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Zinc, the Pancreas, and Diabetes: Insights from Rodent Studies and Future Directions

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Abstract

Molecular and cellular studies have demonstrated several roles for zinc (Zn) in insulin production and the consequent actions of insulin on metabolism. Clinical and epidemiological studies suggest that reduced Zn status is associated with diabetes. Investigations of Zn in rodent models of diabetes have provided a valuable link for understanding the molecular, cellular, clinical and epidemiological observations in the context of inter-organ metabolism and the metabolic disturbances of diabetes. This review highlights some of the current knowledge and future research directions for the role of Zn in the pancreas and diabetes based on rodent studies and experimental manipulations of Zn. Overall, Zn supplementation is effective for preventing or ameliorating diabetes in several rodent models of Type 1 and Type 2 diabetes. Studies with chemically-induced Type 1 diabetes indicate that the protective effects of Zn involve antioxidant mechanisms whether it is Zn alone (as an antioxidant), Zn induction of metallothionein or Zn inhibition of redox-sensitive transcription factors. Further studies are needed to identify the mechanism(s) for Zn protection in Type 2 diabetes, including pancreatic and peripheral effects. Experimental manipulations of Zn status in rodent models of diabetes provide a valuable approach to explore mechanisms for the protective effects of Zn; however, long term clinical studies establishing safety (lack of toxicity) and efficacy are required before any recommendations can be made for people with diabetes.

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Abbreviations

GK rats:

Goto-Kakizaki rats

MT:

metallothionein

STZ:

streptozotocin

Zn:

zinc

References

  • MD Apostolova KH Choo AE Michalska C Tohyama (1997) ArticleTitleAnalysis of the possible protective role of metallothionein in streptozotocin-induced diabetes using metallothionein-null mice J Trace Elem Med Biol 11 IssueID1 1–7 Occurrence Handle9176863

    PubMed  Google Scholar 

  • V Bancila T Cens D Monnier F Chanson C Faure Y Dunant A Bloc (2005) ArticleTitleTwo SUR1-specific histidine residues mandatory for zinc-induced activation of the rat KATP channel J Biol Chem 280 IssueID10 8793–8799 Occurrence Handle10.1074/jbc.M413426200 Occurrence Handle15613469

    Article  PubMed  Google Scholar 

  • JH Beattie AM Wood AM Newman I Bremner KHA Choo AE Michalska JS Duncan P Trayhurn (1998) ArticleTitleObesity and hyperleptinemia in metallothionein (-I and -II) null mice Proc Natl Acad Sci USA 95 358–363 Occurrence Handle10.1073/pnas.95.1.358 Occurrence Handle9419380

    Article  PubMed  Google Scholar 

  • N Begin-Heick M Dalpe-Scott J Rowe HM Heick (1985) ArticleTitleZinc supplementation attenuates insulin secretory activity in pancreatic islets of the ob/ob mouse Diabetes 34 IssueID2 179–184 Occurrence Handle3881305

    PubMed  Google Scholar 

  • TM Bray WJ Bettger (1990) ArticleTitleThe physiological role of zinc as an antioxidant Free Radical Biol Med 8 IssueID3 281–291 Occurrence Handle10.1016/0891-5849(90)90076-U

    Article  Google Scholar 

  • AB Chausmer (1998) ArticleTitleZinc, insulin and diabetes J Am Coll Nutr 17 IssueID2 109–115 Occurrence Handle9550453

    PubMed  Google Scholar 

  • H Chen EC Carlson L Pellet JT Moritz PN Epstein (2001) ArticleTitleOverexpression of metallothionein in pancreatic β-cells reduces streptozotocin-induced DNA damage and diabetes Diabetes 50 2040–2046 Occurrence Handle11522669

    PubMed  Google Scholar 

  • F Chimienti S Devergnas A Favier M Seve (2004) ArticleTitleIdentification and cloning of a β-cell-specific zinc transporter, ZnT-8, localized into insulin secretory granules Diabetes 53 2330–2337 Occurrence Handle15331542

    PubMed  Google Scholar 

  • KS Clifford MJ MacDonald (2000) ArticleTitleSurvey of mRNAs encoding zinc transporters and other metal complexing proteins in pancreatic islets of rats from birth to adulthood: similar patterns in the Sprague-Dawley and wistar BB strains Diabetes Res Clin Pract 49 77–85 Occurrence Handle10.1016/S0168-8227(00)00141-8 Occurrence Handle10963817

    Article  PubMed  Google Scholar 

  • RC Lisle ParticleDe MP Sarras SuffixJr J Hidalgo GK Andrews (1996) ArticleTitleMetallothionein is a component of exocrine pancreas secretion: implications for zinc homeostasis Am J Physiol 271 IssueID4 Pt 1 C1103–C1110 Occurrence Handle8897816

    PubMed  Google Scholar 

  • G Dodson D Steiner (1998) ArticleTitleThe role of assembly in insulin’s biosynthesis Curr Opin Struct Biol 8 IssueID2 189–194 Occurrence Handle10.1016/S0959-440X(98)80037-7 Occurrence Handle9631292

    Article  PubMed  Google Scholar 

  • J Dufner-Beattie YM Kuo J Gitschier GK Andrews (2004) ArticleTitleThe adaptive response to dietary zinc in mice involves the differential cellular localization and zinc regulation of the zinc transporters ZIP4 and ZIP5 J Biol Chem 279 IssueID47 49082–49090 Occurrence Handle10.1074/jbc.M409962200 Occurrence Handle15358787

    Article  PubMed  Google Scholar 

  • ML Failla CY Gardell (1985) ArticleTitleInfluence of spontaneous diabetes on tissue status of zinc, copper, and manganese I the BB wistar rat Proc Soc Exp Biol Med 180 IssueID2 317–322 Occurrence Handle3901016

    PubMed  Google Scholar 

  • S Falkner R Odselius B Blondel M Prentki CB Wollheim (1985) ArticleTitleEnergy dispersive X-ray microanalysis of zinc and calcium in organelles of insulin-producing cells of the mouse, rat, and a fish Biomed Biochim Acta 44 IssueID1 37–43 Occurrence Handle3888207

    PubMed  Google Scholar 

  • P Faure A Roussel C Coudray MJ Richard S Halimi A Favier (1992) ArticleTitleZinc and insulin sensitivity Biol Trace Elem Res 32 305–310 Occurrence Handle1375070

    PubMed  Google Scholar 

  • DP Figlewicz SE Forhan AT Hodgson GM Grodsky (1984) ArticleTitle65Zinc and endogenous zinc content and distribution in islets in relationship to insulin content Endocrinol 115 IssueID3 877–881

    Google Scholar 

  • D Findik P Presek (1988) ArticleTitleZn2+ enhances protein tyrosine kinase activity of human platelet membranes FEBS Lett 235 51–56 Occurrence Handle10.1016/0014-5793(88)81232-8 Occurrence Handle2456950

    Article  PubMed  Google Scholar 

  • Food and Nutrition Board, Institute of Medicine. 2001 Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. The National Academy of Sciences. National Academy Press, Washington, DC [http://www.nap.edu/openbook/0309072794/html/index.html accessed 25/01/2005].

  • LE Fridlyand LH Philipson (2004) ArticleTitleDoes the glucose-dependent insulin secretion mechanism itself cause oxidative stress in pancreatic β-cells Diabetes 53 1942–1948 Occurrence Handle15277370

    PubMed  Google Scholar 

  • J Fugono K Fujimoto H Yasui K Kawabe Y Yoshikawa Y Kojima H Sakurai (2002) ArticleTitleMetallokinetic study of zinc in the blood of normal rats given insulinomimetic zinc(II) complexes and improvement of diabetes mellitus in type 2 diabetic GK rats by their oral administration Drug Metabol Pharmacokin 27 IssueID4 340–347 Occurrence Handle10.2133/dmpk.17.340

    Article  Google Scholar 

  • X Geng L Lehong S Watkins PD Robbins P Drain (2003) ArticleTitleThe insulin secretory granule is the major site of KATP channels of the endocrine pancreas Diabetes 52 767–776 Occurrence Handle12606519

    PubMed  Google Scholar 

  • E Ho TM Bray (1999) ArticleTitleAntioxidants, NFkB activation, and diabetogenesis Exp Biol Med 222 205–213 Occurrence Handle10.1046/j.1525-1373.1999.d01-137.x

    Article  Google Scholar 

  • E Ho N Quan YH Tsai W Lai TM Bray (2001) ArticleTitleDietary zinc supplementation inhibits NFkB activation and protects against chemically induced diabetes in CD1 mice Exp Biol Med 226 103–111

    Google Scholar 

  • LH Ho RE Ruffin C Murgia L Lixin SA Krillis PD Zalewski (2004) ArticleTitleLabile zinc and zinc transporter ZnT4 in mast cell granules: role in regulation of caspase activation and NF-kB Translocation J Immunol 172 7750–7760 Occurrence Handle15187159

    PubMed  Google Scholar 

  • H Ishihara P Maechler A Gjinovci P-L Herrera CB Wollheim (2003) ArticleTitleIslet β-cell secretion determines glucagons release from neighbouring α-cells Nat Cell Biol 5 IssueID4 330–335 Occurrence Handle10.1038/ncb951 Occurrence Handle12640462

    Article  PubMed  Google Scholar 

  • T Kambe H Narita Y Yamaguchi-Iwai J Hirose T Amano N Sugiura R Sasaki K Mori T Iwanaga M Nagao (2002) ArticleTitleCloning and characterization of a novel mammalian zinc transporter, zinc transporter 5, abundantly expressed in pancreatic β cells J Biol Chem 277 IssueID21 19049–19055 Occurrence Handle10.1074/jbc.M200910200 Occurrence Handle11904301

    Article  PubMed  Google Scholar 

  • ML Kennedy ML Failla (1987) ArticleTitleZinc metabolism in genetically obese (ob/ob) mice J Nutr 117 IssueID5 886–893 Occurrence Handle3585542

    PubMed  Google Scholar 

  • Y Kojima Y Yoshikawa E Ueda R Ueda S Yamamoto K Kumekawa N Yanagihara H Sakurai (2003) ArticleTitleInsulinomimetic zinc(II) complexes with natural products: in vitro evaluation and blood glucose lowering effect in KK-Ay mice with type 2 diabetes mellitus Chem Pharm Bull 51 IssueID8 1006–1008 Occurrence Handle10.1248/cpb.51.1006 Occurrence Handle12913247

    Article  PubMed  Google Scholar 

  • LH Kristiansen J Rungby LG Sondergaard M Stoltenberg G Danscher (2001) ArticleTitleAutometallography allows ultrastructural monitoring of zinc in the endocrine pancreas Histochem Cell Biol 115 IssueID2 125–129 Occurrence Handle10.1007/s004180000241 Occurrence Handle11444147

    Article  PubMed  Google Scholar 

  • HM Kubisch J Wang TM Bray JP Phillips (1997) ArticleTitleTargeted overexpression of Cu/Zn superoxide dismutase protects pancreatic beta-cells against oxidative stress Diabetes 46 IssueID10 1563–1566 Occurrence Handle9313750

    PubMed  Google Scholar 

  • HM Kubisch J Wang R Luche E Carlson TM Bray CJ Epstein JP Phillips (1994) ArticleTitleTransgenic copper/zinc superoxide dismutase modulates susceptibility to type 1 diabetes Proc Natl Acad Sci USA 91 9956–9959 Occurrence Handle7937925

    PubMed  Google Scholar 

  • MR L’Abbe PW Fischer (1984a) ArticleTitleThe effects of dietary zinc on the activity of copper-requiring metalloenzymes in the growing rat J Nutr 114 IssueID5 813–822

    Google Scholar 

  • MR L’Abbe PW Fischer (1984b) ArticleTitleThe effects of dietary zinc on the activity of copper-requiring metalloenzymes in the rat J Nutr 114 IssueID5 823–828

    Google Scholar 

  • S Lenzen J Drinkgern M Tiedge (1996) ArticleTitleLow antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues Free Radic Biol Med 20 IssueID3 463–466 Occurrence Handle10.1016/0891-5849(96)02051-5 Occurrence Handle8720919

    Article  PubMed  Google Scholar 

  • AA Like AA Rossini (1976) ArticleTitleStreptozotocin-induced pancreatic insulitis: new model of diabetes mellitus Science 193 IssueID4251 415–417 Occurrence Handle180605

    PubMed  Google Scholar 

  • JP Liuzzi JA Bobo LA Lichten DA Samuelson RJ Cousins (2004) ArticleTitleResponsive transporter genes within the murine intestinal-pancreatic axis form a basis of zinc homeostasis Proc Natl Acad Sci USA 101 IssueID40 14355–14360 Occurrence Handle10.1073/pnas.0406216101 Occurrence Handle15381762

    Article  PubMed  Google Scholar 

  • JP Liuzzi RJ Cousins (2004) ArticleTitleMammalian zinc transporters Annu Rev Nutr 24 151–172 Occurrence Handle10.1146/annurev.nutr.24.012003.132402 Occurrence Handle15189117

    Article  PubMed  Google Scholar 

  • T Mandrup-Poulsen (2003) ArticleTitleApoptotic signal transduction pathways in diabetes Biochem Pharmacol 66 1433–1440 Occurrence Handle10.1016/S0006-2952(03)00494-5 Occurrence Handle14555218

    Article  PubMed  Google Scholar 

  • RJ McIssac (1955) ArticleTitleThe distribution of zinc-65 in the rat pancreas Endocrinol 57 IssueID5 571–579

    Google Scholar 

  • RA Mooney KL Bordwell (1992) ArticleTitleDifferential dephosphorylation of the insulin receptor and its 160-kDa substrate (pp160) in rat adipocytes J Biol Chem 267 14054–14060 Occurrence Handle1321133

    PubMed  Google Scholar 

  • WJ Qian KR Gee RT Kennedy (2003) ArticleTitleImaging of Zn2+ release from pancreatic β-cells at the level of single exocytotic events Anal Chem 75 3468–3475 Occurrence Handle10.1021/ac0341057 Occurrence Handle14570199

    Article  PubMed  Google Scholar 

  • J Quarterman CF Mills WR Humphries (1966) ArticleTitleThe reduced secretion of, and sensitivity to insulin in zinc-deficient rats Biochem Biophys Res Commun 25 354–358 Occurrence Handle10.1016/0006-291X(66)90785-6 Occurrence Handle5972841

    Article  PubMed  Google Scholar 

  • AL Prost A Bloc N Hussy R Derand M Vivaudou (2004) ArticleTitleZinc is both an intracellular and extracellular regulator of KATP channel function J Physiol 559 IssueIDPt 1 157–167 Occurrence Handle10.1113/jphysiol.2004.065094 Occurrence Handle15218066

    Article  PubMed  Google Scholar 

  • RP Robertson J Harmon POT Tran V Poitout (2004) ArticleTitleβ-Cell glucose toxicity, lipotoxicity, and chronic oxidative stress in Type 2 diabetes Diabetes 53 IssueIDSuppl 1 S119–S124 Occurrence Handle14749276

    PubMed  Google Scholar 

  • HP Roth M Kirchgessner (1980) ArticleTitleZn metalloenzyme activities. Changes and biochemical aspects in Zn deficiency World Rev Nutr Diet 34 144–160 Occurrence Handle6766599

    PubMed  Google Scholar 

  • GA Rutter (2004) ArticleTitleVisualising insulin secretion. The Minkowski Lecture 2004 Diabetologia 47 1861–1872 Occurrence Handle10.1007/s00125-004-1541-1 Occurrence Handle15551048

    Article  PubMed  Google Scholar 

  • P Schott-Ohly A Lgssiar HJ Partke M Hassan N Friesen H Gleichmann (2004) ArticleTitlePrevention of spontaneous and experimentally induced diabetes in mice with zinc sulfate-enriched drinking water is associated with activation and reduction of NF-kB and AP-1 in islets, respectively Exp Biol Med 229 1117–1185

    Google Scholar 

  • DA Scott AM Fisher (1938) ArticleTitleThe insulin and the zinc content of normal and diabetic pancreas J Clin Invest 17 725–728

    Google Scholar 

  • GE Sheline IL Chaikoff HB Jones ML Montgomery (1943) ArticleTitleStudies on the metabolism of zinc with the aid of its radioisotope. II. The distribution of administered radioactive zinc in the tissues of mice and dogs J Biol Chem 149 139–151

    Google Scholar 

  • SF Simon CG Taylor (2001) ArticleTitleDietary zinc supplementation attenuates hyperglycemia in db/db mice Exp Biol Med 226 43–51

    Google Scholar 

  • LG Sondergaard M Stoltenberg A Flyvbjerg B Brock O Schmitz G Danscher J Rungby (2003) ArticleTitleZinc ions in β-cells of obese, insulin-resistant, and type 2 diabetic rats traced by autometallography APMIS 111 1147–1154 Occurrence Handle10.1111/j.1600-0463.2003.apm1111211.x Occurrence Handle14678025

    Article  PubMed  Google Scholar 

  • S Southon Z Kechrid AJA Wright SJ Fairweather-Tait (1988) ArticleTitleEffect of reduced dietary zinc intake on carbohydrate and zinc metabolism in the genetically diabetic mouse (C57BL/KsJ db+/db+) Br J Nutr 60 499–507 Occurrence Handle3219321

    PubMed  Google Scholar 

  • S Takita Y Wakamoto I Kunitsugu S Gugiyama M Okuda T Houbara (2004) ArticleTitleAltered tissue concentration of minerals in spontaneous diabetic rats J Toxicol Sci 29 IssueID3 195–199 Occurrence Handle10.2131/jts.29.195 Occurrence Handle15467269

    Article  PubMed  Google Scholar 

  • DL Tallman CG Taylor (1999) ArticleTitlePotential interactions of zinc in the neuroendocrine-endocrine disturbances of diabetes mellitus type 2 Can J Physiol Parmacol 77 919–933 Occurrence Handle10.1139/cjpp-77-12-919

    Article  Google Scholar 

  • DL Tallman CG Taylor (2003) ArticleTitleEffects of dietary fat and zinc on adiposity, serum leptin and adipose fatty acid composition in C57BL/6J mice J Nutr Biochem 14 17–23 Occurrence Handle10.1016/S0955-2863(02)00228-0 Occurrence Handle12559473

    Article  PubMed  Google Scholar 

  • M Tiedge S Lortz J Drinkgern S Lenzen (1997) ArticleTitleRelation between antioxidant enzyme gene expression and antioxidative defense status of insulin-producing cells Diabetes 46 IssueID11 1733–1742 Occurrence Handle9356019

    PubMed  Google Scholar 

  • MH Tobia MM Zdanowicz MA Wingertzahn B McHeffey-Atkinson AE Slonim RA Wapnir (1998) ArticleTitleThe role of dietary zinc in modifying the onset and severity of spontaneous diabetes in the BB wistar rat Mol Genet Metabol 63 205–213 Occurrence Handle10.1006/mgme.1997.2672

    Article  Google Scholar 

  • J Yang MG Cherian (1994) ArticleTitleProtective effects of metallothionein on streptozotocin-induced diabetes in rats Life Sci 55 IssueID1 43–51 Occurrence Handle10.1016/0024-3205(94)90080-9 Occurrence Handle8015348

    Article  PubMed  Google Scholar 

  • Y Yoshikawa E Ueda K Kawabe H Miyake T Takino H Sakurai Y Kojima (2002) ArticleTitleDevelopment of new insulinomimetic zinc (II) picolinate complexes with a Zn(N2O2) coordination mode: structure characterization, in vitro, and in vivo studies J Biol Inorg Chem 7 68–73 Occurrence Handle10.1007/s007750100266 Occurrence Handle11862542

    Article  PubMed  Google Scholar 

  • Y Yoshikawa E Ueda H Miyake H Sakurai Y Kojima (2001) ArticleTitleInsulinomimetic bis(maltolato)zinc(II) complex: blood glucose normalizing effect in KK-Ay mice with type 2 diabetes mellitus Biochem Biophys Res Commun 281 1190–1193 Occurrence Handle10.1006/bbrc.2001.4456 Occurrence Handle11243860

    Article  PubMed  Google Scholar 

  • PD Zalewski SH Millard IJ Forbes O Kapaniris A Slavotinek WH Betts AD Ward SF Lincoln I Mahadevan (1994) ArticleTitleVideo image analysis of labile zinc in viable pancreatic islet cells using a specific fluorescent probe for zinc J Histochem Cytochem 42 IssueID7 877–884 Occurrence Handle8014471

    PubMed  Google Scholar 

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  1. Department of Human Nutritional Sciences, University of Manitoba, R3T 2N2, Manitoba, Winnipeg, Canada

    Carla G. Taylor

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Taylor, C.G. Zinc, the Pancreas, and Diabetes: Insights from Rodent Studies and Future Directions. Biometals 18, 305–312 (2005). https://doi.org/10.1007/s10534-005-3686-x

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