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Zinc in Pancreatic Islet Biology, Insulin Sensitivity, and Diabetes

  • Maret, Wolfgang (Division of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King's College London)
  • Received : 2017.01.18
  • Accepted : 2017.02.23
  • Published : 2017.03.31

Abstract

About 20 chemical elements are nutritionally essential for humans with defined molecular functions. Several essential and nonessential biometals are either functional nutrients with antidiabetic actions or can be diabetogenic. A key question remains whether changes in the metabolism of biometals and biominerals are a consequence of diabetes or are involved in its etiology. Exploration of the roles of zinc (Zn) in this regard is most revealing because 80 years of scientific discoveries link zinc and diabetes. In pancreatic ${\beta}$- and ${\alpha}$-cells, zinc has specific functions in the biochemistry of insulin and glucagon. When zinc ions are secreted during vesicular exocytosis, they have autocrine, paracrine, and endocrine roles. The membrane protein ZnT8 transports zinc ions into the insulin and glucagon granules. ZnT8 has a risk allele that predisposes the majority of humans to developing diabetes. In target tissues, increased availability of zinc enhances the insulin response by inhibiting protein tyrosine phosphatase 1B, which controls the phosphorylation state of the insulin receptor and hence downstream signalling. Inherited diseases of zinc metabolism, environmental exposures that interfere with the control of cellular zinc homeostasis, and nutritional or conditioned zinc deficiency influence the pathobiochemistry of diabetes. Accepting the view that zinc is one of the many factors in multiple gene-environment interactions that cause the functional demise of ${\beta}$-cells generates an immense potential for treating and perhaps preventing diabetes. Personalized nutrition, bioactive food, and pharmaceuticals targeting the control of cellular zinc in precision medicine are among the possible interventions.

Keywords

References

  1. Mertz W. 1982. Trace elements and minerals in diabetes. In Diabetes Mellitus and Obesity. Brodoff BN, Bleicher SJ, eds. Williams & Wilkins, Baltimore, MD, USA. p 343-348.
  2. Maret W. 2016. Metallomics: a primer of integrated biometal sciences. Imperial College Press, London, UK.
  3. Mertz W. 1981. The essential trace elements. Science 213: 1332-1338. https://doi.org/10.1126/science.7022654
  4. Nielsen FH. 2014. Should bioactive trace elements not recognized as essential, but with beneficial health effects, have intake recommendations. J Trace Elem Med Biol 28: 406-408. https://doi.org/10.1016/j.jtemb.2014.06.019
  5. Vincent JB. 2013. The bioinorganic chemistry of chromium. John Wiley & Sons, Inc., Chichester, West Sussex, UK.
  6. McCall AS, Cummings CF, Bhave G, Vanacore R, Page-McCaw A, Hudson BG. 2014. Bromine is an essential trace element for assembly of collagen IV scaffolds in tissue development and architecture. Cell 157: 1380-1392. https://doi.org/10.1016/j.cell.2014.05.009
  7. Maret W. 2016. The metals in the biological periodic system of the elements: concepts and conjectures. Int J Mol Sci 17: 66. https://doi.org/10.3390/ijms17010066
  8. Maret W, Moulis JM. 2013. The bioinorganic chemistry of cadmium in the context of its toxicity. In Metal Ions in Life Sciences. Sigel A, Sigel H, Sigel RKO, eds. Springer Science+ Business Media BV, Dordrecht, The Netherlands. Vol 11, p 1-29.
  9. Maret W. 2017. The bioinorganic chemistry of lead in the context of its toxicity. In Metal Ions in Life Sciences. Sigel A, Sigel H, Sigel RKO, eds. De Gruyter, Berlin, Germany. Vol 17, in press.
  10. El Muayed M, Raja MR, Zhang X, MacRenaris KW, Bhatt S, Chen X, Urbanek M, O'Halloran TV, Lowe WL Jr. 2012. Accumulation of cadmium in insulin-producing ${\beta}$ cells. Islets 4: 405-416. https://doi.org/10.4161/isl.23101
  11. Hoch E, Lin W, Chai J, Hershfinkel M, Fu D, Sekler I. 2012. Histidine pairing at the metal transport site of mammalian ZnT transporters controls $Zn^{2+}$ over $Cd^{2+}$ selectivity. Proc Natl Acad Sci USA 109: 7202-7207. https://doi.org/10.1073/pnas.1200362109
  12. Siddiqui K, Bawazeer N, Joy SS. 2014. Variation in macro and trace elements in progression of type 2 diabetes. Sci World J 2014: 461591.
  13. Tosiello L. 1996. Hypomagnesemia and diabetes mellitus: a review of clinical implications. Arch Intern Med 156: 1143-1148. https://doi.org/10.1001/archinte.1996.00440100029005
  14. Salgueiro MJ, Krebs N, Zubillaga MB, Weill R, Postaire E, Lysionek AE, Caro RA, De Paoli T, Hager A, Boccio J. 2001. Zinc and diabetes mellitus: is there a need of zinc supplementation in diabetes mellitus patients?. Biol Trace Elem Res 81: 215-228. https://doi.org/10.1385/BTER:81:3:215
  15. Praveeena S, Pasula S, Sameera K. 2013. Trace elements in diabetes mellitus. J Clin Diagn Res 7: 1863-1865.
  16. Kruse-Jarres JD, Ruckgauer M. 2000. Trace elements in diabetes mellitus. Peculiarities and clinical validity of determinations in blood cells. J Trace Elem Med Biol 14: 21-27. https://doi.org/10.1016/S0946-672X(00)80019-X
  17. Himsworth HP. 1936. Diabetes mellitus: its differentiation into insulin-sensitive and insulin-insensitive types. The Lancet 227: 127-130. https://doi.org/10.1016/S0140-6736(01)36134-2
  18. King JC. 2011. Zinc: an essential but elusive nutrient. Am J Clin Nutr 94: 679S-684S. https://doi.org/10.3945/ajcn.110.005744
  19. Maret W. 2013. Zinc biochemistry: from a single zinc enzyme to a key element of life. Adv Nutr 4: 82-91. https://doi.org/10.3945/an.112.003038
  20. Hogstrand C, Maret W. 2016. Genetics of human zinc deficiencies. In eLS: Essential for Life Science. John Wiley & Sons, Inc., Chichester, West Sussex, UK. p 1-8.
  21. Raudenska M, Gumulec J, Podlaha O, Sztalmachova M, Babula P, Eckschlager T, Adam V, Kizek R, Masarik M. 2014. Metallothionein polymorphisms in pathological processes. Metallomics 6: 55-68. https://doi.org/10.1039/C3MT00132F
  22. Scott DA, Fisher AM. 1938. The insulin and the zinc content of normal and diabetic pancreas. J Clin Invest 17: 725-728. https://doi.org/10.1172/JCI101000
  23. Chausmer AB. 1998. Zinc, insulin and diabetes. J Am Coll Nutr 17: 109-115. https://doi.org/10.1080/07315724.1998.10718735
  24. Tallman DL, Taylor CG. 1999. Potential interactions of zinc in the neuroendocrine-endocrine disturbances of diabetes mellitus type 2. Can J Physiol Pharmacol 77: 919-933. https://doi.org/10.1139/y99-111
  25. Maret W. 2005. Zinc and diabetes. Biometals 18: 293-294. https://doi.org/10.1007/s10534-005-3684-z
  26. Suckale J, Solimena M. 2010. The insulin secretory granule as a signaling hub. Trends Endocrinol Metab 21: 599-609. https://doi.org/10.1016/j.tem.2010.06.003
  27. Schvartz D, Brunner Y, Coute Y, Foti M, Wollheim CB, Sanchez JC. 2012. Improved characterization of the insulin secretory granule proteomes. J Proteomics 75: 4620-4631. https://doi.org/10.1016/j.jprot.2012.04.023
  28. Hutton JC, Penn EJ, Peshavaria M. 1983. Low-molecularweight constituents of isolated insulin-secretory granules. Bivalent cations, adenine nucleotides and inorganic phosphate. Biochem J 210: 297-305. https://doi.org/10.1042/bj2100297
  29. Dunn MF. 2005. Zinc-ligand interactions modulate assembly and stability of the insulin hexamer-a review. Biometals 18: 295-303. https://doi.org/10.1007/s10534-005-3685-y
  30. Ishihara H, Wollheim CB. 2016. Is zinc an intra-islet regulator of glucagon secretion?. Diabetol Int 7: 106-110. https://doi.org/10.1007/s13340-016-0259-x
  31. Tamaki M, Fujitani Y, Hara A, Uchida T, Tamura Y, Takeno K, Kawaguchi M, Watanabe T, Ogihara T, Fukunaka A, Shimizu T, Mita T, Kanazawa A, Imaizumi MO, Abe T, Kiyonari H, Hojyo S, Fukada T, Kawauchi T, Nagamatsu S, Hirano T, Kawamori R, Watada H. 2013. The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance. J Clin Invest 123: 4513-4524. https://doi.org/10.1172/JCI68807
  32. Gavrilova J, Tougu V, Palumaa P. 2014. Affinity of zinc and copper ions for insulin monomers. Metallomics 6: 1296-1300. https://doi.org/10.1039/C4MT00059E
  33. Keltner Z, Meyer JA, Johnson EM, Palumbo AM, Spence DM, Reid GE. 2010. Mass spectrometric characterization and activity of zinc-activated proinsulin C-peptide and C-peptide mutants. Analyst 135: 278-288. https://doi.org/10.1039/B917600D
  34. Brender JR, Hartman K, Nanga RPR, Popovych N, de la Salud Bea R, Vivekanandan S, Marsh ENG, Ramamoorthy A. 2010. Role of zinc in human islet amyloid polypeptide aggregation. J Am Chem Soc 132: 8973-8983. https://doi.org/10.1021/ja1007867
  35. Wineman-Fisher V, Miller Y. 2016. Effect of $Zn^{2+}$ ions on the assembly of amylin oligomers: insight into the molecular mechanisms. Phys Chem Chem Phys 18: 21590-21599. https://doi.org/10.1039/C6CP04105A
  36. Landreh M, Alvelius G, Johansson J, Jornvall H. 2014. Insulin, islet amyloid polypeptide and C-peptide interactions evaluated by mass spectrometric analysis. Rapid Commun Mass Spectrom 28: 178-184. https://doi.org/10.1002/rcm.6772
  37. Egefjord L, Bak AM, Petersen AB, Rungby J. 2010. Zinc, alpha cells and glucagon secretion. Curr Diabetes Rev 6: 52-57. https://doi.org/10.2174/157339910790442655
  38. Chimienti F, Devergnas S, Favier A, Seve M. 2004. Identification and cloning of a ${\beta}$-cell-specific zinc transporter, ZnT-8, localized into insulin secretory granules. Diabetes 53: 2330-2337. https://doi.org/10.2337/diabetes.53.9.2330
  39. Solomou A, Meur G, Bellomo E, Hodson DJ, Tomas A, Li SM, Philippe E, Herrera PL, Magnan C, Rutter GA. 2015. The zinc transporter Slc30a8/ZnT8 is required in a subpopulation of pancreatic ${\alpha}$-cells for hypoglycemia-induced glucagon secretion. J Biol Chem 290: 21432-21442. https://doi.org/10.1074/jbc.M115.645291
  40. Wenzlau JM, Juhl K, Yu L, Moua O, Sarkar SA, Gottlieb P, Rewers M, Eisenbarth GS, Jensen J, Davidson HW, Hutton JC. 2007. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci USA 104: 17040-17045. https://doi.org/10.1073/pnas.0705894104
  41. Davidson HW, Wenzlau JM, O'Brien RM. 2014. Zinc transporter 8 (ZnT8) and ${\beta}$ cell function . Trends Endocrinol Metab 25: 415-424. https://doi.org/10.1016/j.tem.2014.03.008
  42. Flannick J, Thorleifsson G, Beer NL, Jacobs SB, Grarup N, Burtt NP, Mahajan A, Fuchsberger C, Atzmon G, Benediktsson R, Blangero J, Bowden DW, Brandslund I, Brosnan J, Burslem F, Chambers J, Cho YS, Christensen C, Douglas DA, Duggirala R, Dymek Z, Farjoun Y, Fennell T, Fontanillas P, Forsen T, Gabriel S, Glaser B, Gudbjartsson DF, Hanis C, Hansen T, Hreidarsson AB, Hveem K, Ingelsson E, Isomaa B, Johansson S, Jorgensen T, Jorgensen ME, Kathiresan S, Kong A, Kooner J, Kravic J, Laakso M, Lee JY, Lind L, Lindgren CM, Linneberg A, Masson G, Meitinger T, Mohlke KL, Molven A, Morris AP, Potluri S, Rauramaa R, Ribel-Madsen R, Richard AM, Rolph T, Salomaa V, Segre AV, Skarstrand H, Steinthorsdottir V, Stringham HM, Sulem P, Tai ES, Teo YY, Teslovich T, Thorsteinsdottir U, Trimmer JK, Tuomi T, Tuomilehto J, Vaziri-Sani F, Voight BF, Wilson JG, Boehnke M, McCarthy MI, Njolstad PR, Pedersen O; Go-T2D Consortium; T2D-GENES Consortium, Groop L, Cox DR, Stefansson K, Altshuler D. 2014. Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nat Genet 46: 357-363. https://doi.org/10.1038/ng.2915
  43. Merriman C, Huang Q, Rutter GA, Fu D. 2016. Lipid-tuned zinc transport activity of human ZnT8 protein correlates with risk for type-2 diabetes. J Biol Chem 291: 26950-26957. https://doi.org/10.1074/jbc.M116.764605
  44. Rutter GA, Chimienti F. 2015. SLC30A8 mutations in type 2 diabetes. Diabetologia 58: 31-36. https://doi.org/10.1007/s00125-014-3405-7
  45. Quarterman J, Mills CF, Humphries WR. 1966. The reduced secretion of, and sensitivity to insulin in zinc-deficient rats. Biochem Biophys Res Commun 25: 354-358. https://doi.org/10.1016/0006-291X(66)90785-6
  46. Coulston L, Dandona P. 1980. Insulin-like effect of zinc on adipocytes. Diabetes 29: 665-667. https://doi.org/10.2337/diab.29.8.665
  47. Wong VV, Nissom PM, Sim SL, Yeo JH, Chuah SH, Yap MGS. 2005. Zinc as an insulin replacement in hybridoma cultures. Biotechnol Bioeng 93: 553-563.
  48. Haase H, Maret W. 2003. Intracellular zinc fluctuations modulate protein tyrosine phosphatase activity in insulin/insulin-like growth factor-1 signaling. Exp Cell Res 291: 289-298. https://doi.org/10.1016/S0014-4827(03)00406-3
  49. Haase H, Maret W. 2005. Protein tyrosine phosphatases as targets of the combined insulinomimetic effects of zinc and oxidants. Biometals 18: 333-338. https://doi.org/10.1007/s10534-005-3707-9
  50. Bellomo E, Massarotti A, Hogstrand C, Maret W. 2014. Zinc ions modulate protein tyrosine phosphatase 1B activity. Metallomics 6: 1229-1239. https://doi.org/10.1039/C4MT00086B
  51. Bellomo E, Singh KB, Massarotti A, Hogstrand C, Maret W. 2016. The metal face of protein tyrosine phosphatase 1B. Coord Chem Rev 327-328: 70-83. https://doi.org/10.1016/j.ccr.2016.07.002
  52. Tang X, Shay NF. 2001. Zinc has an insulin-like effect on glucose transport mediated by phosphoinositol-3-kinase and Akt in 3T3-L1 fibroblasts and adipocytes. J Nutr 131: 1414-1420. https://doi.org/10.1093/jn/131.5.1414
  53. Taylor KM, Hiscox S, Nicholson RI, Hogstrand C, Kille P. 2012. Protein kinase CK2 triggers cytosolic zinc signaling pathways by phosphorylation of zinc channel ZIP7. Sci Signal 5: ra11.
  54. Mahadev K, Motoshima H, Wu X, Ruddy JM, Arnold RS, Cheng G, Lambeth JD, Goldstein BJ. 2004. The NAD(P)H oxidase homolog Nox4 modulates insulin-stimulated generation of $H_2O_2$ and plays an integral role in insulin signal transduction. Mol Cell Biol 24: 1844-1854. https://doi.org/10.1128/MCB.24.5.1844-1854.2004
  55. Baynes JW. 1991. Role of oxidative stress in development of complications in diabetes. Diabetes 40: 405-412.
  56. Gerber PA, Rutter GA. 2016. The role of oxidative stress and hypoxia in pancreatic beta-cell dysfunction in diabetes mellitus. Antioxid Redox Signal DOI: 10.1089/ars.2016.6755.
  57. Houstis N, Rosen ED, Lander ES. 2006. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 440: 944-948. https://doi.org/10.1038/nature04634
  58. Maret W. 2006. Zinc coordination environments in proteins as redox sensors and signal transducers. Antioxid Redox Signal 8: 1419-1441. https://doi.org/10.1089/ars.2006.8.1419
  59. Maret W. 2008. Metallothionein redox biology in the cytoprotective and cytotoxic functions of zinc. Exp Gerontol 43: 363-369. https://doi.org/10.1016/j.exger.2007.11.005
  60. Oteiza PI. 2012. Zinc and the modulation of redox homeostasis. Free Radic Biol Med 53: 1748-1759. https://doi.org/10.1016/j.freeradbiomed.2012.08.568
  61. Ayaz M, Turan B. 2006. Selenium prevents diabetes-induced alterations in $[Zn^{2+}]_i$ and metallothionein level of rat heart via restoration of cell redox cycle. Am J Physiol Heart Circ Physiol 290: H1071-H1080. https://doi.org/10.1152/ajpheart.00754.2005
  62. Gerber PA, Bellomo EA, Hodson DJ, Meur G, Solomou A, Mitchell RK, Hollinshead M, Chimienti F, Bosco D, Hughes SJ, Johnson PR, Rutter GA. 2014. Hypoxia lowers SLC30A8/ZnT8 expression and free cytosolic $Zn^{2+}$ in pancreatic beta cells. Diabetologia 57: 1635-1644. https://doi.org/10.1007/s00125-014-3266-0
  63. Chabosseau P, Rutter GA. 2016. Zinc and diabetes. Arch Biochem Biophys 611: 79-85. https://doi.org/10.1016/j.abb.2016.05.022
  64. Hao Q, Maret W. 2006. Aldehydes release zinc from proteins. A pathway from oxidative stress/lipid peroxidation to cellular functions of zinc. FEBS J 273: 4300-4310. https://doi.org/10.1111/j.1742-4658.2006.05428.x
  65. Maret W. 2011. Redox biochemistry of mammalian metallothioneins. J Biol Inorg Chem 16: 1079-1086. https://doi.org/10.1007/s00775-011-0800-0
  66. Li X, Cai L, Feng W. 2007. Diabetes and metallothionein. Mini Rev Med Chem 7: 761-768. https://doi.org/10.2174/138955707781024490
  67. Giacconi R, Bonfigli AR, Testa R, Sirolla C, Cipriano C, Marra M, Muti E, Malavolta M, Costarelli L, Piacenza F, Tesei S, Mocchegiani E. 2008. +647 A/C and +1245 MT1A polymorphisms in the susceptibility of diabetes mellitus and cardiovascular complications. Mol Genet Metab 94: 98-104. https://doi.org/10.1016/j.ymgme.2007.12.006
  68. Pauling L. 1968. Orthomolecular psychiatry. Varying the concentrations of substances normally present in the human body may control mental disease. Science 160: 265-271. https://doi.org/10.1126/science.160.3825.265
  69. Maret W, Sandstead HH. 2006. Zinc requirements and the risks and benefits of zinc supplementation. J Trace Elem Med Biol 20: 3-18. https://doi.org/10.1016/j.jtemb.2006.01.006
  70. Sakurai H, Adachi Y. 2005. The pharmacology of the insulinomimetic effect of zinc complexes. Biometals 18: 319-323. https://doi.org/10.1007/s10534-005-3688-8
  71. Vardatsikos G, Pandey NR, Srivastava AK. 2013. Insulinomimetic and anti-diabetic effects of zinc. J Inorg Biochem 120: 8-17. https://doi.org/10.1016/j.jinorgbio.2012.11.006
  72. Bao B, Prasad AS, Beck FW, Fitzgerald JT, Snell D, Bao GW, Singh T, Cardozo LJ. 2010. Zinc decreases C-reactive protein, lipid peroxidation, and inflammatory cytokines in elderly subjects: a potential implication of zinc as an atheroprotective agent. Am J Clin Nutr 91: 1634-1641. https://doi.org/10.3945/ajcn.2009.28836
  73. El Dib R, Gameiro OL, Ogata MS, Modolo NS, Braz LG, Jorge EC, do Nascimento P Jr, Beletate V. 2015. Zinc supplementation for the prevention of type 2 diabetes mellitus in adults with insulin resistance. Cochrane Database Syst Rev 5: CD005525.
  74. Chu A, Foster M, Samman S. 2016. Zinc status and risk of cardiovascular diseases and type 2 diabetes mellitus-a systematic review of prospective cohort studies. Nutrients 8: 707. https://doi.org/10.3390/nu8110707
  75. Ruz M, Carrasco F, Sanchez A, Perez A, Rojas P. 2016. Does zinc really "metal" with diabetes? The epidemiologic evidence. Curr Diab Rep 16: 111. https://doi.org/10.1007/s11892-016-0803-x

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