Dietary Zinc Reduction, Pyruvate Supplementation, or Zinc Transporter 5 Knockout Attenuates β-Cell Death in Nonobese Diabetic Mice, Islets, and Insulinoma Cells3

Abstract

Pancreatic zinc (Zn(2+)) concentrations are linked to diabetes and pancreatic dysfunction, but Zn(2+) is also required for insulin processing and packaging. Zn(2+) released with insulin increases β-cell pancreatic death after streptozotocin toxin exposure in vitro and in vivo. Triosephosphate accumulation, caused by NAD(+) loss and glycolytic enzyme dysfunction, occur in type-1 diabetics (T1DM) and animal models. We previously showed these mechanisms are also involved in Zn(2+) neurotoxicity and are attenuated by nicotinamide- or pyruvate-induced restoration of NAD(+) concentrations, Zn(2+) restriction, or inhibition of Sir2 proteins. We tested the hypothesis that similar Zn(2+)- and NAD(+)-mediated mechanisms are involved in β-cell toxicity in models of ongoing T1DM using mouse insulinoma cells, islets, and nonobese diabetic (NOD) mice. Zn(2+), streptozotocin, and cytokines caused NAD(+) loss and death in insulinoma cells and islets, which were attenuated by Zn(2+) restriction, pyruvate, nicotinamide, NAD(+), and inhibitors of Sir2 proteins. We measured diabetes incidence and mortality in NOD mice and demonstrated that pyruvate supplementation, or genetic or dietary Zn(2+) reduction, attenuated these measures. T-lymphocyte infiltration, punctate Zn(2+) staining, and β-cell loss increased with time in islets of NOD mice. Dietary Zn(2+) restriction or Zn(2+) transporter 5 knockout reduced pancreatic Zn(2+) staining and increased β-cell mass, glucose homeostasis, and survival in NOD mice, whereas Zn(2+) supplementation had the opposite effects. Pancreatic Zn(2+) reduction or NAD(+) restoration (pyruvate or nicotinamide supplementation) are suggested as novel targets for attenuating T1DM.

TRPM2-mediated intracellular Zn2+ release triggers pancreatic β-cell death

“…First, excess dietary Zn 2 + supplementation potentiates the incidence of diabetes and mortality in non-obese diabetic mice (genetic models of T1D), whereas dietary Zn 2 + restriction has the opposite effect [47]. Secondly, Zn 2 + chelators (calcium EDTA and clioquinol) reduce STZ-induced β-cell death and hyperglycaemia [48,49].…”

“…Secondly, Zn 2 + chelators (calcium EDTA and clioquinol) reduce STZ-induced β-cell death and hyperglycaemia [48,49]. Finally, knockout of zinc transporter 5 (Zn5T) reduced β-cell Zn 2 + levels and improved β-cell mass and glucose homoeostasis in non-obese diabetic mice [47]. Thus there is significant in vivo evidence in support of a role for Zn 2 + in the patho-physiology of T1D.…”

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

“…ZnT5 mRNA is relatively highly expressed in the pancreas, and the ZnT5 protein is associated with insulin granules in pancreatic ␤-cells (195,373). However, its contribution to insulin crystallization is minor (190).…”

hZnT8 (Slc30a8) Transgenic Mice That Overexpress the R325W Polymorph Have Reduced Islet Zn2+ and Proinsulin Levels, Increased Glucose Tolerance After a High-Fat Diet, and Altered Levels of Pancreatic Zinc Binding Proteins

“…In animal models of type 1 diabetes (T1DM), Zn 2+ chelators, compounds that prevent Zn 2+ toxicity, knockout of Zn 2+ transporter 5 ( ZnT5 ), and a chronic Zn 2+ -reduced diet attenuated diabetes incidence and mortality (1–3). However, other studies have suggested that acute Zn 2+ supplementation could be beneficial (reviewed in Taylor [4]).…”

“…We propose that Zn 2+ is transported into the Golgi and endoplasmic reticulum of β-cells for secretory granule incorporation by ZnT5 and ZnT8 . Knockout of ZnT5 decreases free secretory Zn 2+ (3), whereas knockout of ZnT8 decreases both free and some insulin-bound Zn 2+ , inducing a mild reduction in insulin secretion (10). During chronic inflammation induced by obesity and T2DM, secretory Zn 2+ homeostasis is disrupted, leading to Zn 2+ -mediated potentiation of β-cell death or improper processing and packaging of insulin.…”