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.
Highlights
Diabetes mellitus has become a global health issue with about422 million victims in 2014 and 1.5 million-associated deaths in 2019 according to the report from World Health Organization [1]
Diabetes is a quite heterogeneous group of disorders that can be roughly classified into four subtypes: type-1 diabetes mellitus (T1DM), type-2 diabetes mellitus (T2DM), gestational diabetes, and other types like the maturity-onset diabetes of the young (MODY) [2]
Smad signaling to synergize thereview, abovesee canonical or data function inde the role of non-Smad signaling in β cell biology, this review mainly focuses on canonical pendently [29]
Summary
Diabetes mellitus (diabetes thereafter) has become a global health issue with about. 422 million victims in 2014 and 1.5 million-associated deaths in 2019 according to the report from World Health Organization [1]. Even in T2DM with complex etiology, most of the associated genetic factors are related to the regulation of the compensatory function of β cells but not insulin resistance [12], highlighting the important role of β cells in the pathogenesis of diabetes. Genetic mutation-derived intrinsic defects and extrinsic metabolic stress (overwhelming systemic insulin demand) or other detrimental factors (like autoimmune antibodies, glucolipotoxicity, and inflammation) can independently or synergistically contribute to β cell dysfunction or loss. In these procedures, β cells may experience abnormal development, apoptosis, insufficient proliferation, dedifferentiation, and dysfunction with the consequence of overt diabetes [6,7,12–15]. The potential application of β cell-based treatment of diabetes by targeting TGF-β signaling is evaluated
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