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.