Dietary zinc reduction, pyruvate supplementation, or zinc transporter 5 knockout attenuates β-cell death in nonobese diabetic mice, islets, and insulinoma cells.

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.

• Authors: Christian T Sheline, Chunxiao Shi, Toshihiro Takata, Julia Zhu, Wenlan Zhang, P Joshua Sheline, Ai-Li Cai, Li Li
• Journal: The Journal of nutrition (J Nutr) Vol. 142 Issue 12 Pg. 2119-27 (Dec 2012) ISSN: 1541-6100 [Electronic] United States
• PMID: 23096014 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Benzamides
• Calcium Channel Blockers
• Carrier Proteins
• Naphthols
• Reactive Oxygen Species
• sirtinol
• zinc-binding protein
• NAD
• Streptozocin
• Pyruvic Acid
• Zinc

Topics

• Animals
• Benzamides (pharmacology)
• Calcium Channel Blockers (pharmacology)
• Carrier Proteins (physiology)
• Cell Line, Tumor
• Diabetes Mellitus, Experimental (prevention & control)
• Dietary Supplements
• Female
• Insulinoma (pathology)
• Islets of Langerhans (pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Mice, Knockout
• NAD (metabolism)
• Naphthols (pharmacology)
• Pancreatic Neoplasms (pathology)
• Pyruvic Acid (administration & dosage)
• Reactive Oxygen Species (metabolism)
• Streptozocin (toxicity)
• Zinc (administration & dosage, toxicity)