TIMP-3: A NEW CANDIDATE GENE FOR THE COMMON SOIL BETWEEN TYPE 2 DIABETES AND ATHEROSCLEROSIS

Type 2 diabetes is a complex disease sustained by an interaction between peripheral insulin resistance and inadequate insulin secretory capacity of pancreatic beta-cell. Several studies in the last three decades observed that insulin resistance is also associated with a two- to threefold elevation of the risk of cardiovascular mortality, independent of classical cardiovascular risk factors like hypertension and dyslipidemias. Consequently, insulin resistance has been hypothesized to act as a common genetic defect for both Type 2 diabetes and atherosclerosis. However, identification of mechanisms responsible for this common soil driving to diabetes and atherosclerosis is still incomplete. In the last few years we have investigated in depth the common soil between diabetes and atherosclerosis using animal models. We have found that diabetes phenotype occurs in a transgenic animal model characterized by an impairment of insulin signaling (Insr+/- mice) only when a functional loss of the TIMP-3 protein is also present.. TIMP-3 activity is crucial in atherosclerosis and in inflammation. Furthermore, TIMP-3 can block TNF-Alpha Converting-Enzyme (TACE) thus taking part in the regulation of ProTNF-alpha conversion to TNF-alpha. It is well-known that TNF-alpha plays an important role in insulin resistance. Indeed, inhibition of TNF-alpha in type 2 diabetes has been considered as a possible therapy. The overall goal of this project is to test whether modulation of TIMP-3/TACE pathway in animal models of insulin resistance could interfere with glucose metabolism, insulin sensitivity and vascular inflammation. Since several TACE inhibitors are already available positive results could open new therapeutic strategies for patients affected by Type 2 diabetes, Obesity, Coronary Heart Disease, Heart Failure, Neuromuscular disorders .