**3. Selenium in T2D pathogenesis**

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

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,

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 proinflammatory cytokines (TNF-α, IL-6) may contribute to development of diabetic complica-

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 trans-

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

aggravates the diabetes vascular complications [4].

94 Diabetes Food Plan

and that consider their therapeutic potential.

**2. Zinc in T2D pathogenesis**

tions [12, 13] and increased glycated hemoglobin formation [4].

ported across cell membranes via ZnT family's transporters [19].

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 [30–32]. 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].

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

Trace Elements Modulates Oxidative Stress in Type 2 Diabetes

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

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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 [66–69]. 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 produc-

tion, precursor to nitric oxide (NO) formation as endothelial vasodilator [74].

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

**6. Chromium in T2D pathogenesis**

and provence herbs [64].
