Open access peer-reviewed chapter

Trace Elements Modulates Oxidative Stress in Type 2 Diabetes

Written By

Ines Gouaref and Elhadj-Ahmed Koceir

Submitted: 14 July 2017 Reviewed: 21 September 2017 Published: 20 December 2017

DOI: 10.5772/intechopen.71172

From the Edited Volume

Diabetes Food Plan

Edited by Viduranga Waisundara

Chapter metrics overview

1,122 Chapter Downloads

View Full Metrics


The relationship between antioxidant trace elements (ATE) and metabolic disease is subtle and complex due to overproduction of reactive oxygen species (ROS). In type 2 diabetes (T2D), the relationship between ATE and insulin-like trace elements is very complex during oxidative stress (OS), being mediated by hyperglycemia, dyslipidemia and inflammation. The important role assigned to ATE (zinc, selenium, copper, manganese and chromium) by their involvement at different levels: Hemodynamic homeostasis (endothelial function and protein glycation), energy metabolism (carbohydrate and lipid tolerance) and enzymatic antioxidant protection [superoxide dismutase (SOD), glutathione peroxidase (GPx)]. The ROS-mediated cellular signaling process is crucial. Manganese and selenium levels abnormalities might to be useful indicators of oxidative damage. Two major factors were suggested: lack of Mn bioavailability leading to the decrease of mitochondrial SOD activity (cytosolic SOD remains active), and low blood selenium level implying a decrease in GPx activity. In T2D pathophysiology, it appears that antioxidant defense is preserved in the cytosol (Cu/Zn-SOD) in T2D, whereas it is impaired in mitochondria (Mn-SOD) in the three pathologies, which make this cell organelle a true ATE therapeutic target. Future challenges require the in-depth investigations of mitochondrial mechanisms, involved the antioxidant trace elements signaling pathways in T2D pathophysiology.


  • type 2 diabetes
  • oxidative stress
  • antioxidant trace elements (zinc
  • selenium
  • copper
  • manganese
  • and chromium)

1. Introduction

Type 2 diabetes (T2D) is a major risk factor for cardiovascular diseases and acute oxidative stress (OS) by high production of reactive oxygen species (ROS) related to the lipotoxicity and glucotoxicity processes [1]. The mechanisms underlying OS disorders modulated by antioxidant trace elements (ATE) such as selenium (Se), manganese (Mn), zinc (Zn), copper (Cu) and chromium (Cr) status are not completely clear [2]. The role of ATE as an essential micronutrient has been identified for a long time as a potential candidate for improving metabolic disorders, like glucose homeostasis in prediabetes state [3]. Antioxidant enzymatic system (AES) such as superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase plays an important protective role in the emergency of glucose intolerance, insulin resistance and dyslipidemia. T2D is characterized by elevated glycated hemoglobin (HbA1c) and insulin resistance maintains the toxic hyperglycemia and dyslipidemia effects, leads to disturb ATE status. This situation amplifies OS and aggravates the diabetes vascular complications [4].

The ROS neutralization is conducted primarily by AES through ATE integrated as AES cofactors. Cu and Zn are incorporated both into the Cu-Zn-SOD to reduce the cytotoxic ROS effects in cytosolic compartment cells [5]. Mn is incorporated into the Mn-SOD to remove the ROS effects in mitochondrial compartment cells [6]. Se is incorporated into the GPx1 to remove the ROS effects in cytosolic and mitochondrial compartment cells [7]. The present review updates our actual state of knowledge about highlight role of ATE in OS damage in T2D pathogenesis, and that consider their therapeutic potential.

Several studies have reported that pathogenesis of type 2 diabetes (T2D) is related to the imbalance of some antioxidant trace elements such as zinc, selenium, copper, manganese and chromium might adversely affect pancreatic islet and cause development of diabetes [8]. Type 2 diabetes is clearly associated with ROS production and insulin signaling depends on the balance of ROS production and antioxidant defense. Excessive ROS are involved in the multifactorial etiology of insulin resistance and the subsequent development of T2D [9]. Oxidative stress alters the insulin receptor and the insulin receptor substrate (IRS) signaling pathway via kinase activity (serine/threonine), leading to multi-site phosphorylation [10]. These events increase serine IRS phosphorylation and decrease thyrosine, leading to insulin resistance [11]. The ATE trace elements shows a profile disturbance in T2D is associated with increased pro-inflammatory cytokines (TNF-α, IL-6) may contribute to development of diabetic complications [12, 13] and increased glycated hemoglobin formation [4].


2. Zinc in T2D pathogenesis

Zinc (Zn) is a necessary micronutrient which has an essential role in insulin metabolism [14, 15]. In pancreatic beta cells, Zn is required for the synthesis, storage and insulin secretion [79]. It has been described in diabetic subjects pancreas is zinc deficiency compared to normal subject. These data confirmed that zinc is involved in insulin signaling pathways [16]. Zn may stimulate energy consumption in skeletal muscle and brown adipose tissue and may increase the pancreatic insulin content and improve the glucose tolerance test [17]. Zn is found largely in cereals, animal protein and seafood [18]. Zn absorption can be inhibited by iron. Zn is transported across cell membranes via ZnT family’s transporters [19].

In diabetes diseases (insulin resistance, metabolic syndrome), Zn is considered important mainly because: (i) it plays a major role in the stabilization of insulin hexamers and the hormone pancreatic storage [20] and (ii) it is an efficient antioxidant [21]. Zinc deficiency in type 2 diabetes is mainly due to a significant urinary zinc loss [22], nevertheless, this Zinc deficiency is not very significant versus healthy subject [23]. Lower Zn plasma concentrations were found in T2D to relate of cardiovascular risk metabolic syndrome factors [24], and reduced Zn levels in diabetics appear to be related to increased risk for coronary artery disease [25]. It has been described that zinc effects mimic the insulin action mainly via the glycogen synthesis/degradation enzymes signaling pathways [26]. Other mechanisms include Cu/Zn-superoxide dismutase regulation via the post receptor proteins Akt and PI3-kinase via NF_B [27]. On the other hand, some particular forms of Zn have been discovered in ob/ob mice, such Zn-α 2-glycoprotein is an adipokine which stimulates energy expenditure in skeletal muscle and brown adipose tissue, resulting in reductions in glycaemia, triglycerides and Free Fatty Acids. Their level is lower in obese human subcutaneous and visceral adipose tissue and liver, but interestingly does not appear to be related to insulin resistance [28].


3. Selenium in T2D pathogenesis

Early studies indicated that inorganic Se acted as an insulin mimic [29] and epidemiologic investigations showed correlations between abnormal glucose or lipid metabolism and decreased plasma Se concentrations or glutathione peroxidase activity in diabetic subjects [30, 31, 32]. Indeed, intraperitoneal injection or oral administration of sodium selenate improved glucose homeostasis in type 1 and type 2 diabetic animals [33]. Similarly, previous studies have shown that the insulin-like and antidiabetic effects of sodium selenite and selenomethionine were also observed in diabetic animals [34]. Several selenium supplementation studies were undertaken in diabetic subject with vascular complications, unfortunately the beneficial antioxidant effects were not obtained [35, 36].

Se is a key component of GPx, an enzyme that prevents the cells oxidation. Compared with liver, islets contain only 2% GPx [37]. Accordingly, β cells are considered to be low in antioxidant defenses and susceptible to oxidative stress. In diabetic subjects, β-cell apoptosis seems to be more of a deciding factor than replication in controlling the cell mass compared with control subjects [38]. Selenoprotein (SelP), a secretory protein primarily produced by the liver and regulated similar to that of the gluconeogenic enzyme glucose 6-phosphatase [39], by concerted action of peroxisome proliferator-activated receptor co activator 1α (PPAR-1α) and the transcription hepatocyte nuclear factor-4α [40]. It has been shown a positive correlation between hepatic SelP mRNA levels and insulin resistance in humans, a long with a positive correlation between serum SelP levels and both fasting plasma glucose and hemoglobin A1C (HbA1c) levels. The metabolic selenium effects are mediated by selenoproteins (SeP) via the adenosine monophosphate-activated protein kinase (AMPK) inactivation [41]. Probably, SePs insulin-sensitizing effect like to glutathione peroxidase (GPx). However, SelP does not seem to act upon insulin synthesis or a trophic effect on pancreatic beta mass cells [42].

On the other hand, some studies have shown that Tanis (in humans encoded by the SelP gene) was regulated by glucose and altered in the diabetic state [43]. It has been reported that Tanis protein overexpression in H4IIE cells acts at different points: (i) glucose transport; (ii) basal insulin secretion; (iii) glycogen synthesis and storage; (iv) attenuates the phosphoenol pyruvate carboxykinase gene expression [44]. These data confirm that Tanis protein is involved in glycemic homeostasis and hepatic insulin resistance. Furthermore, emerging evidence suggests that elevation of SelP [45] mRNA and protein expression was observed in T2D patients. Otherwise, it has been described that Selenium modulates vascular inflammatory syndrome by reducing p38 MAP kinase and NF-κB signaling pathway [46]. Besides, selenium is able to inhibit atherosclerotic processes by endothelial adhesion molecules expression [47].


4. Copper in T2D pathogenesis

Plasma Cu concentrations have been reported in some studies to be altered in diabetic humans compared to non-diabetics [4], particularly in diabetic patients with microvascular disease complications [48] and proteinuria [49]. Similarly, serum ceruloplasmin has been noted to be higher in T2D subjects compared to non-diabetics in numerous studies [50]. Alterations in Cu metabolism coupled with an increase in glycated proteins [4] may contribute to the progression of diabetes-related pathologies. Several lines of evidence support a role of Cu in diabetes-induced oxidative stress. Several previous studies have showed that ceruloplasmin can be fragmented following non-enzymatic glycosylation [51]. Secondly, glycation of CuZn-SOD in humans with diabetes leads to a site-specific fragmentation resulting in its inactivation [52] as well as the release of Cu, which can further exacerbate oxidative stress. Glycation of CuZn-SOD increases the formation of DNA damage in vitro, which suggests that the release of Cu2+ from glycated SOD can participate in cleavage of nuclear DNA [53]. As CuZn-SOD accounts for 90% of the total SOD activity of the mouse lens [54], the excessively high concentrations of glycated CuZn-SOD in diabetic rat lenses are postulated to be involved in lens pathology [55]. Cu can increase the rate advanced glycated end (AGE) products formation, which is associated with the pathogenesis of secondary complications in diabetes [56]. Agents used to prevent or reduce AGE formation typically have potent Cu chelating [57].


5. Manganese in T2D pathogenesis

The manganese status in T2D is still unclear and the few studies that have addressed this issue in humans are controversial. However, Mn acts as a cofactor in several metalloenzymes including those involved in glucose homeostasis (Pyruvate carboxylase, GTP oxaloacetate carboxylase, Isocitrate dehydrogenase, Malate dehydrogenase, Phosphoenolpyruvate carboxykinase). These enzymes play a critical role in the blood glucose regulation via glycolysis, gluconeogenesis, Krebs cycle [58]. Mn is required for insulin synthesis [59], and to regulate of glucose utilization and lipogenesis in adipose tissue [60]. Previous studies have shown that blood manganese levels are unchanged in plasma, not significantly (approx. 15%) reduced in whole blood [61], or decreased in erythrocytes [62], from diabetic patients as compared to controls. In healthy subjects, manganese is very present in tissues rich in mitochondria (12–16 mg), in particular skeletal muscle, liver, pancreas and kidney. Mn is necessary for the synthesis, secretion and action of insulin. Mn is also indispensable for the maturation of bones and cartilage. Mn plasma levels are essentially regulated via the bile excretion pathway. Mn also participates in vitamins E and B1 synthesis [63]. Mn is found mainly in quinoa, rye, whole rice, soybeans, avocado, egg yolk, green beans, spinach, walnuts, olive oil, oysters, green tea and provence herbs [64].

Our recently diabetes investigation [65], we found Mn blood concentrations are significantly increased (23%) in diabetic patients compared to controls. The correlation is positive with hyperglycemia and HbA1C. Our data suggest that Mn play a crucial role in antioxidant capacity and we hypothesize that antioxidant defense is preserved in the cytosol (superoxide dismutase Cu/Zn-SOD), whereas it is impaired in mitochondria (Mn-SOD), which makes this cell organelle a true therapeutic target in diabetes. In our recent study, we showed the competitive effect between the manganese and iron in T2D. However, when the iron was in the free form and reduced, it was constantly a pro-oxidant, whereas Mn was an anti-oxidant. Several studies suggesting that transferrin (Tf)/Tf receptor (TfR) transport system is the major transport of manganese and iron in plasma. The Mn bioavailability is reduced due to altered Tf/TfR transport system [66, 67, 68, 69]. Consequently, the Mn (III) forms a more stable with Tf than the Mn (II) form [70]. The more complex questions related to the regulation of each by Mn and Fe might affect the insulin secretion and glucose homeostasis. Probably the increased Mn levels would affect the availability or concentration of both various transporters and finally bêta cell Mn distribution [71]. The interactions of Mn, Fe and ferritin are closely related in the following manner; and can lead to hyperglycemia associated to mitochondrial Fe, Mn, copper, and zinc levels [72], demonstrating the interrelationship with glycemia homeostasis. Probably, that the heightened β-cell oxidative stress may result from occurring Tf/Tf receptor system, and elevated manganese is produced via an extracellular Tf-manganese redox mechanism, rather than simply the presence of elevated tissue manganese per se. In this context, the plasma manganese accumulation was associated to iron plasma depletion and ferritin increased, suggesting that mitochondrial iron accumulation resulting in generation of ROS by Fenton chemistry [73]. The Mn is confined to the cytosol where it is associated with decreased mitochondrial SOD-Mn due the lack of mitochondrial manganese. The finding that DT2 pathogenesis are able to regulate manganese transport into, and/or export from, mitochondria and maintain a normal pool of mitochondrial manganese, despite the presence of a two-fold increase in cytosolic manganese content. Among possible explanations for this result, the upregulation of mitochondrial manganese transporters in situations of large changes in metal availability, or a heretofore undescribed function for the transferrin in regulation of mitochondrial metal accumulation. At last, in diabetes vascular complications, Mn is involved in Arginine production, precursor to nitric oxide (NO) formation as endothelial vasodilator [74].


6. Chromium in T2D pathogenesis

Chromium (Cr) that is mineral trace deserves special attention in diabetes pathophysiology, as has been reported during the 50th anniversary of this trace element and they termed it glucose tolerance factor (GTF) [75]. The Cr recommended nutritional requirements are estimated between 50 and 200 mg, but this requirement is estimated at 30 mg/day. Barley is the most important Cr food source [76]. Cr plays a crucial role in glycaemia homeostasis and Cr deficiency leads to a glucose tolerance disorder, moderate fasting hyperglycemia and occasionally dyslipidemia. This observation has been observed both in human clinical and experimental models [77, 78]. Cr plasma concentrations can be explained by its mobilization from its storage site (liver, kidneys) to the blood by chromodulin binding (intracellular transport protein) [79]. However, Cr bioavailability depends on the nutrients with which it is associated: Cr/phenylalanine, Cr/cysteine, Cr/biotin and Cr/vitamin E or Cr/vitamin C complexes have been described [80, 81, 82, 83]. Cr acts as carbohydrate tolerance factor, increases insulin sensitivity, particularly in the skeletal muscle. Indeed, trivalent chromium is an insulin pathway signaling. Cr increases insulin receptors number, insulin internalization and an activation of the GLUT4 and GLUT1 glucose carriers translocation [84]. The insulin binding to the α-subunit receptor is induced by a phosphorylation reactions cascade catalyzed by tyrosine kinase that is activated by Cr; however, phosphotyrosine phosphatase which inactivates the insulin receptor is inhibited by Cr [85]. In type 2 diabetes and obesity, the Cr deficiency can be observed in subjects consuming excessively rapid absorption carbohydrates that increase the urinary elimination of chromium. Cr Supplementation during 6 months may be prescribed in a forms variety: Cr-chloride, Cr-nicotinate, Cr-propionate, Cr-histidinate or Cr-picolinate leads to a significant decrease HbA1c and AGE [86, 87]. Cr supplementation effects appear to be mediated by AMP kinase activation and p38 MAP kinase signaling pathway [88]. Cr controls body fat and body weight by satiety mechanisms (food intake control) and thermogenesis [89]. The Cr effects are observed via the resistin and uncoupling protein (UCP) decoupling proteins signaling pathway [84, 90]. Otherwise, experimental animal studies have shown that Cr modulates the inflammatory state during diabetes by decreasing proinflammatory cytokines production such as tumor necrosis factor (TNF-α), and interleukin IL-6 [91].


7. Conclusions

Glycemic homeostasis is not only dependent on hormonal control, especially insulin; but also the micronutrients such as Chromium, Zinc, Selenium, Manganese and Copper. These Antioxidant Trace Elements act as cofactors of antioxidant enzymes (SOD, GPx) which protect the glucose-dependent tissues from the deleterious effects of reactive oxygen species following oxidation of glucose.



The research was supported by the General Division for Algerian Scientific Research and Technological Development (DG-RSDT). www:


Conflict of interests

The authors declare that there is no conflict of interests regarding this paper.


  1. 1. Zhang J et al. ROS and ROS-mediated cellular signaling. Oxidative Medicine and Cellular Longevity. 2016;2016:4350965
  2. 2. Andersen O, et al. Recent developments in trace element research. Journal of Trace Elements in Medicine and Biology. 2012;26:59-60
  3. 3. Xiu YM. Trace elements in health and diseases. Biomedical and Environmental Sciences. 1996;9:130-136
  4. 4. Viktorínová A, et al. Altered metabolism of copper, zinc, and magnesium is associated with increased levels of glycated hemoglobin in patients with diabetes mellitus. Metabolism. 2009;58:1477-1482
  5. 5. Liochev SI, et al. Mechanism of the peroxidase activity of Cu, Zn superoxide dismutase. Free Radical Biology and Medicine. 2010;48:1565-1569
  6. 6. Bresciani G, et al. Manganese superoxide dismutase and oxidative stress modulation. Advances in Clinical Chemistry. 2015;68:87-130
  7. 7. Brigelius-Flohé R, et al. Glutathione peroxidases. Biochimica et Biophysica Acta. 2013;1830:3289-3303
  8. 8. Wiernsperger N, et al. Trace elements in glucometabolic disorders: An update. Diabetology and Metabolic Syndrome. 2010;2:70
  9. 9. Badran M, et al. Assessment of trace elements levels in patients with Type 2 diabetes using multivariate statistical analysis. Journal of Trace Elements in Medicine and Biology. 2016;33:114-119
  10. 10. Dong K, et al. ROS-mediated glucose metabolic reprogram induces insulin resistance in type 2 diabetes. Biochemical and Biophysical Research Communications. 2016;476:204-211
  11. 11. Evans JL, et al. Oxidative stress and stress activated signalling pathways: A unifying hypothesis of type 2 diabetes. Endocrine Reviews. 2002;23:599-622
  12. 12. Evans JL, et al. The molecular basis for oxidative stress induced insulin resistance. Antioxidants & Redox Signaling. 2005;7:1040-1052
  13. 13. Van Campenhout A, et al. Impact of diabetes mellitus on the relationships between iron-, inflammatory- and oxidative stress status. Diabetes-Metabolism Research and Reviews. 2006;22:444-454
  14. 14. Faure P, et al. Zinc prevents the structural and functional properties of free radical treated-insulin. Biochimica et Biophysica Acta. 1994;1209:260-264
  15. 15. Saper RB, et al. Zinc: An essential micronutrient. American Family Physician. 2009;79:768-772
  16. 16. Chimienti F, et al. Zinc, pancreatic islet cell function and diabetes: New insights into an old story. Nutrition Research Reviews. 2013;26:1-11
  17. 17. Ranasinghe P, et al. Zinc and diabetes mellitus: Understanding molecular mechanisms and clinical implications. Daru Journal of Pharmaceutical Sciences. 2015;23:44
  18. 18. Walsh CT, et al. Zinc: Health effects and research priorities for the 1990s. Environmental Health Perspectives. 1994;102(Suppl 2):5-46
  19. 19. Liuzzi JP, et al. Mammalian zinc transporters. Annual Review of Nutrition. 2004;24:151-172
  20. 20. Wijesekara N, et al. Zinc, a regulator of islet function and glucose homeostasis. Diabetes, Obesity & Metabolism. 2009;11:202-214
  21. 21. Prasad AS, et al. Clinical, immunological, anti-inflammatory and antioxidant roles of zinc. Experimental Gerontology. 2008;43:370-377
  22. 22. Singh RB, et al. 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. Journal of the American College of Nutrition. 1998;17:564-570
  23. 23. Seo JA, et al. The associations between serum zinc levels and metabolic syndrome in the Korean population: Findings from the 2010 Korean National Health and Nutrition Examination Survey. PLoS One. 2014;9:e105990
  24. 24. Obeid O, et al. Plasma copper, zinc, and selenium levels and correlates with metabolic syndrome components of Lebanese adults. Biological Trace Element Research. 2008;123:58-65
  25. 25. Soinio M, et al. Serum zinc level and coronary heart disease events in patients with type 2 diabetes. Diabetes Care. 2007;30:523-528
  26. 26. Ilouz R, et al. Inhibition of glycogen synthase kinase-3beta by bivalent zinc ions: Insight into the insulin-mimetic action of zinc. Biochemical and Biophysical Research Communications. 2002;295:102-106
  27. 27. Rojo AI, et al. Regulation of Cu/Zn-superoxide dismutase expression via the phosphatidylinositol 3 kinase/Akt pathway and nuclear factor-kappaB. Journal of Neuroscience. 2004;24:7324-7334
  28. 28. Russell ST, et al. Antidiabetic properties of zinc-alpha2-glycoprotein in ob/ob mice. Endocrinology. 2010;151:948-957
  29. 29. Stapleton SR. Selenium: An insulin-mimetic. Cellular & Molecular Life Sciences. 2000;57:1874-1879
  30. 30. Asemi Z, et al. Effects of selenium supplementation on glucose homeostasis, inflammation, and oxidative stress in gestational diabetes: Randomized, double-blind, placebo-controlled trial. Nutrition. 2015;31:1874-1879
  31. 31. Faghihi T, et al. A randomized, placebo-controlled trial of selenium supplementation in patients with type 2 diabetes: Effects on glucose homeostasis, oxidative stress, and lipid profile. American Journal of Therapeutics. 2014;21:491-495
  32. 32. Yan X, et al. Dietary selenium deficiency partially rescues type 2 diabetes-like phenotypes of glutathione peroxidase-1-overexpressing male mice. Journal of Nutrition. 2012;142:1975-1982
  33. 33. Atalay M, et al. Treatments with sodium selenate or doxycycline offset diabetes-induced perturbations of thioredoxin-1 levels and antioxidant capacity. Molecular and Cellular Biochemistry. 2011;351:125-131
  34. 34. Berg EA, et al. Insulin-like effects of vanadate and selenate on the expression of glucose-6-phosphate dehydrogenase and fatty acid synthase in diabetic rats. Biochimie. 1995;77:919-924
  35. 35. Zeng MS, et al. A high-selenium diet induces insulin resistance in gestating rats and their offspring. Free Radical Biology and Medicine. 2012;52:1335-1342
  36. 36. Stranges S, et al. A prospective study of dietary selenium in take and risk of type 2 diabetes. BMC Public Health. 2010;10:564
  37. 37. Grankvist K, et al. CuZn-superoxide dismutase, Mn- superoxide dismutase, catalase and glutathione peroxidase in pancreatic islets and other tissues in the mouse. Biochemical Journal. 1981;199:393-398
  38. 38. Butler AE, et al. Increased beta-cell apoptosis prevents adaptive increase in beta-cell mass in mouse model of type 2 diabetes: Evidence for role of islet amyloid formation rather than direct action of amyloid. Diabetes. 2003;52:2304-2314
  39. 39. Jackson MI, et al. S-adenosylmethionine-dependent protein methylation is required for expression of selenoprotein P and gluconeogenic enzymes in HepG2 human hepatocytes. Journal of Biological Chemistry. 2012;287:36455-36464
  40. 40. Speckmann B, et al. Selenoprotein P expression is controlled through interaction of the coactivator PGC-1alpha with FoxO1a and hepatocyte nuclear factor 4alpha transcription factors. Hepatology. 2008;48:1998-2006
  41. 41. Misu H, et al. A liver-derived secretory protein, selenoprotein P, causes insulin resistance. Cell Metabolism. 2010;12:483-495
  42. 42. Steinbrenner H, et al. Localization and regulation of pancreatic selenoprotein P. Journal of Molecular Endocrinology. 2012;50:31-42
  43. 43. Walder K, et al. Tanis: A link between type 2 diabetes and inflammation? Diabetes. 2002;51:1859-1866
  44. 44. Gao Y, et al. Regulation of the selenoprotein SelS by glucose deprivation and endoplasmic reticulum stress-SelS is a novel glucose-regulated protein. FEBS Letters. 2004;563:185-190
  45. 45. Karlsson HK, et al. Relationship between serum amyloid A level and Tanis/SelS mRNA expression in skeletal muscle and adipose tissue from healthy and type 2 diabetic subjects. Diabetes. 2004;53:1424-1428
  46. 46. Zheng HT, et al. Selenium inhibits high glucose- and high insulin-induced adhesion molecule expression in vascular endothelial cells. Archives of Medical Research. 2008;39:373-379
  47. 47. Xun P, et al. Longitudinal association between toenail selenium levels and measures of subclinical atherosclerosis: The CARDIA trace element study. Atherosclerosis. 2010;210:662-667
  48. 48. Walter RM Jr, et al. Copper, zinc, manganese, and magnesium status and complications of diabetes mellitus. Diabetes Care. 1991;14:1050-1056
  49. 49. Khan FA, et al. Comparative study of serum copper, iron, magnesium, and zinc in type 2 diabetes-associated proteinuria. Biological Trace Element Research. 2015;168:321-329
  50. 50. Ohara N, et al. Hypertension increases urinary excretion of immunoglobulin G, ceruloplasmin and transferrin in normoalbuminuric patients with type 2 diabetes mellitus. Journal of Hypertension. 2014;32:432-438
  51. 51. Islam KN, et al. Fragmentation of ceruloplasmin following non-enzymatic glycation reaction. Journal of Biochemistry (Tokyo). 1995;118:1054-1060
  52. 52. Kawamura N, et al. Increased glycated Cu, Zn-superoxide dismutase levels in erythrocytes of patients with insulin-dependent diabetis mellitus. Journal of Clinical Endocrinology and Metabolism. 1992;74:1352-1354
  53. 53. Kaneto H, et al. DNA cleavage induced by glycation of Cu, Zn-superoxide dismutase. Biochemical Journal. 1994;304:219-225
  54. 54. Behndig A, et al. In vitro photochemical cataract in mice lacking copper-zinc superoxide dismutase. Free Radical Biology and Medicine. 2001;31:738-744
  55. 55. Takata I, et al. Glycated Cu, Zn-superoxide dismutase in rat lenses: Evidence for the presence of fragmentation in vivo. Biochemical and Biophysical Research Communications. 1996;219:243-248
  56. 56. Jakus V, et al. Effect of aminoguanidine and copper (II) ions on the formation of advanced glycosylation end products. In vitro study on human serum albumin. Arzneimittel-Forschung. 2001;51:280-283
  57. 57. Brings S, et al. Diabetes-induced alterations in tissue collagen and carboxymethyllysine in rat kidneys: Association with increased collagen-degrading proteinases and amelioration by Cu (II)-selective chelation. Biochimica et Biophysica Acta. 2015;1852:1610-1618
  58. 58. Hill HAO, et al. Manganese metalloproteins and manganese-activated enzymes. Inorganic Biochemistry. 1981;2:249-282
  59. 59. Okun Z, et al. Manganese corroles prevent intracellular nitration and subsequent death of insulin-producing cells. ACS Chemical Biology. 2009;4:910-914
  60. 60. Baquer NZ, et al. Regulation of glucose utilization and lipogenesis in adipose tissue of diabetic and fat fed animals: Effects of insulin and manganese. Journal of Biosciences. 2003;28:215-221
  61. 61. Baker MG, et al. Blood manganese as an exposure biomarker: State of the evidence. Journal of Occupational and Environmental Hygiene. 2014;11:210-217
  62. 62. Ekmekcioglu C, et al. Concentrations of seven trace elements in different hematological matrices in patients with type 2 diabetes as compared to healthy controls. Biological Trace Element Research. 2001;79:205-219
  63. 63. Fitsanakis VA, et al. Manganese (Mn) and iron (Fe): Interdependency of transport and regulation. Neurotoxicity Research. 2010;18:124-131
  64. 64. Food and Nutrition Board of the Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington DC: National Academy Press; 2001 Available from:
  65. 65. Harani H, et al. Preliminary evaluation of the antioxidant trace elements in an Algerian patient with type 2 diabetes: Special role of manganese and chromium. Annales De Biologie Clinique. 2012;70:669-677
  66. 66. Aschner M, et al. Manganese transport across the blood-brain barrier: Relationship to iron homeostasis. Brain Research Bulletin. 1990;24:857-860
  67. 67. Critchfield JW, et al. Manganese + 2 exhibits dynamic binding to multiple ligands in human plasma. Metabolism. 1992;41:1087-1092
  68. 68. Davidsson L, et al. Identification of transferrin as the major plasma carrier protein for manganese introduced orally or intravenously or after in vitro addition in the rat. Journal of Nutrition. 1989;119:1461-1464
  69. 69. Scheuhammer AM, et al. Binding of manganese in human and rat plasma. Biochimica et Biophysica Acta. 1985;840:163-169
  70. 70. Harris WR, et al. Electron paramagnetic resonance and difference ultraviolet studies of Mn2+ binding to serum transferring. Journal of Inorganic Biochemistry. 1994;54:1-19
  71. 71. Meyer A, et al. Manganese-mediated MRI signals correlate with functional β-cell mass during diabetes progression. Diabetes. 2015;64:2138-2147
  72. 72. Jouihan HA, et al. Iron-mediated inhibition of mitochondrial manganese uptake mediates mitochondrial dysfunction in a mouse model of hemochromatosis. Molecular Medicine. 2008;14:98-108
  73. 73. Bokare AD, et al. Review of iron-free Fenton-like systems for activating H2O2 in advanced oxidation processes. Journal of Hazardous Materials. 2014;275:121-135
  74. 74. Klimis-Zacas D, et al. Manganese: Modulator of vascular function, structure, and metabolism. Cell Biology and Toxicology. 2008;24:S1-S130
  75. 75. Vincent JB. Chromium: Celebrating 50 years as an essential element? Dalton Transactions. 2010;39:3787-3794
  76. 76. Richard MJ, et al. Les glutathion peroxydases: intérêt de leur dosage en biologie clinique. Annales de Biologie Clinique. 1997;55:195-208
  77. 77. Goldhaber SB. Trace element risk assessment: Essentiality vs toxicity. Regulatory Toxicology and Pharmacology. 2003;38:232-242
  78. 78. Wallach S. Clinical and biochemical aspects of chromium deficiency. Journal of the American College of Nutrition. 1985;4:107-120
  79. 79. Iskra RI, et al. Biochemical mechanisms of chromium action in the human and animal organism. Ukrainskiĭ Biokhimicheskiĭ Zhurnal. 2011;83:5-12
  80. 80. Zhao P, et al. A newly synthetic chromium complex-chromium [D-phenylalanine] 3 activates AMP-activated protein kinase and stimulates glucose transport. Biochemical Pharmacology. 2009;77:1002-1010
  81. 81. Sreejayan N, et al. Safety and toxicological evaluation of a novel chromium [III] dinicocysteinate complex. Toxicology Mechanisms and Methods. 2010;20:321-333
  82. 82. Fuhr JP Jr, et al. Use of chromium picolinate and biotin in the management of type 2 diabetes: An economic analysis. Disease Management. 2005;8:265-275
  83. 83. Lai MH. Antioxidant effects and insulin resistance improvement of chromium combined with vitamin C and E supplementation for type 2 diabetes mellitus. Journal of Clinical Biochemistry and Nutrition. 2008;43:191-198
  84. 84. Qiao W, et al. Chromium improves glucose uptake and metabolism through upregulating the mRNA levels of IR, GLUT4, GS, and UCP3 in skeletal muscle cells. Biological Trace Element Research. 2009;131:133-142
  85. 85. Vladeva SV, et al. Effect of chromium on the insulin resistance in patients with type II diabetes mellitus. Folia Medica (Plovdiv). 2005;47:59-62
  86. 86. Krol E, et al. Effects of chromium brewer’s yeast supplementation on body mass, blood carbohydrates, and lipids and minerals in type 2 diabetic patients. Biological Trace Element Research. 2011;143:726-737
  87. 87. Vinson JA, et al. Beneficial effects of a novel IH636 grape seed proanthocyanidin extract and a niacin-bound chromium in a hamster atherosclerosis model. Molecular and Cellular Biochemistry. 2002;240:99-103
  88. 88. Wang YQ, et al. Effects of chromium picolinate on glucose uptake in insulin-resistant 3T3-L1 adipocytes involve activation of p38 MAPK. The Journal of Nutritional Biochemistry. 2009;20:982-991
  89. 89. Anton SD, et al. Effects of chromium picolinate on food intake and satiety. Diabetes Technology & Therapeutics. 2008;10:405-412
  90. 90. Wang YQ, et al. Chromium picolinate inhibits resistin secretion in insulin-resistant 3T3-L1 adipocytes via activation of AMP-activated protein kinase. Clinical and Experimental Pharmacology & Physiology. 2009;36:843-849
  91. 91. Jain SK, et al. Effect of chromium niacinate and chromium picolinate supplementation on lipid peroxidation, TNF-alpha, IL-6, CRP, glycated hemoglobin, triglycerides, and cholesterol levels in blood of streptozotocin-treated diabetic rats. Free Radical Biology & Medicine. 2007;43:1124-1131

Written By

Ines Gouaref and Elhadj-Ahmed Koceir

Submitted: 14 July 2017 Reviewed: 21 September 2017 Published: 20 December 2017