreted endogenous Zn super(2+) after the first pulse. Such an inhibition on Zn super(2+) secretion following the second pulse was completely reversed by Zn super(2+) chelation, suggesting a negative feedback mechanism, in which the initial glucose-stimulated Zn super(2+) release inhibits subsequent Zn super(2+) secretion, subsequently inhibiting insulin co-secretion as well. Taken together, these data suggest a negative feedback mechanism on GSZS and GSIS by Zn super(2+) secreted from beta -cells, and the co-secreted Zn super(2+) may act as an autocrine inhibitory modulator.