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

Oleh:

Sheline, Christian T. ; Shi, Chunxiao ; Takata, Toshihiro ; Zhu, Julia ; Sadikin-Susilo

Jenis: Article from Journal - ilmiah internasional
Dalam koleksi: JN: The Journal of Nutrition vol. 142 no. 12 (Dec. 2012), page 2119-2127.
Topik: Nutrition Disease

Ketersediaan

Perpustakaan FK Nomor Panggil: J42.K.2012.02 Non-tandon: 1 (dapat dipinjam: 0) Tandon: tidak ada

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Isi artikel

Pancreatic zinc (Zn2+) concentrations are linked to diabetes and pancreatic dysfunction, but Zn2+ is also required for insulin processing and packaging. Zn2+ released with insulin increases ß-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 Zn2+ neurotoxicity and are attenuated by nicotinamide- or pyruvate-induced restoration of NAD+ concentrations, Zn2+ restriction, or inhibition of Sir2 proteins. We tested the hypothesis that similar Zn2+- and NAD+-mediated mechanisms are involved in ß-cell toxicity in models of ongoing T1DM using mouse insulinoma cells, islets, and nonobese diabetic (NOD) mice. Zn2+, streptozotocin, and cytokines caused NAD+ loss and death in insulinoma cells and islets, which were attenuated by Zn2+ 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 Zn2+ reduction, attenuated these measures. T-lymphocyte infiltration, punctate Zn2+ staining, and ß-cell loss increased with time in islets of NOD mice. Dietary Zn2+ restriction or Zn2+ transporter 5 knockout reduced pancreatic Zn2+ staining and increased ß-cell mass, glucose homeostasis, and survival in NOD mice, whereas Zn2+ supplementation had the opposite effects. Pancreatic Zn2+ reduction or NAD+ restoration (pyruvate or nicotinamide supplementation) are suggested as novel targets for attenuating T1DM.

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