Role of TGF-Beta Signaling in Beta Cell Proliferation and Function in Diabetes

摘要

Beta (beta) cell dysfunction or loss is the common pathological feature in all types of diabetes mellitus (diabetes). Resolving the underlying mechanism may facilitate the treatment of diabetes by preserving the beta cell population and function. It is known that TGF-beta signaling plays diverse roles in beta cell development, function, proliferation, apoptosis, and dedifferentiation. Inhibition of TGF-beta signaling expands beta cell lineage in the development. However, deletion of Tgfbr1 has no influence on insulin demand-induced but abolishes inflammation-induced beta cell proliferation. Among canonical TGF-beta signaling, Smad3 but not Smad2 is the predominant repressor of beta cell proliferation in response to systemic insulin demand. Deletion of Smad3 simultaneously improves beta cell function, apoptosis, and systemic insulin resistance with the consequence of eliminated overt diabetes in diabetic mouse models, revealing Smad3 as a key mediator and ideal therapeutic target for type-2 diabetes. However, Smad7 shows controversial effects on beta cell proliferation and glucose homeostasis in animal studies. On the other hand, overexpression of Tgfb1 prevents beta cells from autoimmune destruction without influence on beta cell function. All these findings reveal the diverse regulatory roles of TGF-beta signaling in beta cell biology.