Effects of Zn2+ on glucose-induced electrical activity and insulin release from mouse pancreatic islets

Abstract

The effects of Zn2+ and CO2+ on glucose-induced beta-cell electrical activity and on insulin release from microdissected mouse pancreatic islets were studied. In 11 mM glucose the electrical activity is characterized by a burst pattern with a bimodal distribution of spike amplitudes along the plateau phase. Zn2+ at 0.05 mM induced a reduction in the number of spikes during the bursts and preferentially blocked the large action potentials. Zn2+ at 0.1 mM and CO2+ at 1.0 mM completely inhibited the electrical activity in response to glucose. Zn2+ inhibition of electrical activity was poorly reversible, whereas CO2+ inhibition was rapidly and completely reversible. Zn2+ and CO2+ inhibited the glucose-stimulated insulin release from microdissected perifused islets. Half-maximal inhibition occurred at about 0.3 mM for both metals. Zn2+ also inhibited K+-induced insulin release in the absence of glucose, indicating that Zn2+ inhibition does not involve glucose metabolism. It is proposed that Zn2+ blocks the voltage-gated Ca2+ channels in pancreatic beta-cells.

The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance

“…Therefore, we rigorously examined whether zinc could suppress insulin secretion in various experimental settings, using isolated islets from ZnT8KO mice ( Figure 2B and Figure 5D), the addition of zinc chelator to C57BL/6J islets ( Figure 5C), and pancreas perfusion ( Figure 2D), in addition to simple comparison between control and ZnT8KO mice. The results of all these experiments strongly supported the previous reports demonstrating that zinc suppresses insulin secretion from β cells (8)(9)(10)(14)(15)(16).…”

“…Zinc secreted from β cells is known to affect neighboring endocrine cells (7,11). Consistent with previous reports (10,(14)(15)(16), addition of zinc to the perfusate (30 μM) markedly suppressed insulin hypersecretion in ZnT8KO mice, almost to control levels ( Figure 2D). Furthermore, the addition of zinc chelator calcium EDTA (2.5 mM) (7) significantly increased insulin secretion from isolated C57BL/6J islets ( Figure 5C and Supplemental Figure 2B).…”

“…However, in that study, the discrepancy between these 2 observations was not fully explored. Previous studies reported that insulin secretion from pancreatic islets was suppressed by zinc through enhanced outward current of the K-ATP channel (8)(9)(10)(14)(15)(16). Therefore, we rigorously examined whether zinc could suppress insulin secretion in various experimental settings, using isolated islets from ZnT8KO mice ( Figure 2B and Figure 5D), the addition of zinc chelator to C57BL/6J islets ( Figure 5C), and pancreas perfusion ( Figure 2D), in addition to simple comparison between control and ZnT8KO mice.…”

“…Insulin granules contain high amounts of zinc, and zinc that is cosecreted with insulin affects neighboring endocrine cells in the islets of Langerhans in both paracrine and autocrine fashions (7)(8)(9)(10)(11). While studies of ZnT8 deletion or overexpression in insulinoma cells have suggested that it contributes to the maintenance of glucose-stimulated insulin secretion (GSIS) (12,13), others have reported that zinc suppresses insulin secretion from pancreatic β cells (8)(9)(10)(14)(15)(16). In addition, recent loss-of-function studies of Slc30a8 in mice demonstrated that ZnT8 is important for the crystallization of insulin molecules and efficient insulin processing in insulin granules, but there is no agreement on the precise role of ZnT8 in increased susceptibility to type 2 diabetes (17)(18)(19)(20)(21).…”

Zinc and diabetes

“…Indeed, secreted zinc feedback negatively at the level of the ATP-sensitive K + channels (K ATP ) and Ca 2+ channels to reduce insulin secretion [90,91]. Zinc also has a paracrine effect on neighbouring cells, notably on α cells where it can inhibit glucagon secretion [88].…”