To compensate for the increased insulin demand under conditions of insulin resistance, beta-cell hypertrophy and hyperplasia develops, leading to hyperinsulinaemia (Butler et al., 2003 Rhodes, 2005). Thus, obesity-induced insulin resistance contributing to the low-grade inflammation of metabolic tissues and the low-grade inflammation contributing to insulin resistance perpetuate each other. Deregulated nutrient uptake itself can activate inflammation by various mechanisms (Pal et al., 2012 Tremaroli and Backhed, 2012 Odegaard and Chawla, 2013). In this scenario, insulin resistance might be considered protective as it prevents the further excess uptake of nutrients and the deterioration of the cells within the metabolic tissues (Lumeng and Saltiel, 2011 Saltiel, 2012 Odegaard and Chawla, 2013). Furthermore, mainly via inhibitory serine/threonine phosphorylation of the insulin receptor substrate 1, some pro-inflammatory cytokines inhibit insulin signalling, thereby escalating insulin resistance (Tamemoto et al., 1994 Aguirre et al., 2000 Hirosumi et al., 2002 Ueki et al., 2004 Werner et al., 2004). This subacute inflammation within the metabolic tissues leads to increased secretion of pro-inflammatory cytokines, which reinforces inflammatory signals and decreases the secretion of protective factors such as adiponectin (Hotamisligil et al., 1995 Hotta et al., 2000 Donath and Shoelson, 2011 Lumeng and Saltiel, 2011 Odegaard and Chawla, 2013). The cellular stress activates diverse signalling pathways, including the JNKs and the IκB kinase β (IKKβ), which, in turn, inhibit insulin signalling pathways and trigger inflammation within the WAT and other tissues (Donath and Shoelson, 2011 Lumeng and Saltiel, 2011 Odegaard and Chawla, 2013). However, under conditions of chronic over-nutrition, their storage capacity is eventually exceeded and mitochondrial dysfunction, oxidative stress, endothelial reticulum stress and abnormal post-translational modification of intracellular proteins ensue. The excess of nutrients is stored mainly in the white adipose tissue (WAT), the liver and the skeletal muscle. For the development of type 2 diabetes, obesity caused by the chronic imbalance between calorie intake and energy expenditure is the major risk factor (American Diabetes Association, 2004 Lazar, 2005). In general, two forms of diabetes mellitus are distinguished: type 1 diabetes is caused by the autoimmune destruction of the insulin-producing beta-cells in early childhood and resulting in an absolute lack of insulin (American Diabetes Association, 2004). Indeed, more than 60% of type 2 diabetics die of myocardial infarction or stroke (Giorgino et al., 2013).
Among the consequences of diabetes are micro- and macrovascular complications such as retinopathy and nephropathy leading to blindness and renal insufficiency, respectively, and cardiovascular and cerebrovascular diseases (Alberti and Zimmet, 1998 Stratton et al., 2000). Their suitability as ‘ideal anti-diabetic drugs’ will be discussed.ĭiabetes mellitus belongs to the most rapidly increasing diseases worldwide.
In addition, emerging strategies for the treatment of diabetes will be described, among them the inhibition of glucagon action and anti-inflammatory drugs. This review will briefly summarize current oral anti-diabetic drugs. Despite the many anti-diabetic drugs already in use, there is an ongoing research for additional drugs, guided by different concepts of the pathogenesis of type 2 diabetes. An ideal oral anti-diabetic drug should not only correct glucose homeostasis but also preserve or even augment beta-cell function and mass, ameliorate the subclinical inflammation present under insulin-resistant conditions and prevent the macro- and microvascular consequences of diabetes in order to reduce the mortality. Considering the complications of this chronic disease, a reliable anti-diabetic treatment is indispensable. Approximately 90–95% of these patients suffer from type 2 diabetes mellitus, which is characterized by peripheral insulin resistance and the progressive loss of beta-cell function and mass. Diabetes mellitus belongs to the most rapidly increasing diseases worldwide.
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