**1. Introduction**

### **1.1. Type 1 diabetes mellitus**

Diabetes mellitus is considered to be one of the most common chronic diseases worldwide, and recognized as one of the leading causes of morbidity and mortality (American Diabetes Association, 2010). It has been reported that the prevalence of diabetes mellitus will increase from 6% to over 10% in the next decade (Rosen et al., 2001). According to the World Health Organization in 2000, a total of 171 million people in all age groups worldwide (2.8% of the global population) have been affected by diabetes mellitus, and the number of persons is ex‐ pected to increase to 366 million (4.4% of the global population) by 2030 (Wild et al., 2004).

Type 1 diabetes mellitus accounts for 5-10% of all diagnosed cases of diabetes mellitus, and exhibits hyperglycemia as its hallmark. It is caused by pancreatic β-islet cell failure with re‐ sulting insulin deficiency mortality and risk factors may be autoimmune, genetic, or envi‐ ronmental (American Diabetes Association, 2004). Type 1 diabetes mellitus is an autoimmune disorder involving immune-mediated recognition of islet β-cells by auto-reac‐ tive T cells. This subsequently leads to the liberation of pro-inflammatory cytokines and re‐ active oxygen species. There is destruction of pancreatic β-cells in the islets of Langerhans and loss of insulin secretion (Delmastro & Piganelli, 2011). The Jun kinase pathway is also activated by the pro-inflammatory cytokines, and there is evidence that oxidative stress is involved in β-cell destruction (Kaneto et al., 2007). The loss of β-cell mass consequential to the activation of pro-apoptotic signaling events is increasingly recognized as a causal and committed stage in the development of type 1 diabetes mellitus (Watson & Loweth, 2009).

© 2013 A. McGrowder et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Moreover, pancreatic β-cells are sensitive to cytotoxic damage caused by reactive oxygen species as gene expression and activity of antioxidant enzymes such as glutathione peroxi‐ dase activity is decreased in these cells (Lenzen et al., 1996).

insulin action and elevation of the complication incidence (Ceriello, 2006). Furthermore, there is evidence for the role of reactive oxygen species and oxidative stress in the development of type 1 diabetic complications including retinopathy, nephropathy, neuropathy, and accelerat‐

Biochemical Evaluation of Oxidative Stress in Type 1 Diabetes

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It has also been reported that oxidative stress induced by reactive oxygen and nitrogen spe‐ cies is critically involved in the impairment of β-cell function, and thus play a role in the pathology of type 1 diabetes mellitus (West, 2000). Islet β-cells are highly susceptible to oxi‐ dative stress because of their reduced levels of endogenous antioxidants (*Azevedo-Martins et al., 2003; Kajikawa et al., 2002).* With decreased antioxidant capacity, β-cells are extremely sensitive towards oxidative stress. Cell metabolism and potassium (adenosine-5'-triphos‐ phate) channels in β-cells are important targets for reactive oxygen species and other oxi‐ dants. The alterations of potassium (adenosine-5'-triphosphate) channel activity by the oxidants, is crucial for oxidant-induced dysfunction as genetic ablation of potassium (adeno‐ sine-5'-triphosphate) channels attenuates the effects of oxidative stress on β-cell function

Oxidative stress may reduce insulin sensitivity and damage the β-cells within the pancreas. The reactive oxygen species produced by oxidative stress can penetrate through cell mem‐ branes and cause damage to the β-cells of pancreas (Chen et al., 2005; Lepore et al., 2004). Reactive oxygen species produced from free fatty acids can cause mitochondrial deoxyribo‐ nucleic acid damage and impaired pancreatic β-cell function (Rachek et al., 2006). Mitochon‐ drial and nitrogen oxides (NOx)-derived reactive oxygen species have been implicated in βcell destruction and subsequently type 1 diabetes mellitus. Furthermore, increased glucose can cause rapid induction of the Krebs cycle within the β-cell mitochondria, leading to aug‐ mented reactive oxygen species production (Newsholme et al., 2007). The superoxide leaked from the mitochondria can contribute to the formation of hydrogen peroxide which may play a role in uncoupling glucose metabolism from insulin secretion (Maechler et al., 1999).

**3. Oxidative stress induced by hyperglycaemia in type 1diabetes**

There are multiple sources of reactive oxygen species production in diabetes including those of non-mitochondrial and mitochondrial origins. Reactive oxygen species accelerates four important molecular mechanisms that are involved in oxidative tissue damage induced by hyperglycemia. These four pathways are increased advanced glycation end product, in‐ creased hexosamine pathway flux, activation of protein kinase C, and increased polyol path‐ way flux (also known as the sorbitol-aldose reductase pathway) (Rolo & Palmeira, 2006).

In the polyol pathway, the two enzymes aldose reductase and sorbitol dehydrogenase cause reactive oxygen species production. Glucose is reduced to sorbitol through the use of re‐ duced nicotinamide adenine dinucleotide phosphate, a reaction catalyzed by aldose reduc‐ tase. This pathway metabolizes 30 - 35% of the glucose present during hyperglycemia. The

**3.1. Pathways involved in the production of oxidants**

ed coronary artery disease (Phillips et al., 2004; Niedowicz & Daleke, 2005).

(Drews, 2010).

Increasing evidence in both experimental and clinical studies suggests that oxidative stress plays a central role in the onset of diabetes mellitus as well as in the development of vascu‐ lar and neurologic complications of the disease (Niedowicz & Daleke, 2005). Studies advanc‐ ing the role of oxidative stress in vascular endothelial cells proposed that oxidative stress mediate the diversion of glycolytic intermediates into pathological pathways (Rolo & Pal‐ meira, 2006; Turk, 2010). Oxidative stress is increased in diabetes mellitus owing to an in‐ crease in the production of oxygen free radicals and a deficiency in antioxidant defense mechanisms. Free radicals are formed disproportionately in diabetes by glucose oxidation, non-enzymatic glycation of proteins, and the subsequent oxidative degradation of glycated proteins (Rodiño-Janeiro et al., 2010). Abnormally high levels of free radicals and the simul‐ taneous decline of antioxidant defense mechanisms can lead to damage of cellular organ‐ elles and enzymes, increased lipid peroxidation, and development of insulin resistance (Ceriello, 2006).

This review will explore recent evidence in the literature of the use of biomarkers to assess oxidative stress which is recognized as a significant mediator in the development of macro‐ vascular or cardiovascular complication in type 1 diabetes mellitus, as well as the potential for prevention of complications through the use of antioxidants. There is also a search for other biomarker of oxidative stress which might be clinically useful in patients with diabetes mellitus. Such a biomarker could potentially indicate the severity of disease, identify those at increased risk of complications and monitor response to treatment.
