title: 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.affiliation: Department of Ophthalmology and the Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA. csheli@lsuhsc.edu
authors.forename: Christian T
authors.initials: CT
authors.lastname: Sheline
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Shi
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Takata
authors.forename: Julia
authors.initials: J
authors.lastname: Zhu
authors.forename: Wenlan
authors.initials: W
authors.lastname: Zhang
authors.forename: P Joshua
authors.initials: PJ
authors.lastname: Sheline
authors.forename: Ai-Li
authors.initials: AL
authors.lastname: Cai
authors.forename: Li
authors.initials: L
authors.lastname: Li
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002352:Carrier Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D003921:Diabetes Mellitus, Experimental / Q000517:prevention & control; D019587:Dietary Supplements; D005260:Female; D007340:Insulinoma / Q000473:pathology*; D007515:Islets of Langerhans / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D009243:NAD / Q000378:metabolism; D009284:Naphthols / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000473:pathology*; D019289:Pyruvic Acid / Q000008:administration & dosage*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013311:Streptozocin / Q000633:toxicity; D015032:Zinc / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D001549:Benzamides; D002121:Calcium Channel Blockers; D002352:Carrier Proteins; D009284:Naphthols; D017382:Reactive Oxygen Species; C439060:sirtinol; C017800:zinc-binding protein; D009243:NAD; D013311:Streptozocin; D019289:Pyruvic Acid; D015032:Zinc