Emerging roles for the TGFbeta family in pancreatic beta-cell homeostasis

Abstract

Loss of functional beta-cells is the primary cause of type 2 diabetes, so that there is an acute need to understand how beta-cell number and function are regulated in the adult under normal physiological conditions. Recent studies suggest that members of the transforming growth factor (TGF)-beta family regulate beta-cell function and glucose homeostasis. These factors are also likely to influence beta-cell proliferation and/or the incorporation of new beta-cells from progenitors in adults. Soluble TGFbeta antagonists also appear to have important roles in maintaining homeostasis, and the coordinated activity of TGFbeta family members is likely to regulate the differentiation and function of adult beta-cells, raising the possibility of developing new diabetes therapies based on TGFbeta agonists or antagonists.

Figure 1

Schematic of TGFβ family signaling. (a) TGFβ and Activin form one subfamily that have separate receptors and antagonists, but common 2^nd messenger Smads. (b) BMPs form a second subfamily with their own receptors and antagonists, as well as a different set of 2^nd messengers. All receptor Smads dimerize with the common Smad (Smad4) and the complex translocates to the nucleus to alter gene transcription. MSTN, myostatin; LAP, latency protein; FST, follistatin; FSTL3, follistatin like-3; ALK, activin like kinase.

Figure 2

TGFβ family ligands and signaling pathways reported in islets. TGFβ family ligands representing members of both TGFβ/activin and BMP subfamilies that have been identified in islets are shown with their receptors, soluble inhibitors, second messengers, and inhibitory Smads. Whereas this family is known for promiscuity in receptor usage owing to the more than 40 members sharing 5 Type II and 7 Type I receptors, there are also differences within the subfamilies that allow some degree of specificity when analyzing genetic alterations in mouse models. For example, Smad7 overexpression inhibits all members of the TGFβ/activin subfamily but usually not members of the BMP subfamily. Follistatin and FSTL3 inhibit members of the activin branch of the TGFβ/activin subfamily but not TGFβ itself. Noggin inhibits BMP ligands but not activin or TGFβ. Despite these mouse models, the actions of individual ligands in regulating β-cell function and glucose homeostasis remain to be elucidated. Adapted from [4] with permission.