Insulin resistance (i.r.), a condition defined as a relative inability of body tissues to respond to the action of insulin, is one of the main culprits in the association between obesity, particularly visceral, and metabolic diseases such as type 2 diabetes mellitus (T2DM). In obese individuals, adipose tissue releases increased amounts of non-esterified fatty acids, glycerol, hormones, proinflammatory cytokines and other factors that are involved in the development of i.r.. However, despite these association have been proved, the exact mechanisms promoting the onset of i.r. are still unclear.
During the last years, biliverdin reductase-A (BVR-A) emerged as a novel mediator of the insulin signaling machinery, possibly involved in the regulation glucose uptake. In that frame, it has been demonstrated that other than its canonical activity in the degradation pathway of heme, BVR-A is a direct target of the insulin receptor (IR) similar to IRS1. Once activated by insulin, IR promotes the phosphorylation of BVR-A on specific Tyr residues, which leads to the activation of BVR-A as a unique Ser/Thr/Tyr kinase. Through this kinase activity BVR-A regulate the insulin signaling at different levels. It is an upstream regulator of IRS1, as well as a downstream regulator of both Akt and MAPK activation. These features make the protein of great interest in the contest of the comprehension of insulin signaling defects.
The aim of this project will be the characterization of the role of BVR-A in the onset of i.r. in lymphocytes collected from obese (Ob) and obese who develope diabetes (Ob/T2DM) before and after bariatric surgery, this latter known to cause significant long-term loss of weight and recovery from T2DM.
This knowledge will be fostering exploration of the molecular and genetic basis of the disease and new approaches to its treatment and prevention.
Obesity complications are due to aberrant fat deposition in non-adipose tissues, profoundly altering the organ function, secondary to the low-grade chronic inflammation in the adipose tissue. Inflammatory state, ectopic fat accumulation and the consequent metabolic alterations may be the premise of chronic diseases that largely affect general population worldwide, such as diabetes, atherosclerosis and cardiovascular disease, which represent the first cause of death in Western countries and has a remarkable impact on life quality and health care costs.
To this end, it is of utmost priority to identify new predictors of risk in affected subjects. Acquiring new knowledge about factors that promotes the onset of the disease would help to identify new markers useful in creating new prevention tools. Discovering new pathogenetic processes would also help to implement innovative treatment strategies by identifying specific subgroups of particularly at-risk patients.
I.r., drives most of the events described above, even if a specific mechanism and easy-detectable markers of i.r. have not been identified so far. The identification of possible genetic and circulating markers of i.r., may be therefore considered a significant goal for a better risk stratification and a starting point for novel therapeutic interventions.
The results of this project as regard the role of BVR-A in obesity and T2DM pathogenesis will propose a new target of intervention. As outlined above in this proposal, the pleiotropic functions of BVR-A together with its prominent position in the insulin pathway, make this protein of great interest for further researches. Indeed, being BVR-A a quite unknown target with regard to its real therapeutic potential, the gain of knowledge deriving from the results of this proposal will represent a step ahead in the field of metabolic disorders for several reasons (i) it will contribute to highlight a new mechanism driving i.r. in obesity and T2DM; (ii) it will propose a new target on which focuses future intervention; (iii) the results about BVR-A will serve to attract pharmaceutical companies to invest money for the development of novel therapeutic strategies aimed to prevent or rescue i.r. in metabolic disorders.
Furthemore, the results collected in this project will have an important role to play for the achievement of the Europe 2020 strategy and of the Innovation Union. Indeed, it perfectly matches the aims of the Innovation Union initiative because: (i) innovation in products will be represented by providing in the next future with new drugs/agents able to modulate BVR-A activities; (ii) innovation in service will be represented by providing general population with new therapeutic intervention to delay or cure i.r.. The finish line of this initiative, fixed for 2020 thus represents a good time frame during which put all the efforts to obtain the hoped results.