Autocrine effect of Zn2+ on the glucose-stimulated insulin secretion

Abstract

It is well known that zinc (Zn(2+)) is required for the process of insulin biosynthesis and the maturation of insulin secretory granules in pancreatic beta (β)-cells, and that changes in Zn(2+) levels in the pancreas have been found to be associated with diabetes. Glucose-stimulation causes a rapid co-secretion of Zn(2+) and insulin with similar kinetics. However, we do not know whether Zn(2+) regulates insulin availability and secretion. Here we investigated the effect of Zn(2+) on glucose-stimulated insulin secretion (GSIS) in isolated mouse pancreatic islets. Whereas Zn(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(2+) from the extracellular milieu of the islets, resulted in significantly increased GSIS, suggesting an overall inhibitory role of secreted Zn(2+) on GSIS. The inhibitory action of Zn(2+) was mostly mediated through the activities of KATP/Ca(2+) channels. Furthermore, during brief paired-pulse glucose-stimulated Zn(2+) secretion (GSZS), Zn(2+) secretion following the second pulse was significantly attenuated, probably by the secreted endogenous Zn(2+) after the first pulse. Such an inhibition on Zn(2+) secretion following the second pulse was completely reversed by Zn(2+) chelation, suggesting a negative feedback mechanism, in which the initial glucose-stimulated Zn(2+) release inhibits subsequent Zn(2+) secretion, subsequently inhibiting insulin co-secretion as well. Taken together, these data suggest a negative feedback mechanism on GSZS and GSIS by Zn(2+) secreted from β-cells, and the co-secreted Zn(2+) may act as an autocrine inhibitory modulator.

Early differences in islets from prediabetic NOD mice: combined microarray and proteomic analysis

“…Enrichment analysis of the differential genes in NOD vs C57Bl/6 islets revealed dysregulation of genes related to metal ion transport, in line with recent studies showing that pancreatic changes in Zn 2+ levels influence the availability and action of insulin [30,31]. In addition, genes implicated in the regulation of protein kinase activity were affected in NOD islets, which could lead to disturbances in the regulation of several molecular processes.…”

Zinc and diabetes mellitus: understanding molecular mechanisms and clinical implications

“…In-vitro environments increasing the extracellular Zinc concentration is known to increase the free insulin concentration in the immediate vicinity of β-cells, mediated by enhanced Zinc-insulin dissociation [ 63 ]. However, glucose stimulated insulin secretion in β-cells of the pancreas is inhibited by Zinc, suggesting that co-secreted Zinc acts in an autocrine inhibitory modulator [ 64 , 65 ]. In pancreatic β-cells of mice and clonal HIT-T15 β-cells, KCl and glucose induced an increase in free cytosolic Zinc levels, which facilitated the processing and/or storage of insulin [ 66 , 67 ].…”

Zinc status is associated with inflammation, oxidative stress, lipid, and glucose metabolism

“…Six insulin monomers congregate in β-cells into a hexamer with two zinc ions in the center, and this form is stored and transported across the cell membrane as an insulin-zinc crystal in the normal functioning of β-cells. Slepchenko et al [ 120 ] have shown inhibition of the zinc feature upon further glucose-stimulated secretion of insulin. After the zinc–insulin complexes have been secreted, they start to dissociate; only the insulin monomer is an active form of the hormone.…”