**Trace Elements Modulates Oxidative Stress in Type 2 Diabetes Diabetes**

**Trace Elements Modulates Oxidative Stress in Type 2** 

DOI: 10.5772/intechopen.71172

Ines Gouaref and Elhadj-Ahmed Koceir

Ines Gouaref and Elhadj-Ahmed Koceir Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

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

#### **Abstract**

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.

**Keywords:** 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

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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].

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].

Trace Elements Modulates Oxidative Stress in Type 2 Diabetes

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

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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

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

**3. Selenium in T2D pathogenesis**

antioxidant effects were not obtained [35, 36].

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 proinflammatory cytokines (TNF-α, IL-6) may contribute to development of diabetic complications [12, 13] and increased glycated hemoglobin formation [4].
