Metals in the pathogenesis of type 2 diabetes
© Khan and Awan; licensee BioMed Central Ltd. 2014
Received: 27 August 2013
Accepted: 30 December 2013
Published: 8 January 2014
Minerals are one of the components of food, though they are not synthesized in the body but they are essential for optimal health. Several essential metals are required for the proper functioning of many enzymes, transcriptional factors and proteins important in various biochemical pathways. For example Zn, Mg and Mn are cofactors of hundreds of enzymes, and Zn is involved in the synthesis and secretion of insulin from the pancreatic beta-cells. Similarly, Cr enhances the insulin receptor activity on target tissues, especially in muscle cells. Insulin is the key hormone required to maintain the blood glucose level in normal range. In case of insulin deficiency or resistance, blood glucose concentration exceeds the upper limit of the normal range of 126 mg/dl. Persistent increase of blood serum glucose level leads to overt chronic hyperglycemia, which is a major clinical symptom of diabetes mellitus. Poor glycemic control and diabetes alters the levels of essential trace elements such as Zn, Mg, Mn, Cr, Fe etc. by increasing urinary excretion and their concomitant decrease in the blood. Hence, the main purpose of this review is to discuss the important roles of essential trace elements in normal homeostasis and physiological functioning. Moreover, perturbation of essential trace elements is also discussed in perspective of type 2 diabetes pathobiology.
KeywordsDiabetes Essential metals Toxic metals Insulin Zinc
Metals and type 2 diabetes (T2D)
Metals are naturally occurring inorganic elements which are present in very small amounts in the living tissues but are important for the vital processes of life . Some metals (e.g. magnesium) are known as macro-metals and are found in high amount in the body tissues, therefore they are also called macro-nutrients . At least 100 mg of each macro-nutrient is required in the daily diet . In contrast, some metals e.g. copper (Cu), zinc (Zn), iron (Fe) and manganese (Mn), chromium (Cr) etc. are needed in the body in very small amounts, less than 100 parts per million (ppm), hence, these are called trace elements or micro-nutrients . Metals are involved in a range of physiological processes such as prosthetic groups of many proteins, water balance, cofactors of many enzymes etc. . Several metals function as part of proteins/enzymes as metalloproteinase/metalloenzymes . Such proteins without metal containing prosthetic groups are unable to perform their physiological functions . The regulation of various metallic contents in the body is pre-requisite for their proper functioning . Metals enable the muscles to contract or relax, and also transmit impulses through the nerves. Most metals are available in the soluble salt forms, which regulate the composition of biofluids. The proper metabolic functioning of the trace elements depends on their normal levels in various body tissues . Due to the diversified metabolic characteristics and functions; various metals such as Mg, Zn, Cr, Fe, Mn and Cu are considered as essential for normal human health .
Several studies have reported that the imbalance of some essential metals might adversely affect pancreatic islet and cause development of diabetes . It is also manifested that some reactive oxygen species (ROS) are produced during diabetes due to imbalance of essential metals. This oxidative stress might decrease the insulin gene promoter activity and mRNA expression in pancreatic islet cells due to hyperglycemic condition [11–13].
On contrary to essential metals, some toxic metals have also been identified which accumulate in various biological samples of T2D patients. Uncontrolled pollution and industrialization might be a potential source to expose human population against toxic metals such as lead (Pb), nickel (Ni), cadmium (Cd) and arsenic (As). Some of the toxic metals are implicated to disrupt the glucose uptake and alter the related molecular mechanism in glucose regulation [14, 15].
Essential metals and their physiological roles
Iron (Fe) is an essential transition metal required for the synthesis of two important functional proteins such as hemoglobin and myoglobin, which are involved in the transport of molecular oxygen during respiration . It is also required in the elastin production along with Zn and ascorbic acid and collagen synthesis . In blood stream small fraction of serum Fe is transported by a glycoprotein, called transferrin into the cells . In the body tissues, ferritin stores free Fe, which is increased in newly diagnosed diabetic subjects [19, 20]. Jiang et al. manifested higher level of ferritin in diabetics as compared to the non-diabetic subjects. Recently, a report showed a positive correlation between serum ferritin and Fe deposition in tissues, which linearly increased with diabetes duration . The serum ferritin elevation is regarded as an index of Fe overload, which successively leads to a condition called hemochromatosis . Several studies showed association between hemochromatosis and type 2 diabetes (T2D) [23–25]. The elevated Fe level oxidizes various biomolecules such as nucleic acids, proteins and lipids, which may contribute to T2D development by decreasing insulin secretion from pancreatic beta cells with concomitant increase of insulin resistance [13, 26–29]. Previous studies [30, 31] manifested a strong relationship between serum ferritin level and insulin resistance at preclinical stage prior to the development of full blown diabetes mellitus. Regarding this, studies also suggested that in addition to the glucose elevation, serum ferritin level might become a surrogate marker of diabetes to predict disease onset [32, 33].
Mg is the most abundant macro-nutrient which is essential for the maintenance of proper health. It is required for the activity of more than 300 enzymes, which serve several important physiological functions in the human body . Mg containing enzymes are involved in the glucose homeostasis, nerve transmission, DNA and RNA production .
In prospective cohort studies an association was investigated between Mg consumption through diet and the risk of type 2 diabetes. Furthermore, it was demonstrated that Mg deficiency might lead to a decrease in insulin mediated glucose uptake [34, 36]. On the other hand, Mg supplementation prevented insulin resistance and also reduced the development of diabetes in animal models . Some studies reported low level of Mg in the blood serum and an increased urinary excretion of Mg in the diabetics relative to their healthy control subjects .
Mn acts as a cofactor in several enzymes including those involved in bone marrow production, and metabolism of carbohydrates, proteins and fats . It is essential for the proper utilization of choline, thiamine, biotin, vitamin C and vitamin E. Mn as a cofactor of enzymes is also involved in mitochondrial glycoproteins synthesis .
Impaired activity of these enzymes, due to Mn deficiency leads to abnormal cartilage production . Mn is also a cofactor of pyruvate carboxylase, which plays a role in the conversion of various non-carbohydrate compounds into glucose via gluconeogenesis for their subsequent use. In short, Mn is also required for normal insulin synthesis, its secretion, and an alteration in its metabolism has been implicated in diabetes development . Very recently, in an elegant study by Forte and colleagues reported Mn deficiency in type 2 diabetic patients with respect to their control subjects .
Cu is another essential mineral, which is needed for several biological functions. It is required for the catalytic activity of superoxide dismutase (SOD) that participates in the protection of cells from superoxide radicals . Cu imbalance is implicated in cholesterol elevation by disrupting normal high density lipoproteins (HDL) and low density lipoproteins (LDL) balance . Cu also activates cytochrome oxidase which is involved in the electron transport chain of the mitochondria . In case of copper deficiency, cytochrome oxidase reduces its activity which might lead to the distortion of mitochondria in metabolically active tissues such as pancreatic acinar cells, hepatocytes etc. [44, 45].
Published data show that Cu deficiency is one of the reasons for the development of cardiovascular diseases . Other reports suggest that Cu is also beneficial to prevent arthritis associated inflammation and epilepsy . More recently, it has been reported that disturbances in copper levels in various biofluids and tissues are associated with abnormalities implicated in metabolic pathways of diabetes and its complications [1, 48]. Copper as well as zinc metals play roles in order to protect oxidative damage of body tissues [49, 50].
Zinc (Zn) is an essential trace element which is required for normal cell processing e.g. cell division and apoptosis. Zn participates in multiple biochemical pathways such as in transcription, translation and cell divisions . More than 300 enzymes need Zn for their catalytic activities. On the other hand, removal of Zn from catalytic site leads to the loss of enzymatic activity .
About 70% of the Zn is bound to albumin and any pathological alteration of albumin affects the serum Zn levels . Zn malabsorption results in various types of disorders including the dermal, gastrointestinal, neurological and immunological abnormalities .
Recently, published studies revealed that type 2 diabetic patients have suboptimal Zn status in blood due to its increased urinary depletion [1, 40]. As a result, hypozincemia and hyperzincuria are developed in diabetics [1, 54]. Zn plays a key role in the storage and secretion of insulin, which subsequently increases the uptake of glucose [1, 55]. The decreased plasma level of Zn adversely affects the ability of islet cells to produce and secrete insulin [55, 56].
It is well established that Zn transporter (ZnT8) is a key protein for the regulation of insulin secretion from the pancreatic β-cells. Recently a mutation in ZnT8 transporter has been associated with T2D . Briefly all these evidences show the importance of Zn in the maintenance and integration of insulin hexamer and its role in the metabolic regulation .
The biological activity of Cr depends on its valence state and chemical complexes it forms [9, 58, 59]. Trivalent form of Cr has high biological activity which is required for the optimal glucose uptake by cells [59, 60]. Cr regulates insulin and blood glucose levels by stimulating insulin signaling pathway and metabolism by up-regulating glucose transporter (GLUT4) translocation in muscle cells .
Cr deficiency results in the elevation of blood glucose levels and if it is persisted for a prolonged period, it may lead to the development of diabetes . Some reports show that Cr supplements decrease the blood sugar level in diabetes . Prolonged hyperglycemia increases Cr urinary excretion [1, 40].
Briefly, cumulative evidences indicate the essential nature of these metals for the maintenance of human normal physiology. While their imbalance predisposes to glucose intolerance which subsequently converts to diabetes related complications .
Toxic metals and health
Toxic metals e.g. lead (Pb), nickel (Ni), cadmium (Cd) and arsenic (As) deposit in tissues and are non-degradable. Hence, these metals remain in the tissues for a long period, and it is often difficult to eliminate metal-based problem. Body tissues can tolerate a certain level of metals, and beyond such threshold limits tissues get damaged due to metal toxicity. Some of the toxic metals including Ni, As etc. are manifested as carcinogens [11, 64, 65].
The mechanism of metal induced carcinogenesis is elusive, which might be due to complex nature of interactions of metals in biological systems . Furthermore, essential metals also have carcinogenic effects if present in excess amounts than they are required. For example, Cr3+ is essential while Cr4+ behaves as carcinogenic agent . Similarly, hemochromatosis increases the risk of hepatocarcinoma . Preponderance of these toxic metals in the environment is potentially alarming and harmful for human health . They are common in the nature and present in air, water and soil, which increases the probability of human exposure .
Toxic metals react with various proteins in the body that may modify their functions and kinetics. Moreover, when diet is low in essential metals, the body absorbs and makes use of more toxic metals. In the current environmental conditions several human populations are exposed to high levels of toxic metals including Pb, Cd, As and Ni . An abundance of a toxic metal competes with essential metal for enzymes activity and various body physiological functions . For example, Zn is required for the activity of many enzymes. In case of Zn deficiency and increased exposure to toxic metals such as lead (Pb), body will use Pb instead of Zn .
Some toxic metals including Pb, Cd, As and Ni are elevated in biological samples of diabetic patients, which adversely affect health status of an individual by disrupting organ physiology and functions. Free Pb in blood plasma is rapidly transferred to soft body tissues .
Some toxic metals including Pb were reported in higher concentration in the biological samples (i.e. blood plasma and urine) of diabetics than the non-diabetics . Pb is hazardous to most of the human body organs, and interferes with metabolism and cellular functions . Previous reports showed a linear relationship between blood Pb level and renal dysfunction in age-related diseases. This may be due to the frequent exposure to environmental Pb .
Studies demonstrated that exposure to Pb badly affects the antioxidant pathways . Existing evidences indicate that metal induced toxicity may cause derangement of antioxidant mechanisms in living tissues; as a consequence highly reactive oxygen species (ROS) are generated. This antioxidant imbalance might lead to the degradation of proteins, nucleic acids and lipid peroxidation. An oxidative attack of cellular components by ROS is implicated in the pathogenesis of several human diseases including diabetes [14, 74].
Cd is a heavy metal which is widely detected in environment such as air, water and soil. Increased Cd level in water is absorbed by plants, animals and humans . Frequent exposure to Cd contributes to its excess accumulation in kidney, which results in renal damage and nephropathy . Furthermore, Cd high level reduces calcium absorption, which becomes an impending cause of bone and kidney losses, called Itai-Itai disease. It has also been reported that Cd might down-regulate glucose transporter-4 (GLUT4) translocation by insulin and enhanced the induction of pancreatic beta cells’ disruption in diabetes .
Arsenic is a naturally occurring deadly semi-metal, which is mainly used in copper alloys and lead batteries. As is also used in the insecticides, herbicides and pesticides production. Ground water contamination with arsenic is becoming an alarming threat for human lives thoughout the world [11, 71]. Frequent exposure to arsenic linked to various diseases including certain types of cancers and diabetes. Previous studies indicate that As implicates in the disruption of glucose metabolism due to an alteration in cell signaling tranduction factors such as tumor necrosis factor-α (TNF-α), mitogen-activated protein kinase (MAPK) etc., subsequently GLUT4 translocation to membrane might be arrested. Some studies manifest the connection of arsenic in beta-cell dysfunction [14, 75].
Ni is ferromagnetic element which is mostly used in Ni-Cd batteries. Most of the human populations are exposed to Ni through different means such as drinking polluted water, air and eating nickel contaminated food . It has been observed that kidney is the major organ for Ni accumulation, thus contributes in renal dysfunction . Most recently, Forte et al. found that type 2 diabetic patients have 0.89 ng/ml of Ni in the blood relative to 0.77 ng/ml in the control subjects .
Briefly, investigators have analyzed various biofluids such as blood serum/plasma, hair, urine etc. in order to know the altered metabolism of metals in various diseases including diabetes. Among these biological samples, urine was unique because it is readily available and non-invasively sampled. In some previously published studies, researchers have shown urinary levels of metals which correspond to their blood serum status of this metal [1, 14]. Aforementioned studies showed the existence of link between the levels of toxic metals and essential trace metals .
From published literature on derangement of metals in diabetes, it could be concluded that normal levels of essential metals are disturbed in T2D patients. The status of essential trace elements in various body tissues is influenced by renal excretion. Alteration in the level of one metal may influence normal levels of other metals. It can also be suggested that toxic metals such as Pb, Ni and Cd may have a role to induce renal tubular dysfunction in diabetic subjects. Subsequently dysfunctional kidneys may become a potential source for the loss of several essential trace elements through urine voiding rather than their retention in blood plasma /serum in order to retain the homeostasis of blood and other tissues. The high urinary excretion of Zn results in its reduced levels in blood plasma/serum which is the sign of disruptions in Zn based antioxidant mechanism. Therefore, in future large population based prospective studies on urinary analysis of various essential and toxic metals, may help to have scientific as well as practical implications in understanding and controlling diabetes or its complications like diabetic nephropathy.
ARK has background in Chemistry, who did his PhD thesis research in FRA’s lab. ARK has recently submitted his PhD thesis on diabetes research. FRA holds a PhD degree in Biochemistry and working as a Senior Scientist at the Diabetes and Cardio-Metabolic Disorder (D&C-MD) Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan. FRA is also affiliated with QAU (Quaid-i-Azam University) and PIEAS (Pakistan Institute of Engineering and Applied Sciences), Islamabad, Pakistan as Adjunct Faculty.
This review originated from the Ph.D. study of ARK who was enrolled at the Department of Biotechnology, NIBGE, Faisalabad Campus of Quaid-i-Azam University, Islamabad. This study was funded by the Higher Education Commission (HEC), Pakistan. Both authors acknowledge the support from these institutes/organizations.
- Kazi TG, Afridi HI, Kazi N, Jamali MK, Arain MB, Jalbani N, Kandhro GA: Copper, chromium, manganese, iron, nickel, and zinc levels in biological samples of diabetes mellitus patients. Biol Trace Elem Res 2008, 122(1):1–18. 10.1007/s12011-007-8062-yPubMedView ArticleGoogle Scholar
- Simsek A, Aykut O: Evaluation of the microelement profile of turkish hazelnut (corylus avellana L.) varieties for human nutrition and health. Int J Food Sci Nutr 2007, 58(8):677–688. 10.1080/09637480701403202PubMedView ArticleGoogle Scholar
- Soetan KO, Olaiya CO, Oyewole OE: The importance of mineral elements for humans, domestic animals and plants: a review. Afr J Food Sci 2010, 4(5):220–222.Google Scholar
- Grivetti L: Value of traditional foods in meeting of macro- and micronutrients needs: the wild plants connection. Nutr Res Rev 2000, 13: 31–46. 10.1079/095442200108728990PubMedView ArticleGoogle Scholar
- Fraga CG: Relevance, essentiality and toxicity of trace elements in human health. Mol Aspects Med 2005, 26(4–5):235–244.PubMedView ArticleGoogle Scholar
- McCall KA, Huang C, Fierke CA: Function and mechanism of zinc metalloenzymes. J Nutr 2000, 130(5S Suppl):1437S-1446S.PubMedGoogle Scholar
- Lu Y, Yeung N, Sieracki N, Marshall NM: Design of functional metalloproteins. Nature 2009, 460(7257):855–862. 10.1038/nature08304PubMedPubMed CentralView ArticleGoogle Scholar
- Lutsenko S, Barnes NL, Bartee MY, Dmitriev OY: Function and regulation of human copper-transporting ATPases. Physiol Rev 2007, 87(3):1011–1046. 10.1152/physrev.00004.2006PubMedView ArticleGoogle Scholar
- Guidotti T, McNamara J, Moses M: The interpretation of trace element analysis in body fluids. Indian J Med Res 2010, 128(4):524.Google Scholar
- Chen YW: Heavy metals, islet function and diabetes development. Islets 2009, 1(3):169–176. 10.4161/isl.1.3.9262PubMedView ArticleGoogle Scholar
- Valko M, Morris H, Cronin MT: Metals, toxicity and oxidative stress. Curr Med Chem 2005, 12(10):1161–1208. 10.2174/0929867053764635PubMedView ArticleGoogle Scholar
- Galhardi CM, Diniz YS, Faine LA, Rodrigues HG, Burneiko RC, Ribas BO, Novelli EL: Toxicity of copper intake: lipid profile, oxidative stress and susceptibility to renal dysfunction. Food Chem Toxicol 2004, 42(12):2053–2060. 10.1016/j.fct.2004.07.020PubMedView ArticleGoogle Scholar
- Jiang R, Manson JE, Meigs JB, Ma J, Rifai N, Hu FB: Body iron stores in relation to risk of type 2 diabetes in apparently healthy women. JAMA 2004, 291(6):711–717. 10.1001/jama.291.6.711PubMedView ArticleGoogle Scholar
- Kazi TG, Jalbani N, Kazi N, Arain MB, Jamali MK, Afridi HI, Kandhro GA, Sarfraz RA, Shah AQ, Ansari R: Estimation of toxic metals in scalp hair samples of chronic kidney patients. Biol Trace Elem Res 2009, 127(1):16–27. 10.1007/s12011-008-8222-8PubMedView ArticleGoogle Scholar
- Serdar MA, Bakir F, Hasimi A, Celik T, Akin O, Kenar L, Aykut O, Yildirimkaya M: Trace and toxic element patterns in nonsmoker patients with noninsulin-dependent diabetes mellitus, impaired glucose tolerance, and fasting glucose. Int J Diabetes Dev Ctries 2009, 29(1):35–40. 10.4103/0973-3930.50713PubMedPubMed CentralView ArticleGoogle Scholar
- Ganz T, Nemeth E: Iron imports. IV. Hepcidin and regulation of body iron metabolism. Am J Physiol Gastrointest Liver Physiol 2006, 290(2):G199–203. 10.1152/ajpgi.00412.2005PubMedView ArticleGoogle Scholar
- Stechmiller JK: Understanding the role of nutrition and wound healing. Nutr Clin Pract 2010, 25(1):61–68. 10.1177/0884533609358997PubMedView ArticleGoogle Scholar
- Wish JB: Assessing iron status: beyond serum ferritin and transferrin saturation. Clin J Am Soc Nephrol 2006, 1(Supplement 1):S4-S8. 10.2215/CJN.01490506PubMedView ArticleGoogle Scholar
- McClain DA, Abraham D, Rogers J, Brady R, Gault P, Ajioka R, Kushner JP: High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis. Diabetologia 2006, 49(7):1661–1669. 10.1007/s00125-006-0200-0PubMedView ArticleGoogle Scholar
- Kundu D, Roy A, Mandal T, Bandyopadhyay U, Ghosh E, Ray D: Relation of iron stores to oxidative stress in type 2 diabetes. Niger J Clin Pract 2013, 16(1):100–103. 10.4103/1119-3077.106776PubMedView ArticleGoogle Scholar
- Raj S, Rajan G: Correlation between elevated serum ferritin and HbA1c in type 2 diabetes mellitus. Int J 2013, 1(1):12.Google Scholar
- Rajpathak S, Ma J, Manson J, Willett WC, Hu FB: Iron intake and the risk of type 2 diabetes in women: a prospective cohort study. Diabetes Care 2006, 29(6):1370–1376. 10.2337/dc06-0119PubMedView ArticleGoogle Scholar
- Adams PC, Reboussin DM, Barton JC, McLaren CE, Eckfeldt JH, McLaren GD, Dawkins FW, Acton RT, Harris EL, Gordeuk VR: Hemochromatosis and iron-overload screening in a racially diverse population. New Engl J Med 2005, 352(17):1769–1778. 10.1056/NEJMoa041534PubMedView ArticleGoogle Scholar
- Acton RT, Barton JC, Passmore LV, Adams PC, Speechley MR, Dawkins FW, Sholinsky P, Reboussin DM, McLaren GD, Harris EL: Relationships of serum ferritin, transferrin saturation, and HFE mutations and self-reported diabetes in the hemochromatosis and iron overload screening (HEIRS) study. Diabetes Care 2006, 29(9):2084–2089. 10.2337/dc05-1592PubMedView ArticleGoogle Scholar
- Worwood M: Serum transferrin receptor assays and their application. Ann Clin Biochem 2002, 39(3):221–230. 10.1258/0004563021902152PubMedView ArticleGoogle Scholar
- Jehn M, Clark JM, Guallar E: Serum ferritin and risk of the metabolic syndrome in US adults. Diabetes Care 2004, 27(10):2422–2428. 10.2337/diacare.27.10.2422PubMedView ArticleGoogle Scholar
- Fernández-Real JM, Peñarroja G, Castro A, García-Bragado F, Hernández-Aguado I, Ricart W: Blood letting in high-ferritin type 2 diabetes effects on insulin sensitivity and β-cell function. Diabetes 2002, 51(4):1000–1004. 10.2337/diabetes.51.4.1000PubMedView ArticleGoogle Scholar
- Papanikolaou G, Pantopoulos K: Iron metabolism and toxicity. Toxicol Appl Pharmacol 2005, 202(2):199–211. 10.1016/j.taap.2004.06.021PubMedView ArticleGoogle Scholar
- Lee D-H, Liu DY, Jacobs DR, Shin H-R, Song K, Lee I-K, Kim B, Hider RC: Common presence of Non–transferrin-bound iron among patients with type 2 diabetes. Diabetes Care 2006, 29(5):1090–1095. 10.2337/dc05-2471PubMedView ArticleGoogle Scholar
- Sharifi F, Nasab NM, Zadeh HJ: Elevated serum ferritin concentrations in prediabetic subjects. Diab Vasc Dis Res 2008, 5(1):15–18. 10.3132/dvdr.2008.003PubMedView ArticleGoogle Scholar
- Kim C-H, Kim H-K, Bae SJ, Park J-Y, Lee K-U: Association of elevated serum ferritin concentration with insulin resistance and impaired glucose metabolism in Korean men and women. Metabolism 2011, 60(3):414–420. 10.1016/j.metabol.2010.03.007PubMedView ArticleGoogle Scholar
- Forouhi N, Harding A, Allison M, Sandhu M, Welch A, Luben R, Bingham S, Khaw K, Wareham N: Elevated serum ferritin levels predict new-onset type 2 diabetes: results from the EPIC-Norfolk prospective study. Diabetologia 2007, 50(5):949–956. 10.1007/s00125-007-0604-5PubMedView ArticleGoogle Scholar
- Rajpathak S, Wylie-Rosett J, Gunter M, Negassa A, Kabat G, Rohan T, Crandall J: Biomarkers of body iron stores and risk of developing type 2 diabetes. Diabetes Obes Metab 2009, 11(5):472–479. 10.1111/j.1463-1326.2008.00985.xPubMedView ArticleGoogle Scholar
- Lopez-Ridaura R, Willett WC, Rimm EB, Liu S, Stampfer MJ, Manson JE, Hu FB: Magnesium intake and risk of type 2 diabetes in men and women. Diabetes Care 2004, 27(1):134–140. 10.2337/diacare.27.1.134PubMedView ArticleGoogle Scholar
- Swaminathan R: Magnesium metabolism and its disorders. Clin Biochemist Rev 2003, 24(2):47–66.Google Scholar
- Afridi HI, Kazi TG, Kazi N, Jamali MK, Arain MB, Jalbani N, Sarfaraz RA, Shah A, Kandhro GA, Shah AQ, et al.: Potassium, calcium, magnesium, and sodium levels in biological samples of hypertensive and nonhypertensive diabetes mellitus patients. Biol Trace Elem Res 2008, 124(3):206–224. 10.1007/s12011-008-8142-7PubMedView ArticleGoogle Scholar
- Mooren FC, Kruger K, Volker K, Golf SW, Wadepuhl M, Kraus A: Oral magnesium supplementation reduces insulin resistance in non-diabetic subjects - a double-blind, placebo-controlled, randomized trial. Diabetes Obes Metab 2011, 13(3):281–284. 10.1111/j.1463-1326.2010.01332.xPubMedView ArticleGoogle Scholar
- Orbea A, Ortiz-Zarragoitia M, Sole M, Porte C, Cajaraville MP: Antioxidant enzymes and peroxisome proliferation in relation to contaminant body burdens of PAHs and PCBs in bivalve molluscs, crabs and fish from the Urdaibai and Plentzia estuaries (Bay of Biscay). Aquat Toxicol 2002, 58(1–2):75–98.PubMedView ArticleGoogle Scholar
- Rico H, Gomez-Raso N, Revilla M, Hernandez ER, Seco C, Paez E, Crespo E: Effects on bone loss of manganese alone or with copper supplement in ovariectomized rats. A morphometric and densitomeric study. Eur J Obstet Gynecol Reprod Biol 2000, 90(1):97–101. 10.1016/S0301-2115(99)00223-7PubMedView ArticleGoogle Scholar
- Forte G, Bocca B, Peruzzu A, Tolu F, Asara Y, Farace C, Oggiano R, Madeddu R: Blood metals concentration in type 1 and type 2 diabetics. Biol Trace Elem Res 2013, 156(1–3):79–90.PubMedView ArticleGoogle Scholar
- Olivares M, Araya M, Uauy R: Copper homeostasis in infant nutrition: deficit and excess. J Pediatr Gastroenterol Nutr 2000, 31(2):102–111. 10.1097/00005176-200008000-00004PubMedView ArticleGoogle Scholar
- Jackson RF, Roche GC, Wisler K: Reduction in Cholesterol and Triglyceride Serum Levels Following Low-Level Laser Irradiation: A Noncontrolled, Nonrandomized Pilot Study. The American Journal of Cosmetic Surgery 2010, 27(4):177–184.Google Scholar
- Kako K, Takehara A, Arai H, Onodera T, Takahashi Y, Hanagata H, Ogra Y, Takagi H, Kodama H, Suzuki KT, et al.: A selective requirement for copper-dependent activation of cytochrome c oxidase by Cox17p. Biochem Biophys Res Commun 2004, 324(4):1379–1385. 10.1016/j.bbrc.2004.09.211PubMedView ArticleGoogle Scholar
- Lin C-C, Huang J-F, Tsai L-Y, Huang Y-L: Selenium, iron, copper, and zinc levels and copper-to-zinc ratios in serum of patients at different stages of viral hepatic diseases. Biol Trace Elem Res 2006, 109(1):15–23. 10.1385/BTER:109:1:015PubMedView ArticleGoogle Scholar
- Quilliot D: Evidence that diabetes mellitus favors impaired metabolism of zinc, copper, and selenium in chronic pancreatitis. Pancreas 2001, 22(3):299–306. 10.1097/00006676-200104000-00012PubMedView ArticleGoogle Scholar
- Klevay L: Cardiovascular disease from copper deficiency. J Nutr 2000, 130: 489S-492S.PubMedGoogle Scholar
- Chwiej J, Winiarski W, Ciarach M, Janeczko K, Lankosz M, Rickers K, Setkowicz Z: The role of trace elements in the pathogenesis and progress of pilocarpine-induced epileptic seizures. J Biol Inorg Chem 2008, 13(8):1267–1274. 10.1007/s00775-008-0411-6PubMedView ArticleGoogle Scholar
- Eaton JW, Qian M: Interactions of copper with glycated proteins: possible involvement in the etiology of diabetic neuropathy. Mol Cell Biochem 2002, 234–235(1–2):135–142.PubMedView ArticleGoogle Scholar
- John E, Laskow TC, Buchser WJ, Pitt BR, Basse PH, Butterfield LH, Kalinski P, Lotze MT: Zinc in innate and adaptive tumor immunity. J Transl Med 2010, 8: 118. 10.1186/1479-5876-8-118PubMedPubMed CentralView ArticleGoogle Scholar
- Zheng H, Blat D, Fridkin M: Novel neuroprotective neurotrophic NAP analogs targeting metal toxicity and oxidative stress: potential candidates for the control of neurodegenerative diseases. J Neural Transm Suppl 2006, 71: 163–172.PubMedView ArticleGoogle Scholar
- Karamouzis MV, Gorgoulis VG, Papavassiliou AG: Transcription factors and neoplasia: vistas in novel drug design. Clin Cancer Res 2002, 8(5):949–961.PubMedGoogle Scholar
- Jansen J, Karges W, Rink L: Zinc and diabetes–clinical links and molecular mechanisms. J Nutr Biochem 2009, 20(6):399–417. 10.1016/j.jnutbio.2009.01.009PubMedView ArticleGoogle Scholar
- Droge W: Free radicals in the physiological control of cell function. Physiol Rev 2002, 82(1):47–95.PubMedView ArticleGoogle Scholar
- Wapnir RA: Zinc deficiency, malnutrition and the gastrointestinal tract. J Nutr 2000, 130(5S Suppl):1388S-1392S.PubMedGoogle Scholar
- Rungby J: Zinc, zinc transporters and diabetes. Diabetologia 2010, 53(8):1549–1551. 10.1007/s00125-010-1793-xPubMedView ArticleGoogle Scholar
- Brender JR, Hartman K, Nanga RP, Popovych N, de la Salud BR, Vivekanandan S, Marsh EN, Ramamoorthy A: Role of zinc in human islet amyloid polypeptide aggregation. J Am Chem Soc 2010, 132(26):8973–8983. 10.1021/ja1007867PubMedPubMed CentralView ArticleGoogle Scholar
- Wijesekara N, Dai FF, Hardy AB, Giglou PR, Bhattacharjee A, Koshkin V, Chimienti F, Gaisano HY, Rutter GA, Wheeler MB: Beta cell-specific Znt8 deletion in mice causes marked defects in insulin processing, crystallisation and secretion. Diabetologia 2010, 53(8):1656–1668. 10.1007/s00125-010-1733-9PubMedView ArticleGoogle Scholar
- Guidotti TL, McNamara J, Moses MS: The interpretation of trace element analysis in body fluids. Indian J Med Res 2008, 128(4):524–532.PubMedGoogle Scholar
- Tudan C, Weber FX, Levine KE: The status of trace elements analysis in biological systems. Bioanalysis 2011, 3(15):1695–1697. 10.4155/bio.11.171PubMedView ArticleGoogle Scholar
- Belinda S, O’Connell B: Select vitamins and minerals in the management of diabetes. Diabetes Spectr 2001, 14(3):133–148. 10.2337/diaspect.14.3.133View ArticleGoogle Scholar
- Qiao W, Peng Z, Wang Z, Wei J, Zhou A: Chromium improves glucose uptake and metabolism through upregulating the mRNA levels of IR, GLUT4, GS, and UCP3 in skeletal muscle cells. Biol Trace Elem Res 2009, 131(2):133–142. 10.1007/s12011-009-8357-2PubMedView ArticleGoogle Scholar
- Wiernsperger N, Rapin J: Trace elements in glucometabolic disorders: an update. Diabetology & Metabolic Syndrome 2010, 2(70):1–9.Google Scholar
- Lai MH, Chen YY, Cheng HH: Chromium yeast supplementation improves fasting plasma glucose and LDL-cholesterol in streptozotocin-induced diabetic rats. Int J Vitam Nutr Res 2006, 76(6):391–397. 10.1024/0300-9822.214.171.1241PubMedView ArticleGoogle Scholar
- Chiu A, Katz AJ, Beaubier J, Chiu N, Shi X: Genetic and cellular mechanisms in chromium and nickel carcinogenesis considering epidemiologic findings. Mol Cell Biochem 2004, 255(1):181–194.PubMedView ArticleGoogle Scholar
- Yabe J, Nakayama SMM, Ikenaka Y, Muzandu K, Ishizuka M, Umemura T: Uptake of lead, cadmium, and other metals in the liver and kidneys of cattle near a lead-zinc mine in Kabwe, Zambia. Environ Toxicol Chem 2011, 30(8):1892–1897. 10.1002/etc.580PubMedView ArticleGoogle Scholar
- Kowdley KV: Iron, hemochromatosis, and hepatocellular carcinoma. Gastroenterology 2004, 127(5):S79-S86. 10.1016/j.gastro.2004.09.019PubMedView ArticleGoogle Scholar
- Schwarzenbach RP, Egli T, Hofstetter TB, Von Gunten U, Wehrli B: Global water pollution and human health. Annu Rev Environ Resour 2010, 35: 109–136. 10.1146/annurev-environ-100809-125342View ArticleGoogle Scholar
- Flora SJ: Structural, chemical and biological aspects of antioxidants for strategies against metal and metalloid exposure. Oxidative Med Cell Longev 2009, 2(4):191–206. 10.4161/oxim.2.4.9112View ArticleGoogle Scholar
- Duruibe J: Heavy metal pollution and human biotoxic effects. Int J Phys Sci 2007, 2(5):112–118.Google Scholar
- Afridi HI, Kazi TG, Kazi NG, Jamali MK, Arain MB, Sirajuddin , Baig JA, Kandhro GA, Wadhwa SK, Shah AQ: Evaluation of cadmium, lead, nickel and zinc status in biological samples of smokers and nonsmokers hypertensive patients. J Hum Hypertens 2010, 24(1):34–43. 10.1038/jhh.2009.39PubMedPubMed CentralView ArticleGoogle Scholar
- Afridi HI, Kazi TG, Kazi N, Jamali MK, Arain MB, Jalbani N, Baig JA, Sarfraz RA: Evaluation of status of toxic metals in biological samples of diabetes mellitus patients. Diabetes Res Clin Pract 2008, 80(2):280–288. 10.1016/j.diabres.2007.12.021PubMedView ArticleGoogle Scholar
- Martinez-Finley EJ, Chakraborty S, Fretham SJ, Aschner M: Cellular transport and homeostasis of essential and nonessential metals. Metallomics 2012, 4: 593–605. 10.1039/c2mt00185cPubMedView ArticleGoogle Scholar
- Yu CC, Lin JL, Lin-Tan DT: Environmental exposure to lead and progression of chronic renal diseases: a four-year prospective longitudinal study. J Am Soc Nephrol 2004, 15(4):1016–1022. 10.1097/01.ASN.0000118529.01681.4FPubMedView ArticleGoogle Scholar
- Beyersmann D, Hartwig A: Carcinogenic metal compounds: recent insight into molecular and cellular mechanisms. Arch Toxicol 2008, 82(8):493–512. 10.1007/s00204-008-0313-yPubMedView ArticleGoogle Scholar
- Chen YW, Yang CY, Huang CF, Hung DZ, Leung YM, Liu SH: Heavy metals, islet function and diabetes development. Islets 2009, 1(3):169–176. 10.4161/isl.1.3.9262PubMedView ArticleGoogle Scholar
- Das KK, Das SN, Dhundasi SA: Nickel, its adverse health effects & oxidative stress. Indian J Med Res 2008, 128(4):412–425.PubMedGoogle Scholar
- Kubrak OI, Husak VV, Rovenko BM, Poigner H, Mazepa MA, Kriews M, Abele D, Lushchak VI: Tissue specificity in nickel uptake and induction of oxidative stress in kidney and spleen of goldfish carassius auratus, exposed to waterborne nickel. Aquat Toxicol 2012, 118–119: 88–96.PubMedView ArticleGoogle Scholar
- Barany E, Bergdahl IA, Bratteby LE, Lundh T, Samuelson G, Skerfving S, Oskarsson A: Iron status influences trace element levels in human blood and serum. Environ Res 2005, 98(2):215–223. 10.1016/j.envres.2004.09.010PubMedView ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.