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Bridges in translational medicine: a case for metabolism, inflammation, and nutrition.

Type 2 diabetes (T2D) is a complex multifactorial disorder for which the etiology is still a cause for debate. However it is generally accepted that dysregulated glucose sensing and (or) insulin secretion leading to insufficient compensation for peripheral insulin resistance is a major feature of the pathogenesis of TD2 (Patarrão et al. 2012). The prevalence of this chronic disease is a global public health concern, and insufficient health care guidelines have been developed to address its prevention based on education, lifestyle intervention, and therapeutics. On the other hand, there is already comprehensive knowledge about insulin signaling and insulin receptor substrates (irs), specifically irs1 and irs2, which mediate the pleiotropic effects of insulin. Irs1 acts mainly in skeletal muscle insulin signaling and growth, whereas irs2 is widely expressed and has a broader role in insulin signaling. The paper by Oliveira et al. in this issue of CJPP reviews the role of irs2 in several perspectives, highlighting the involvement of irs2 in protecting against beta-cell failure; an important feature of all types of diabetes. Moreover, irs2 is also relevant for the maintenance of glucose metabolism in T2D. White et al. contributed to establishing this theory when they found that irs2-deficient mice develop diabetes (Withers et al. 1999; White 2006). In their review, Oliveira et al. (2014b) also focus on therapies that target IRS2 signaling to prevent the development of diabetes in Irs2−/− mice. In their recent paper they observed that sodium tungstate attenuates beta-cell apoptosis by decreasing the expression of proapoptotic genes in Irs2−/− islets, with increased beta-cell mass and improvement of glucose homeostasis preventing the development to T2D (Oliveira et al. 2014a). Another important topic, which was addressed by Bouzakri et al., is the implication of inflammatory factors in irs2 function and degradation (Bouzakri et al. 2009). Experiments with tumour necrosis factor alpha (TNF ) revealed a mechanism linking inflammatory cytokines to dysmetabolism, as TNF promotes serine phosphorylation of IRS2, correlating closely with insulin resistance. Although a subclinical inflammatory state occurs in T2D, is still not clear how inflammation is triggered. A case has been put forward connecting changes in the intestinal microbiota and development of T2D. These observations suggested that increased concentrations of circulating lipopolysaccharide (LPS), promoted by changes in intestinal permeability, might have a pivotal role in the progression to T2D. Understanding the main trigger of this alteration in our gut microbial communities is essential, as diet, nutritional status, the immune system, and microbial ecology in humans at different stages of life may have a role in the T2D etiological complex. It has become clear that food shapes the gut microbiome. Whether the interdependent effects of diet– microbiota–TNF have a direct impact on pancreatic irs2 signaling, making beta cells more susceptible to failure or unable to compensate for peripheral insulin resistance, is an issue that remains to be proven. Nevertheless, from an interventional standpoint, this vicious cycle needs to be broken. If this hypothesis is proven to be correct, we should start to integrate the impact on intestinal microbiota composition and subsequent inflammatory responses in the nutritional value of foods, as a proxy for predicting the potential to evoke dysmetabolic states (Fig. 1).