**2. Oxidative stress and beta-cell destruction**

Impairment in the oxidant/antioxidant equilibrium creates a condition known as oxidative stress. There is a complex interaction between antioxidants and oxidants such as reactive oxygen species, which modulates the generation of oxidative stress. Oxidative stress takes place in a cellular system when the generation of reactive oxygen species increases and over‐ whelms the body's antioxidant capacity and defenses (Baynes, 1991). If the free radicals are not removed by the cellular antioxidants, they may attack and damage lipids, carbohy‐ drates, proteins and nucleic acids (Baynes & Thorpe, 1999).

Oxidative stress is known to be a component of molecular and cellular tissue damage mecha‐ nisms in a wide spectrum of human diseases (Maritim et al., 2003; Isabella et al., 2006). There is growing evidence that have connected oxidative stress to a variety of pathological conditions, including cancer, cardiovascular diseases, chronic inflammatory disease, post-ischaemic or‐ gan injury, diabetes mellitus, xenobiotic/drug toxicity, and rheumatoid arthritis (El Farama‐ wy & Rizk, 2011; Samanthi et al., 2011). In recent years, much attention has been focused on the role of oxidative stress. It has been reported that oxidative stress participates in the pro‐ gression and pathogenesis of secondary diabetic complications. This includes impairment of 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‐ ed coronary artery disease (Phillips et al., 2004; Niedowicz & Daleke, 2005).

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 (Drews, 2010).

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).
