The Incretin Hormones and their analogues as physiological and pharmacological regulators of a complex multi-organ network

Strategies aiming at increasing plasma glucagon-like peptide-1 (GLP-1) concentration or use of GLP-1 Receptor Agonists (RAs) are among the recommended treatment for type 2 diabetes mellitus (T2D). A more in-depth knowledge of the metabolic pathways mediating GLP-1 and GLP-1 RAs actions is, thus, of the outmost importance to exploit fully this system for clinical advantages. Indeed, enhancing GLP-1 action might favorably impact at least five members of the ominous octet indicated as the culprit of T2D: β and α pancreatic cell, liver, gut and brain. Recent evidence suggests that GLP-1, by affecting the genetic and microenvironment factors involved in the differentiation process of intestinal cells, might even modulate incretin hormones release. Moreover, it has been shown that the activation of GPR120, a G-protein receptor expressed in K and/or L cells, results in insulin-sensitizing effects, thought to be mediated by the release of GLP-1 and GIP. Thus, the development of molecules capable of activating GPR120 or of modulating its functions is also part of the vast scenario, where the incretin system is exploited for clinical uses. On this background, our research proposal aims to understand the mechanisms underlying the pleiotropic effects of incretin hormones and their analogues on a complex multi-organ network, throughout a comprehensive in vitro, ex-vivo and in vivo approach.