Zinc homeostasis in the metabolic syndrome and diabetes

Frontiers of Medicine in China

Volumn 7, Issue 1, 2013, Pages 31-52

  Miao, Xiao ^a,c   Sun, Weixia ^b,c   Fu, Yaowen ^b   Miao, Lining ^a   Cai, Lu ^c,d  

^a THE SECOND HOSPITAL OF JILIN UNIVERSITY   (China)

^b THE FIRST HOSPITAL OF JILIN UNIVERSITY   (China)

^c University of Louisville School of Medicine   (United States)

^d WENZHOU MEDICAL UNIVERSITY   (China)

Author keywords

antioxidant; diabetes; diabetic complications; insulin resistance; metallothionein; zinc; zinc transporters

Indexed keywords

EID: 84874798770     PISSN: 16737342     EISSN: 16737458     Source Type: Journal    
DOI: 10.1007/s11684-013-0251-9     Document Type: Review

References (196)

1. Cai L, Li XK, Song Y, Cherian MG. Essentiality, toxicology and chelation therapy of zinc and copper. Curr Med Chem 2005; 12(23): 2753-2763.
2. Prasad AS. Zinc: an overview. Nutrition 1995; 11(1 Suppl): 93-99.
3. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988; 37(12): 1595-1607.
4. Sumner AD, Sardi GL, Reed JF 3rd. Components of the metabolic syndrome differ between young and old adults in the US population. J Clin Hypertens (Greenwich) 2012; 14(8): 502-506.
5. Bardsley JK, Want LL. Overview of diabetes. Crit Care Nurs Q 2004; 27(2): 106-112.
6. Jayawardena R, Ranasinghe P, Galappatthy P, Malkanthi R, Constantine G, Katulanda P. Effects of zinc supplementation on diabetes mellitus: a systematic review and meta-analysis. Diabetol Metab Syndr 2012; 4(1): 13.
7. Gupta R, Garg VK, Mathur DK, Goyal RK. Oral zinc therapy in diabetic neuropathy. J Assoc Physicians India 1998; 46(11): 939-942.
8. Tapiero H, Tew KD. Trace elements in human physiology and pathology: zinc and metallothioneins. Biomed Pharmacother 2003; 57(9): 399-411.
9. Kambe T, Yamaguchi-Iwai Y, Sasaki R, Nagao M. Overview of mammalian zinc transporters. Cell Mol Life Sci 2004; 61(1): 49-68.
10. Cai L, Satoh M, Tohyama C, Cherian MG. Metallothionein in radiation exposure: its induction and protective role. Toxicology 1999; 132(2-3): 85-98.
11. Cai L, Klein JB, Kang YJ. Metallothionein inhibits peroxynitriteinduced DNA and lipoprotein damage. J Biol Chem 2000; 275(50): 38957-38960.
12. Cai L. Metallothionein and cardiomyopathy. In: Zatta P. Metallothioneins in Biochemistry and Pathology. New Jersey: World Scientific, 2008: 227-269.
13. Prasad AS. Clinical, immunological, anti-inflammatory and antioxidant roles of zinc. Exp Gerontol 2008; 43(5): 370-377.
14. Prasad AS. Discovery of human zinc deficiency: 50 years later. J Trace Elem Med Biol 2012; 26(2-3): 66-69.
15. Goldman J, Carpenter FH. Zinc binding, circular dichroism, and equilibrium sedimentation studies on insulin (bovine) and several of its derivatives. Biochemistry 1974; 13(22): 4566-4574.
16. Bakaysa DL, Radziuk J, Havel HA, Brader ML, Li S, Dodd SW, Beals JM, Pekar AH, Brems DN. Physicochemical basis for the rapid time-action of LysB28ProB29-insulin: dissociation of a protein-ligand complex. Protein Sci 1996; 5(12): 2521-2531.
17. Wang X, Zhou B. Dietary zinc absorption: A play of Zips and ZnTs in the gut. IUBMB Life 2010; 62(3): 176-182.
18. Fukada T, Kambe T. Molecular and genetic features of zinc transporters in physiology and pathogenesis. Metallomics 2011; 3(7): 662-674.
19. Kambe T. An overview of a wide range of functions of ZnT and Zip zinc transporters in the secretory pathway. Biosci Biotechnol Biochem 2011; 75(6): 1036-1043.
20. Fukada T, Yamasaki S, Nishida K, Murakami M, Hirano T. Zinc homeostasis and signaling in health and diseases: Zinc signaling. J Biol Inorg Chem 2011; 16(7): 1123-1134.
21. Chimienti F, Devergnas S, Favier A, Seve M. Identification and cloning of a beta-cell-specific zinc transporter, ZnT-8, localized into insulin secretory granules. Diabetes 2004; 53(9): 2330-2337.
22. 8+ T cell epitope in HLA-A2+ type 1 diabetic patients. Diabetologia 2012; 55(7): 2026-2031.
23. Kawasaki E. ZnT8 and type 1 diabetes. Endocr J 2012; 59(7): 531-537.
24. Xu J, Wang J, Chen B. SLC30A8 (ZnT8) variations and type 2 diabetes in the Chinese Han population. Genet Mol Res 2012; 11(2): 1592-1598.
25. Cai L. Metallothionein as an adaptive protein prevents diabetes and its toxicity. Nonlinearity Biol Toxicol Med 2004; 2(2): 89-103.
26. Cai L. Diabetic cardiomyopathy and its prevention by metallothionein: experimental evidence, possible mechanisms and clinical implications. Curr Med Chem 2007; 14(20): 2193-2203.
27. Park JH, Grandjean CJ, Hart MH, Erdman SH, Pour P, Vanderhoof JA. Effect of pure zinc deficiency on glucose tolerance and insulin and glucagon levels. Am J Physiol 1986; 251(3 Pt 1): E273-E278.
28. Faure P, Roussel AM, Martinie M, Osman M, Favier A, Halimi S. Insulin sensitivity in zinc-depleted rats: assessment with the euglycaemic hyperinsulinic clamp technique. Diabete Metab 1991; 17(3): 325-331.
29. Jou MY, Philipps AF, Lönnerdal B. Maternal zinc deficiency in rats affects growth and glucose metabolism in the offspring by inducing insulin resistance postnatally. J Nutr 2010; 140(9): 1621-1627.
30. Singh RB, Niaz MA, Rastogi SS, Bajaj S, Gaoli Z, Shoumin Z. Current zinc intake and risk of diabetes and coronary artery disease and factors associated with insulin resistance in rural and urban populations of North India. J Am Coll Nutr 1998; 17(6): 564-570.
31. Himoto T, Yoneyama H, Kurokochi K, Inukai M, Masugata H, Goda F, Haba R, Watanabe S, Senda S, Masaki T. Contribution of zinc deficiency to insulin resistance in patients with primary biliary cirrhosis. Biol Trace Elem Res 2011; 144(1-3): 133-142.
32. Chausmer AB. Zinc, insulin and diabetes. J Am Coll Nutr 1998; 17(2): 109-115.
33. Haglund B, Ryckenberg K, Selinus O, Dahlquist G. Evidence of a relationship between childhood-onset type I diabetes and low groundwater concentration of zinc. Diabetes Care 1996; 19(8): 873-875.
34. Zhao HX, Mold MD, Stenhouse EA, Bird SC, Wright DE, Demaine AG, Millward BA. Drinking water composition and childhood-onset Type 1 diabetes mellitus in Devon and Cornwall, England. Diabet Med 2001; 18(9): 709-717.
35. Benson VS, Vanleeuwen JA, Taylor J, Somers GS, McKinney PA, van Til L. Type 1 diabetes mellitus and components in drinking water and diet: a population-based, case-control study in Prince Edward Island, Canada. J Am Coll Nutr 2010; 29(6): 612-624.
36. Samuelsson U, Oikarinen S, Hyöty H, Ludvigsson J. Low zinc in drinking water is associated with the risk of type 1 diabetes in children. Pediatr Diabetes 2011; 12(3 Pt 1): 156-164.
37. Moltchanova E, Rytkönen M, Kousa A, Taskinen O, Tuomilehto J, Karvonen M. Zinc and nitrate in the ground water and the incidence of Type 1 diabetes in Finland. Diabet Med 2004; 21(3): 256-261.
38. Goldberg ED, Eshchenko VA, Bovt VD. The diabetogenic and acidotropic effects of chelators. Exp Pathol 1991; 42(1): 59-64.
39. Goldberg ED, Eshchenko VA, Bovt VD. Diabetogenic activity of chelators in some mammalian species. Endocrinologie 1990; 28(2): 51-55.
40. Kechrid Z, Bouzerna N, Zio MS. Effect of low zinc diet on (65)Zn turnover in non-insulin dependent diabetic mice. Diabetes Metab 2001; 27(5 Pt 1): 580-583.
41. Reiterer G, MacDonald R, Browning JD, Morrow J, Matveev SV, Daugherty A, Smart E, Toborek M, Hennig B. Zinc deficiency increases plasma lipids and atherosclerotic markers in LDLreceptor-deficient mice. J Nutr 2005; 135(9): 2114-2118.
42. Shen H, MacDonald R, Bruemmer D, Stromberg A, Daugherty A, Li XA, Toborek M, Hennig B. Zinc deficiency alters lipid metabolism in LDL receptor deficient mice treated with rosiglitazone. J Nutr 2007; 137(11): 2339-2345.
43. Tomat AL, Weisstaub AR, Jauregui A, Piñeiro A, Balaszczuk AM, Costa MA, Arranz CT. Moderate zinc deficiency influences arterial blood pressure and vascular nitric oxide pathway in growing rats. Pediatr Res 2005; 58(4): 672-676.
44. Tomat AL, Costa MA, Girgulsky LC, Veiras L, Weisstaub AR, Inserra F, Balaszczuk AM, Arranz CT. Zinc deficiency during growth: influence on renal function and morphology. Life Sci 2007; 80(14): 1292-1302.
45. Shen H, Oesterling E, Stromberg A, Toborek M, MacDonald R, Hennig B. Zinc deficiency induces vascular pro-inflammatory parameters associated with NF-κB and PPAR signaling. J Am Coll Nutr 2008; 27(5): 577-587.
46. Zhao Y, Tan Y, Dai J, Li B, Guo L, Cui J, Wang G, Shi X, Zhang X, Mellen N, Li W, Cai L. Exacerbation of diabetes-induced testicular apoptosis by zinc deficiency is most likely associated with oxidative stress, p38 MAPK activation, and p53 activation in mice. Toxicol Lett 2011; 200(1-2): 100-106.
47. Zhao Y, Tan Y, Dai J, Wang B, Li B, Guo L, Cui J, Wang G, Li W, Cai L. Zinc deficiency exacerbates diabetic down-regulation of Akt expression and function in the testis: essential roles of PTEN, PTP1B and TRB3. J Nutr Biochem 2012; 23(8): 1018-1026.
48. Zhang C, Lu X, Tan Y, Li B, Miao X, Jin L, Shi X, Zhang X, Miao L, Li X, Cai L. Diabetes-induced hepatic pathogenic damage, inflammation, oxidative stress, and insulin resistance was exacerbated in zinc deficient mouse model. PLoS ONE 2012; 7(12): e49257.
49. Soinio M, Marniemi J, Laakso M, Pyörälä K, Lehto S, Rönnemaa T. Serum zinc level and coronary heart disease events in patients with type 2 diabetes. Diabetes Care 2007; 30(3): 523-528.
50. Terrés-Martos C, Navarro-Alarcón M, Martín-Lagos F, López-G de la Serrana H, Pérez-Valero V, López-Martínez MC. Serum zinc and copper concentrations and Cu/Zn ratios in patients with hepatopathies or diabetes. J Trace Elem Med Biol 1998; 12(1): 44-49.
51. Anderson RA, Roussel AM, Zouari N, Mahjoub S, Matheau JM, Kerkeni A. Potential antioxidant effects of zinc and chromium supplementation in people with type 2 diabetes mellitus. J Am Coll Nutr 2001; 20(3): 212-218.
52. Anetor JI, Senjobi A, Ajose OA, Agbedana EO. Decreased serum magnesium and zinc levels: atherogenic implications in type-2 diabetes mellitus in Nigerians. Nutr Health 2002; 16(4): 291-300.
53. Roussel AM, Kerkeni A, Zouari N, Mahjoub S, Matheau JM, Anderson RA. Antioxidant effects of zinc supplementation in Tunisians with type 2 diabetes mellitus. J Am Coll Nutr 2003; 22(4): 316-321.
54. Levine AS, McClain CJ, Handwerger BS, Brown DM, Morley JE. Tissue zinc status of genetically diabetic and streptozotocininduced diabetic mice. Am J Clin Nutr 1983; 37(3): 382-386.
55. Faure P, Roussel A, Coudray C, Richard MJ, Halimi S, Favier A. Zinc and insulin sensitivity. Biol Trace Elem Res 1992; 32(1-3): 305-310.
56. el-Yazigi A, Hannan N, Raines DA. Effect of diabetic state and related disorders on the urinary excretion of magnesium and zinc in patients. Diabetes Res 1993; 22(2): 67-75.
57. Golik A, Cohen N, Ramot Y, Maor J, Moses R, Weissgarten J, Leonov Y, Modai D. Type II diabetes mellitus, congestive heart failure, and zinc metabolism. Biol Trace Elem Res 1993; 39(2-3): 171-175.
58. Williams NR, Rajput-Williams J, West JA, Nigdikar SV, Foote JW, Howard AN. Plasma, granulocyte and mononuclear cell copper and zinc in patients with diabetes mellitus. Analyst (Lond) 1995; 120(3): 887-890.
59. Blostein-Fujii A, DiSilvestro RA, Frid D, Katz C, Malarkey W. Short-term zinc supplementation in women with non-insulindependent diabetes mellitus: effects on plasma 5′-nucleotidase activities, insulin-like growth factor I concentrations, and lipoprotein oxidation rates in vitro. Am J Clin Nutr 1997; 66(3): 639-642.
60. Honnorat J, Accominotti M, Broussolle C, Fleuret AC, Vallon JJ, Orgiazzi J. Effects of diabetes type and treatment on zinc status in diabetes mellitus. Biol Trace Elem Res 1992; 32(1-3): 311-316.
61. Quilliot D, Dousset B, Guerci B, Dubois F, Drouin P, Ziegler O. Evidence that diabetes mellitus favors impaired metabolism of zinc, copper, and selenium in chronic pancreatitis. Pancreas 2001; 22(3): 299-306.
62. Pathak A, Sharma V, Kumar S, Dhawan DK. Supplementation of zinc mitigates the altered uptake and turnover of 65Zn in liver and whole body of diabetic rats. Biometals 2011; 24(6): 1027-1034.
63. Smidt K, Jessen N, Petersen AB, Larsen A, Magnusson N, Jeppesen JB, Stoltenberg M, Culvenor JG, Tsatsanis A, Brock B, Schmitz O, Wogensen L, Bush AI, Rungby J. SLC30A3 responds to glucose- and zinc variations in beta-cells and is critical for insulin production and in vivo glucose-metabolism during beta-cell stress. PLoS ONE 2009; 4(5): e5684.
64. Jansen J, Rosenkranz E, Overbeck S, Warmuth S, Mocchegiani E, Giacconi R, Weiskirchen R, Karges W, Rink L. Disturbed zinc homeostasis in diabetic patients by in vitro and in vivo analysis of insulinomimetic activity of zinc. J Nutr Biochem 2012; 23(11): 1458-1466.
65. Liu BY, Jiang Y, Lu Z, Li S, Lu D, Chen B. Down-regulation of zinc transporter 8 in the pancreas of db/db mice is rescued by Exendin-4 administration. Mol Med Report 2011; 4(1): 47-52.
66. Foster M, Karra M, Picone T, Chu A, Hancock DP, Petocz P, Samman S. Dietary fiber intake increases the risk of zinc deficiency in healthy and diabetic women. Biol Trace Elem Res 2012; 149(2): 135-142.
67. Failla ML, Kiser RA. Altered tissue content and cytosol distribution of trace metals in experimental diabetes. J Nutr 1981; 111(11): 1900-1909.
68. Failla ML, Kiser RA. Hepatic and renal metabolism of copper and zinc in the diabetic rat. Am J Physiol 1983; 244(2): E115-E121.
69. Craft NE, Failla ML. Zinc, iron, and copper absorption in the streptozotocin-diabetic rat. Am J Physiol 1983; 244(2): E122-E128.
70. Escobar O, Sandoval M, Vargas A, Hempe JM. Role of metallothionein and cysteine-rich intestinal protein in the regulation of zinc absorption by diabetic rats. Pediatr Res 1995; 37(3): 321-327.
71. Chen ML, Failla ML. Metallothionein metabolism in the liver and kidney of the streptozotocin-diabetic rat. Comp Biochem Physiol B 1988; 90(2): 439-445.
72. Jin T, Nordberg G, Sehlin J, Vesterberg O. Protection against cadmium-metallothionein nephrotoxicity in streptozotocininduced diabetic rats: role of increased metallothionein synthesis induced by streptozotocin. Toxicology 1996; 106(1-3): 55-63.
73. Kennedy ML, Failla ML. Zinc metabolism in genetically obese (ob/ob) mice. J Nutr 1987; 117(5): 886-893.
74. Failla ML, Gardell CY. Influence of spontaneous diabetes on tissue status of zinc, copper, and manganese in the BB Wistar rat. Proc Soc Exp Biol Med 1985; 180(2): 317-322.
75. Cai L, Chen S, Evans T, Cherian MG, Chakrabarti S. Endothelin-1-mediated alteration of metallothionein and trace metals in the liver and kidneys of chronically diabetic rats. Int J Exp Diabetes Res 2002; 3(3): 193-198.
76. Ayaz M, Turan B. Selenium prevents diabetes-induced alterations in [Zn2+]i and metallothionein level of rat heart via restoration of cell redox cycle. Am J Physiol Heart Circ Physiol 2006; 290(3): H1071-H1080.
77. Tadros WM, Awadallah R, Doss H, Khalifa K. Protective effect of trace elements (Zn, Mn, Cr, Co) on alloxan-induced diabetes. Indian J Exp Biol 1982; 20(1): 93-94.
78. Yang J, Cherian MG. Protective effects of metallothionein on streptozotocin-induced diabetes in rats. Life Sci 1994; 55(1): 43-51.
79. Ho E, Quan N, Tsai YH, Lai W, Bray TM. Dietary zinc supplementation inhibits NFkappaB activation and protects against chemically induced diabetes in CD1 mice. Exp Biol Med (Maywood) 2001; 226(2): 103-111.
80. Ohly P, Dohle C, Abel J, Seissler J, Gleichmann H. Zinc sulphate induces metallothionein in pancreatic islets of mice and protects against diabetes induced by multiple low doses of streptozotocin. Diabetologia 2000; 43(8): 1020-1030.
81. Sitasawad S, Deshpande M, Katdare M, Tirth S, Parab P. Beneficial effect of supplementation with copper sulfate on STZdiabetic mice (IDDM). Diabetes Res Clin Pract 2001; 52(2): 77-84.
82. Marreiro DN, Geloneze B, Tambascia MA, Lerário AC, Halpern A, Cozzolino SM. Effect of zinc supplementation on serum leptin levels and insulin resistance of obese women. Biol Trace Elem Res 2006; 112(2): 109-118.
83. Hashemipour M, Kelishadi R, Shapouri J, Sarrafzadegan N, Amini M, Tavakoli N, Movahedian-Attar A, Mirmoghtadaee P, Poursafa P. Effect of zinc supplementation on insulin resistance and components of the metabolic syndrome in prepubertal obese children. Hormones (Athens) 2009; 8(4): 279-285.
84. Kim J, Lee S. Effect of zinc supplementation on insulin resistance and metabolic risk factors in obese Korean women. Nurs Res Pract 2012; 6(3): 221-225.
85. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001; 414(6865): 813-820.
86. Cai L, Kang YJ. Oxidative stress and diabetic cardiomyopathy: a brief review. Cardiovasc Toxicol 2001; 1(3): 181-193.
87. Srinivasan S, Hatley ME, Bolick DT, Palmer LA, Edelstein D, Brownlee M, Hedrick CC. Hyperglycaemia-induced superoxide production decreases eNOS expression via AP-1 activation in aortic endothelial cells. Diabetologia 2004; 47(10): 1727-1734.
88. Zou MH, Shi C, Cohen RA. Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. J Clin Invest 2002; 109(6): 817-826.
89. Mooradian AD, Morley JE, Scarpace PJ. The role of zinc status in altered cardiac adenylate cyclase activity in diabetic rats. Acta Endocrinol (Copenh) 1988; 119(2): 174-180.
90. Noh SK, Koo SI. Feeding of a low-zinc diet lowers the tissue concentrations of alpha-tocopherol in adult rats. Biol Trace Elem Res 2001; 81(2): 153-168.
91. Chvapil M, Owen JA. Effect of zinc on acute and chronic isoproterenol induced heart injury. J Mol Cell Cardiol 1977; 9(2): 151-159.
92. Singal PK, Dhillon KS, Beamish RE, Dhalla NS. Protective effect of zinc against catecholamine-induced myocardial changes electrocardiographic and ultrastructural studies. Lab Invest 1981; 44(5): 426-433.
93. Satoh M, Naganuma A, Imura N. Modulation of adriamycin toxicity by tissue-specific induction of metallothionein synthesis in mice. Life Sci 2000; 67(6): 627-634.
94. Fushimi H, Inoue T, Yamada Y, Horie H, Kameyama M, Inoue K, Minami T, Okazaki Y. Zinc deficiency exaggerates diabetic osteoporosis. Diabetes Res Clin Pract 1993; 20(3): 191-196.
95. Faure P, Benhamou PY, Perard A, Halimi S, Roussel AM. Lipid peroxidation in insulin-dependent diabetic patients with early retina degenerative lesions: effects of an oral zinc supplementation. Eur J Clin Nutr 1995; 49(4): 282-288.
96. Kajanachumpol S, Srisurapanon S, Supanit I, Roongpisuthipong C, Apibal S. Effect of zinc supplementation on zinc status, copper status and cellular immunity in elderly patients with diabetes mellitus. J Med Assoc Thai 1995; 78(7): 344-349.
97. de Sena KC, Arrais RF, das Graças Almeida M, de Araújo DM, dos Santos MM, de Lima VT, de Fãtima Campos Pedrosa L. Effects of zinc supplementation in patients with type 1 diabetes. Biol Trace Elem Res 2005; 105(1-3): 1-9.
98. Seet RC, Lee CY, Lim EC, Quek AM, Huang H, Huang SH, Looi WF, Long LH, Halliwell B. Oral zinc supplementation does not improve oxidative stress or vascular function in patients with type 2 diabetes with normal zinc levels. Atherosclerosis 2011; 219(1): 231-239.
99. Evans SA, Overton JM, Alshingiti A, Levenson CW. Regulation of metabolic rate and substrate utilization by zinc deficiency. Metabolism 2004; 53(6): 727-732.
100. Simon SF, Taylor CG. Dietary zinc supplementation attenuates hyperglycemia in db/db mice. Exp Biol Med (Maywood) 2001; 226(1): 43-51.
101. Mantzoros CS, Prasad AS, Beck FW, Grabowski S, Kaplan J, Adair C, Brewer GJ. Zinc may regulate serum leptin concentrations in humans. J Am Coll Nutr 1998; 17(3): 270-275.
102. Chen MD, Song YM, Lin PY. Zinc effects on hyperglycemia and hypoleptinemia in streptozotocin-induced diabetic mice. Horm Metab Res 2000; 32(3): 107-109.
103. Chen MD, Song YM, Lin PY. Zinc may be a mediator of leptin production in humans. Life Sci 2000; 66(22): 2143-2149.
104. Canesi L, Betti M, Ciacci C, Gallo G. Insulin-like effect of zinc in mytilus digestive gland cells: modulation of tyrosine kinasemediated cell signaling. Gen Comp Endocrinol 2001; 122(1): 60-66.
105. Tang X, Shay NF. Zinc has an insulin-like effect on glucose transport mediated by phosphoinositol-3-kinase and Akt in 3T3-L1 fibroblasts and adipocytes. J Nutr 2001; 131(5): 1414-1420.
106. Haase H, Maret W. Intracellular zinc fluctuations modulate protein tyrosine phosphatase activity in insulin/insulin-like growth factor-1 signaling. Exp Cell Res 2003; 291(2): 289-298.
107. Miranda ER, Dey CS. Effect of chromium and zinc on insulin signaling in skeletal muscle cells. Biol Trace Elem Res 2004; 101(1): 19-36.
108. May JM, Contoreggi CS. The mechanism of the insulin-like effects of ionic zinc. J Biol Chem 1982; 257(8): 4362-4368.
109. Chen MD, Liou SJ, Lin PY, Yang VC, Alexander PS, Lin WH. Effects of zinc supplementation on the plasma glucose level and insulin activity in genetically obese (ob/ob) mice. Biol Trace Elem Res 1998; 61(3): 303-311.
110. Kolaczynski JW, Caro JF. Insulin-like growth factor-1 therapy in diabetes: physiologic basis, clinical benefits, and risks. Ann Intern Med 1994; 120(1): 47-55.
111. McCusker RH, Mateski RL, Novakofski J. Zinc alters the kinetics of IGF-II binding to cell surface receptors and binding proteins. Endocrine 2003; 21(3): 279-288.
112. McCusker RH, Novakofski J. Zinc partitions IGFs from soluble IGF binding proteins (IGFBP)-5, but not soluble IGFBP-4, to myoblast IGF type 1 receptors. J Endocrinol 2004; 180(2): 227-246.
113. Ilouz R, Kaidanovich O, Gurwitz D, Eldar-Finkelman H. Inhibition of glycogen synthase kinase-3beta by bivalent zinc ions: insight into the insulin-mimetic action of zinc. Biochem Biophys Res Commun 2002; 295(1): 102-106.
114. Chanoit G, Lee S, Xi J, Zhu M, McIntosh RA, Mueller RA, Norfleet EA, Xu Z. Exogenous zinc protects cardiac cells from reperfusion injury by targeting mitochondrial permeability transition pore through inactivation of glycogen synthase kinase-3beta. Am J Physiol Heart Circ Physiol 2008; 295(3): H1227-H1233.
115. Lee S, Chanoit G, McIntosh R, Zvara DA, Xu Z. Molecular mechanism underlying Akt activation in zinc-induced cardioprotection. Am J Physiol Heart Circ Physiol 2009; 297(2): H569-H575.
116. Haase H, Maret W. Protein tyrosine phosphatases as targets of the combined insulinomimetic effects of zinc and oxidants. Biometals 2005; 18(4): 333-338.
117. Haase H, Maret W. Fluctuations of cellular, available zinc modulate insulin signaling via inhibition of protein tyrosine phosphatases. J Trace Elem Med Biol 2005; 19(1): 37-42.
118. Wu W, Wang X, Zhang W, Reed W, Samet JM, Whang YE, Ghio AJ. Zinc-induced PTEN protein degradation through the proteasome pathway in human airway epithelial cells. J Biol Chem 2003; 278(30): 28258-28263.
119. Cameron AR, Anil S, Sutherland E, Harthill J, Rena G. Zincdependent effects of small molecules on the insulin-sensitive transcription factor FOXO1a and gluconeogenic genes. Metallomics 2010; 2(3): 195-203.
120. Prasad AS, Bao B, Beck FW, Kucuk O, Sarkar FH. Antioxidant effect of zinc in humans. Free Radic Biol Med 2004; 37(8): 1182-1190.
121. Kakkar R, Mantha SV, Radhi J, Prasad K, Kalra J. Increased oxidative stress in rat liver and pancreas during progression of streptozotocin-induced diabetes. Clin Sci (Lond) 1998; 94(6): 623-632.
122. Collet JF, D'Souza JC, Jakob U, Bardwell JC. Thioredoxin 2, an oxidative stress-induced protein, contains a high affinity zinc binding site. J Biol Chem 2003; 278(46): 45325-45332.
123. Hagay ZJ, Weiss Y, Zusman I, Peled-Kamar M, Reece EA, Eriksson UJ, Groner Y. Prevention of diabetes-associated embryopathy by overexpression of the free radical scavenger copper zinc superoxide dismutase in transgenic mouse embryos. Am J Obstet Gynecol 1995; 173(4): 1036-1041.
124. Bray TM, Bettger WJ. The physiological role of zinc as an antioxidant. Free Radic Biol Med 1990; 8(3): 281-291.
125. Anderson RA, Roussel AM, Zouari N, Mahjoub S, Matheau JM, Kerkeni A. Potential antioxidant effects of zinc and chromium supplementation in people with type 2 diabetes mellitus. J Am Coll Nutr 2001; 20(3): 212-218.
126. Roussel AM, Kerkeni A, Zouari N, Mahjoub S, Matheau JM, Anderson RA. Antioxidant effects of zinc supplementation in Tunisians with type 2 diabetes mellitus. J Am Coll Nutr 2003; 22(4): 316-321.
127. Moi P, Chan K, Asunis I, Cao A, Kan YW. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci USA 1994; 91(21): 9926-9930.
128. Li B, Liu S, Miao L, Cai L. Prevention of diabetic complications by activation of Nrf2: diabetic cardiomyopathy and nephropathy. Exp Diabetes Res 2012; 2012: 216512.
129. Mehta AJ, Joshi PC, Fan X, Brown LA, Ritzenthaler JD, Roman J, Guidot DM. Zinc supplementation restores PU. 1 and Nrf2 nuclear binding in alveolar macrophages and improves redox balance and bacterial clearance in the lungs of alcohol-fed rats. Alcohol Clin Exp Res 2011; 35(8): 1519-1528.
130. Cortese MM, Suschek CV, Wetzel W, Kröncke KD, Kolb-Bachofen V. Zinc protects endothelial cells from hydrogen peroxide via Nrf2-dependent stimulation of glutathione biosynthesis. Free Radic Biol Med 2008; 44(12): 2002-2012.
131. Ha KN, Chen Y, Cai J, Sternberg P Jr. Increased glutathione synthesis through an ARE-Nrf2-dependent pathway by zinc in the RPE: implication for protection against oxidative stress. Invest Ophthalmol Vis Sci 2006; 47(6): 2709-2715.
132. Aguilar MV, Laborda JM, Martínez-Para MC, González MJ, Meseguer I, Bernao A, Mateos CJ. Effect of diabetes on the tissular Zn/Cu ratio. J Trace Elem Med Biol 1998; 12(3): 155-158.
133. Zargar AH, Shah NA, Masoodi SR, Laway BA, Dar FA, Khan AR, Sofi FA, Wani AI. Copper, zinc, and magnesium levels in noninsulin dependent diabetes mellitus. Postgrad Med J 1998; 74(877): 665-668.
134. Ripa S, Ripa R, Giustiniani S. Are failured cardiomyopathies a zinc-deficit related disease? A study on Zn and Cu in patients with chronic failured dilated and hypertrophic cardiomyopathies. Minerva Med 1998; 89(11-12): 397-403.
135. Canatan H, Bakan I, Akbulut M, Halifeoglu I, Cikim G, Baydas G, Kilic N. Relationship among levels of leptin and zinc, copper, and zinc/copper ratio in plasma of patients with essential hypertension and healthy normotensive subjects. Biol Trace Elem Res 2004; 100(2): 117-123.
136. Maldonado Martín A, Gil Extremera B, Fernández Soto M, Ruiz Martínez M, González Jiménez A, Guijarro Morales A, de Dios Luna del Castillo J. Zinc levels after intravenous administration of zinc sulphate in insulin-dependent diabetes mellitus patients. Klin Wochenschr 1991; 69(14): 640-644.
137. Niewoehner CB, Allen JI, Boosalis M, Levine AS, Morley JE. Role of zinc supplementation in type II diabetes mellitus. Am J Med 1986; 81(1): 63-68.
138. Mocchegiani E, Boemi M, Fumelli P, Fabris N. Zinc-dependent low thymic hormone level in type I diabetes. Diabetes 1989; 38(7): 932-937.
139. Kajanachumpol S, Srisurapanon S, Supanit I, Roongpisuthipong C, Apibal S. Effect of zinc supplementation on zinc status, copper status and cellular immunity in elderly patients with diabetes mellitus. J Med Assoc Thai 1995; 78(7): 344-349.
140. Kang YJ. The antioxidant function of metallothionein in the heart. Proceedings of the Society for Experimental Biology and Medicine. Soci Exp Biol Med. 1999; 222(3): 263-273.
141. Cai L, Cherian MG. Adaptive response to ionizing radiationinduced chromosome aberrations in rabbit lymphocytes: effect of pre-exposure to zinc, and copper salts. Mutat Res 1996; 369(3-4): 233-241.
142. Cai L, Cherian MG, Iskander S, Leblanc M, Hammond RR. Metallothionein induction in human CNS in vitro: neuroprotection from ionizing radiation. Int J Radiat Biol 2000; 76(7): 1009-1017.
143. Cai L, Iskander S, Cherian MG, Hammond RR. Zinc- or cadmiumpre-induced metallothionein protects human central nervous system cells and astrocytes from radiation-induced apoptosis. Toxicol Lett 2004; 146(3): 217-226.
144. Satoh M, Naganuma A, Imura N. Modulation of adriamycin toxicity by tissue-specific induction of metallothionein synthesis in mice. Life Sci 2000; 67(6): 627-634.
145. Ali MM, Frei E, Straub J, Breuer A, Wiessler M. Induction of metallothionein by zinc protects from daunorubicin toxicity in rats. Toxicology 2002; 179(1-2): 85-93.
146. Song Y, Wang J, Li Y, Du Y, Arteel GE, Saari JT, Kang YJ, Cai L. Cardiac metallothionein synthesis in streptozotocin-induced diabetic mice, and its protection against diabetes-induced cardiac injury. Am J Pathol 2005; 167(1): 17-26.
147. Wang Y, Feng W, Xue W, Tan Y, Hein DW, Li XK, Cai L. Inactivation of GSK-3beta by metallothionein prevents diabetesrelated changes in cardiac energy metabolism, inflammation, nitrosative damage, and remodeling. Diabetes 2009; 58(6): 1391-1402.
148. Xu J, Wang G, Wang Y, Liu Q, Xu W, Tan Y, Cai L. Diabetes- and angiotensin II-induced cardiac endoplasmic reticulum stress and cell death: metallothionein protection. J Cell Mol Med 2009; 13(8a 8A): 1499-1512.
149. Liang Q, Carlson EC, Donthi RV, Kralik PM, Shen X, Epstein PN. Overexpression of metallothionein reduces diabetic cardiomyopathy. Diabetes 2002; 51(1): 174-181.
150. Ye G, Metreveli NS, Ren J, Epstein PN. Metallothionein prevents diabetes-induced deficits in cardiomyocytes by inhibiting reactive oxygen species production. Diabetes 2003; 52(3): 777-783.
151. Cai L. Suppression of nitrative damage by metallothionein in diabetic heart contributes to the prevention of cardiomyopathy. Free Radic Biol Med 2006; 41(6): 851-861.
152. Cai L, Wang Y, Zhou G, Chen T, Song Y, Li X, Kang YJ. Attenuation by metallothionein of early cardiac cell death via suppression of mitochondrial oxidative stress results in a prevention of diabetic cardiomyopathy. J Am Coll Cardiol 2006; 48(8): 1688-1697.
153. Wang J, Song Y, Elsherif L, Song Z, Zhou G, Prabhu SD, Saari JT, Cai L. Cardiac metallothionein induction plays the major role in the prevention of diabetic cardiomyopathy by zinc supplementation. Circulation 2006; 113(4): 544-554.
154. Tang Y, Yang Q, Lu J, Zhang X, Suen D, Tan Y, Jin L, Xiao J, Xie R, Rane M, Li X, Cai L. Zinc supplementation partially prevents renal pathological changes in diabetic rats. J Nutr Biochem 2010; 21(3): 237-246.
155. Özcelik D, Nazi{dotless}roglu M, Tunçdemir M, Celik O, Oztürk M, Flores-Arce MF. Zinc supplementation attenuates metallothionein and oxidative stress changes in kidney of streptozotocin-induced diabetic rats. Biol Trace Elem Res 2012; 150(1-3): 342-349.
156. Salgueiro MJ, Krebs N, Zubillaga MB, Weill R, Postaire E, Lysionek AE, Caro RA, De Paoli T, Hager A, Boccio J. Zinc and diabetes mellitus: is there a need of zinc supplementation in diabetes mellitus patients? Biol Trace Elem Res 2001; 81(3): 215-228.
157. Foster M, Samman S. Zinc and redox signaling: perturbations associated with cardiovascular disease and diabetes mellitus. Antioxid Redox Signal 2010; 13, 1549-1573.
158. Yoshikawa Y, Ueda E, Kojima Y, Sakurai H. The action mechanism of zinc(II) complexes with insulinomimetic activity in rat adipocytes. Life Sci 2004; 75(6): 741-751.
159. Cai L, Li XK, Song Y, Cherian MG. Essentiality, toxicology and chelation therapy of zinc and copper. Curr Med Chem 2005; 12(23): 2753-2763.
160. Bonham M, O'Connor JM, McAnena LB, Walsh PM, Downes CS, Hannigan BM, Strain JJ. Zinc supplementation has no effect on lipoprotein metabolism, hemostasis, and putative indices of copper status in healthy men. Biol Trace Elem Res 2003; 93(1-3): 75-86.
161. Bonham M, O'Connor JM, Alexander HD, Coulter J, Walsh PM, McAnena LB, Downes CS, Hannigan BM, Strain JJ. Zinc supplementation has no effect on circulating levels of peripheral blood leucocytes and lymphocyte subsets in healthy adult men. Br J Nutr 2003; 89(5): 695-703.
162. Alissa EM, Bahijri SM, Lamb DJ, Ferns GA. The effects of coadministration of dietary copper and zinc supplements on atherosclerosis, antioxidant enzymes and indices of lipid peroxidation in the cholesterol-fed rabbit. Int J Exp Pathol 2004; 85(5): 265-275.
163. Anetor JI, Senjobi A, Ajose OA, Agbedana EO. Decreased serum magnesium and zinc levels: atherogenic implications in type-2 diabetes mellitus in Nigerians. Nutr Health 2002; 16(4): 291-300.
164. Baydas B, Karagoz S, Meral I. Effects of oral zinc and magnesium supplementation on serum thyroid hormone and lipid levels in experimentally induced diabetic rats. Biol Trace Elem Res 2002; 88(3): 247-253.
165. Disilvestro RA. Zinc in relation to diabetes and oxidative disease. J Nutrition 2000; 130(5S Suppl): 1509S-1511S.
166. Coulston L, Dandona P. Insulin-like effect of zinc on adipocytes. Diabetes 1980; 29(8): 665-667.
167. Moniz T, Amorim MJ, Ferreira R, Nunes A, Silva A, Queirós C, Leite A, Gameiro P, Sarmento B, Remião F, Yoshikawa Y, Sakurai H, Rangel M. Investigation of the insulin-like properties of zinc(II) complexes of 3-hydroxy-4-pyridinones: identification of a compound with glucose lowering effect in STZ-induced type I diabetic animals. J Inorg Biochem 2011; 105(12): 1675-1682.
168. McClain CJ, McClain M, Barve S, Boosalis MG. Trace metals and the elderly. Clin Geriatr Med 2002; 18(4): 801-818, vii-viii (viiviii.).
169. Sbarbati A, Mocchegiani E, Marzola P, Tibaldi A, Mannucci R, Nicolato E, Osculati F. Effect of dietary supplementation with zinc sulphate on the aging process: a study using high field intensity MRI and chemical shift imaging. Biomed Pharmacother 1998; 52(10): 454-458.
170. Cunningham JJ, Fu A, Mearkle PL, Brown RG. Hyperzincuria in individuals with insulin-dependent diabetes mellitus: concurrent zinc status and the effect of high-dose zinc supplementation. Metabolism 1994; 43(12): 1558-1562.
171. Velázquez-Pérez L, Rodríguez-Chanfrau J, García-Rodríguez JC, Sánchez-Cruz G, Aguilera-Rodríguez R, Rodríguez-Labrada R, Rodríguez-Díaz JC, Canales-Ochoa N, Gotay DA, Almaguer Mederos LE, Laffita Mesa JM, Porto-Verdecia M, Triana CG, Pupo NR, Batista IH, López-Hernandez OD, Polanco ID, Novas AJ. Oral zinc sulphate supplementation for six months in SCA2 patients: a randomized, double-blind, placebo-controlled trial. Neurochem Res 2011; 36(10): 1793-1800.
172. Somi MH, Rezaeifar P, Ostad Rahimi A, Moshrefi B. Effects of low dose zinc supplementation on biochemical markers in nonalcoholic cirrhosis: a randomized clinical trial. Arch Iran Med 2012; 15(8): 472-476.
173. Yang J, Cherian MG. Protective effects of metallothionein on streptozotocin-induced diabetes in rats. Life Sci 1994; 55(1): 43-51.
174. Chen MD, Lin PY, Cheng V, Lin WH. Zinc supplementation aggravates body fat accumulation in genetically obese mice and dietary-obese mice. Biol Trace Elem Res 1996; 52(2): 125-132.
175. Tobia MH, Zdanowicz MM, Wingertzahn MA, McHeffey-Atkinson B, Slonim AE, Wapnir RA. The role of dietary zinc in modifying the onset and severity of spontaneous diabetes in the BB Wistar rat. Mol Genet Metab 1998; 63(3): 205-213.
176. Simon SF, Taylor CG. Dietary zinc supplementation attenuates hyperglycemia in db/db mice. Exp Biol Med (Maywood) 2001; 226(1): 43-51.
177. Ho E, Quan N, Tsai YH, Lai W, Bray TM. Dietary zinc supplementation inhibits NFkappaB activation and protects against chemically induced diabetes in CD1 mice. Exp Biol Med (Maywood) 2001; 226(2): 103-111.
178. im Walde SS, Dohle C, Schott-Ohly P, Gleichmann H. Molecular target structures in alloxan-induced diabetes in mice. Life Sci 2002; 71(14): 1681-1694.
179. Schott-Ohly P, Lgssiar A, Partke HJ, Hassan M, Friesen N, Gleichmann H. Prevention of spontaneous and experimentally induced diabetes in mice with zinc sulfate-enriched drinking water is associated with activation and reduction of NF-kappa B and AP-1 in islets, respectively. Exp Biol Med (Maywood) 2004; 229(11): 1177-1185.
180. Yoshikawa Y, Adachi Y, Yasui H, Hattori M, Sakurai H. Oral administration of Bis(aspirinato)zinc(II) complex ameliorates hyperglycemia and metabolic syndrome-like disorders in spontaneously diabetic KK-A(y) mice: structure-activity relationship on zinc-salicylate complexes. Chem Pharm Bull (Tokyo) 2011; 59(8): 972-977.
181. Chen H, Carlson EC, Pellet L, Moritz JT, Epstein PN. Over-expression of metallothionein in pancreatic beta-cells reduces streptozotocin-induced DNA damage and diabetes. Diabetes 2001; 50(9): 2040-2046.
182. Faure P, Benhamou PY, Perard A, Halimi S, Roussel AM. Lipid peroxidation in insulin-dependent diabetic patients with early retina degenerative lesions: effects of an oral zinc supplementation. Eur J Clin Nutr 1995; 49(4): 282-288.
183. Gupta R, Garg VK, Mathur DK, Goyal RK. Oral zinc therapy in diabetic neuropathy. J Assoc Physicians India 1998; 46(11): 939-942.
184. Parham M, Amini M, Aminorroaya A, Heidarian E. Effect of zinc supplementation on microalbuminuria in patients with type 2 diabetes: a double blind, randomized, placebo-controlled, crossover trial. Rev Diabet Stud 2008; 5(2): 102-109.
185. Heidarian E, Amini M, Parham M, Aminorroaya A. Effect of zinc supplementation on serum homocysteine in type 2 diabetic patients with microalbuminuria. Rev Diabet Stud 2009; 6(1): 64-70.
186. Yamaguchi M, Uchiyama S. Preventive effect of zinc acexamate administration in streptozotocin-diabetic rats: Restoration of bone loss. Int J Mol Med 2003; 12(5): 755-761.
187. Uchiyama S, Yamaguchi M. Alteration in serum and bone component findings induced in streptozotocin-diabetic rats is restored by zinc acexamate. Int J Mol Med 2003; 12(6): 949-954.
188. Moustafa SA. Zinc might protect oxidative changes in the retina and pancreas at the early stage of diabetic rats. Toxicol Appl Pharmacol 2004; 201(2): 149-155.
189. Kumar SD, Vijaya M, Samy RP, Dheen ST, Ren M, Watt F, Kang YJ, Bay BH, Tay SS. Zinc supplementation prevents cardiomyocyte apoptosis and congenital heart defects in embryos of diabetic mice. Free Radic Biol Med 2012; 53(8): 1595-1606.
190. Karatug A, Kaptan E, Bolkent S, Mutlu O, Yanardag R. Alterations in kidney tissue following zinc supplementation to stz-induced diabetic rats. J Trace Elem Med Biol 2012 Aug 31. [Epub ahead of print].
191. Kojima Y, Yoshikawa Y, Ueda E, Ueda R, Yamamoto S, Kumekawa K, Yanagihara N, Sakurai H. Insulinomimetic 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 (Tokyo) 2003; 51(8): 1006-1008.
192. Hwang IK, Go VL, Harris DM, Yip I, Kang KW, Song MK. Effects of cyclo (his-pro) plus zinc on glucose metabolism in genetically diabetic obese mice. Diabetes Obes Metab 2003; 5(5): 317-324.
193. Song MK, Hwang IK, Rosenthal MJ, Harris DM, Yamaguchi DT, Yip I, Go VL. Anti-hyperglycemic activity of zinc plus cyclo (hispro) in genetically diabetic Goto-Kakizaki and aged rats. Exp Biol Med (Maywood) 2003; 228(11): 1338-1345.
194. Yoshikawa Y, Ueda E, Sakurai H, Kojima Y. Anti-diabetes effect of Zn(II)/carnitine complex by oral administration. Chem Pharm Bull (Tokyo) 2003; 51(2): 230-231.
195. Adachi Y, Yoshida J, Kodera Y, Kato A, Yoshikawa Y, Kojima Y, Sakurai H. A new insulin-mimetic bis(allixinato)zinc(II) complex: structure-activity relationship of zinc(II) complexes. J Biol Inorg Chem 2004; 9(7): 885-893.
196. Saha TK, Yoshikawa Y, Sakurai H. A [meso-tetrakis(4-sulfonatophenyl) porphyrinato]zinc(ii) complex as an oral therapeutic for the treatment of type 2 diabetic KKA(y) mice. ChemMedChem 2007; 2(2): 218-225.