Zinc, Alpha Cells and Glucagon Secretion

Abstract

Zinc concentrates in islet cells and is related to insulin secretion. Islet cells act as a unit within islets and hormone secretion in the islets is profoundly influenced by paracrine and autocrine regulation. Zinc has been recognised as a candidate paracrine inhibitor of glucagon secretion in alpha-cells. Further zinc fluxes may contribute to regulation of cell mass, Zn2+ may be cytotoxic and Zn2+ depletion by itself can cause cell death induced by oxidative stress. Recently, both free zinc ions and a number of zinc transporters have been localized in alpha-cells. These include zinc importers, ZIP1, ZIP10, and ZIP14 of the SLC39A family and zinc exporters, ZnT1, and ZnT4-8 of the SLC30A family. Furthermore, the redox state of thiol groups and Voltage Gated Ca2+ Channels (VGCC) add to the maintenance of a tight cytoplasmatic zinc homeostasis in the alpha-cells. The ZnT8 protein has emerged as particularly interesting since this zinc transporter has been identified as a genetic risk factor for the development of both type 1 and type 2 diabetes in which both alpha- and beta-cell functions are affected. Recent data discussed here suggest specific effects of Zn2+ on glucagon secretion and other alpha-cell functions.

Physiological and Pathophysiological Control of Glucagon Secretion by Pancreatic α-Cells

“…ZnT8 appears largely dispensable for α-cell function because α-cell-specific ZnT8 knockout mice show no evident abnormalities in plasma glucagon and glucose homeostasis (Wijesekara et al 2010). Nevertheless, since tiny amounts of Zn 2+ can still be present in the cells independently of ZnT8 (Egefjord et al 2010;Gyulkhandanyan et al 2008), these experiments do not exclude the remote possibility that Zn 2+ can affect somehow glucagon secretion.…”

“…High extracellular local concentrations of zinc (μM) are therefore anticipated within the islet (Huang et al 1995). It has been suggested that Zn 2+ released from stimulated β-cells inhibits glucagon release (Ishihara et al 2003) and might therefore be responsible for the inhibitory effect of glucose (Egefjord et al 2010;Hardy et al 2011). A "switch-off" hypothesis involving Zn 2+ instead of insulin has also been suggested (Zhou et al 2007;Robertson et al 2011).…”

Zinc in Pancreatic Islet Biology, Insulin Sensitivity, and Diabetes

“…C-peptide and amylin form 1:1 heterodimers with insulin, thus removing insulin oligomers and suppressing aggregation (36). Zinc ions localize to the granules of α-cells, where a zinc-specific stain detects them at the membrane (37). Their secretion is thought to have an autocrine effect on α-cells as well (30).…”

Synthesis and Characterization of Nano-doped Zinc Oxide and its Application as Protective Oxidative Changes in the Retina of Diabetic Rats

“…Additionally, Egefjord et al [40] investigated that zinc regulate glucagon secretion from pancreatic acells. As a result, glucagonstimulated hepatic pathways (i.e., glycogenesis and gluconeogenesis) would be suppressed in the fasting state [41] contributing to a reduction of fasted glucose levels.…”