General Discussion and Future Perspectives

Abstract

The prevalence of obesity is reaching pandemic proportions, mainly because of adopting the so-called Western lifestyle, i.e. a high intake of energy dense food and a low physical activity pattern. 1 These lifestyle changes lead to one of the key abnormalities underlying the metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM), i.e. insulin resistance with concomitant central obesity, hyperinsulinemia, hypertension and dyslipidemia, all established risk factors for the development of cardiovascular disease (CVD). 2 In susceptible individuals with (genetically) compromised beta-cell function and/or beta-cell functional mass, the constant demand on the beta-cells will ultimately lead to failure of the beta-cells with ensuing hyperglycemia and T2DM. In insulin resistant individuals with T2DM, the metabolic abnormalities become even more pronounced upon challenge, such as in response to a meal, resulting in prolonged hyperglycemia, hypertriglyceridemia, elevated fatty acids and hyperinsulinemia. In these individuals, due to these prolonged and exaggerated metabolic derangements, all organ systems, including the heart and the vascular endothelium, are exposed to a pro-atherogenic, pro-inflammatory and pro-thrombotic milieu for almost 24 hours a day. As the abnormal metabolic responses usually concur, it makes it more difficult to tease out their relative contribution to cardiovascular damage and to design studies focusing on the effects of a single factor. Furthermore, seemingly distinct mechanisms of action, when concurring, interact and produce synergistic increases in oxidative stress, protein kinase-C (PKC) activation and advanced glycation end-product receptor (RAGE) activation. 3,4 Collectively, these derangements result in systemic and vascular inflammation, impaired endothelial function and ultimately, in CVD. 5,6 Besides, chronic inflammation and elevated oxidative stress are not only associated with the complications of obesity or diabetes, but have also been linked to insulin resistance in vitro and in vivo.