**6. Chromium in T2D pathogenesis**

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 athero-

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 diabetesinduced 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

sclerotic processes by endothelial adhesion molecules expression [47].

prevent or reduce AGE formation typically have potent Cu chelating [57].

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

**4. Copper in T2D pathogenesis**

96 Diabetes Food Plan

**5. Manganese 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 [80–83]. 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].

**Author details**

**References**

Ines Gouaref and Elhadj-Ahmed Koceir

Longevity. 2016;**2016**:4350965

Metabolism. 2009;**58**:1477-1482

and Metabolic Syndrome. 2010;**2**:70

1996;**9**:130-136

3289-3303

2016;**33**:114-119

\*Address all correspondence to: e.koceir@gmail.com

Elements in Medicine and Biology. 2012;**26**:59-60

Free Radical Biology and Medicine. 2010;**48**:1565-1569

Advances in Clinical Chemistry. 2015;**68**:87-130

Houari Boumediene (USTHB), Algiers, Algeria

Department of Bioenergetics and Intermediary Metabolism, Biology and Organisms Physiology Laboratory, Biological Sciences Faculty, University of Sciences and Technology

[1] Zhang J et al. ROS and ROS-mediated cellular signaling. Oxidative Medicine and Cellular

Trace Elements Modulates Oxidative Stress in Type 2 Diabetes

http://dx.doi.org/10.5772/intechopen.71172

99

[2] Andersen O, et al. Recent developments in trace element research. Journal of Trace

[3] Xiu YM. Trace elements in health and diseases. Biomedical and Environmental Sciences.

[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.

[5] Liochev SI, et al. Mechanism of the peroxidase activity of Cu, Zn superoxide dismutase.

[6] Bresciani G, et al. Manganese superoxide dismutase and oxidative stress modulation.

[7] Brigelius-Flohé R, et al. Glutathione peroxidases. Biochimica et Biophysica Acta. 2013;**1830**:

[8] Wiernsperger N, et al. Trace elements in glucometabolic disorders: An update. Diabetology

[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.

[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] Evans JL, et al. Oxidative stress and stress activated signalling pathways: A unifying

hypothesis of type 2 diabetes. Endocrine Reviews. 2002;**23**:599-622
