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

Abstract

Beta (β) 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 β cell population and function. It is known that TGF-β signaling plays diverse roles in β cell development, function, proliferation, apoptosis, and dedifferentiation. Inhibition of TGF-β signaling expands β cell lineage in the development. However, deletion of Tgfbr1 has no influence on insulin demand-induced but abolishes inflammation-induced β cell proliferation. Among canonical TGF-β signaling, Smad3 but not Smad2 is the predominant repressor of β cell proliferation in response to systemic insulin demand. Deletion of Smad3 simultaneously improves β 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 β cell proliferation and glucose homeostasis in animal studies. On the other hand, overexpression of Tgfb1 prevents β cells from autoimmune destruction without influence on β cell function. All these findings reveal the diverse regulatory roles of TGF-β signaling in β cell biology.

Keywords: TGF-β signaling; apoptosis; dedifferentiation; diabetes; function; proliferation; β cell.

Figure 1

This schematic graph illustrates the classical TGF-β signaling and its roles in the regulation of β cell development, proliferation, apoptosis, dedifferentiation, and function. The TGF-β ligands are synthesized as latent TGF-βs. After being released, TGF-β binds to TGFBR2, which recruits and activates TGFBR1. TGFBR1 phosphorylates intracellular Smad2/3 which then binds to Smad4 and translocates into the nucleus to regulate the transcription of target genes. Smad7 negatively regulates TGF-β signaling by competing for the TGFBR1 with Smad2/3 and inducing the degradation of TGFBR1. The roles of each component of TGF-β signaling on different β cell biological processes are indicated in the insert. The solid line indicates a confirmative role while the dotted line suggests a role under debate. The line with the arrow represents positive regulation, while the line with blunted end stands for negative regulation. LAP, latency-associated peptide. LABP, latent TGF-β-binding protein.

Figure 2

Benefits of Smad3 deficiency on β cell biology and insulin resistance. Smad3 deficiency in mice promotes β cell development, augments β cell function (by elevating insulin synthesis and GSIS), enhances β cell proliferation in response to systemic insulin demand, and suppresses/eliminates β cell apoptosis, β cell dedifferentiation, and insulin resistance in conditions of T2DM.