Emerging roles for the TGFβ family in pancreatic β-cell homeostasis

Abstract

Loss of functional β-cells is a primary mechanism of type 2 diabetes creating an acute need for understanding how β-cell number and function are regulated in adults under normal physiological conditions. Recent studies suggest a role for TGFβ family ligands in regulating β-cell function and glucose homeostasis. These ligands might influence β-cell proliferation and/or incorporation of new β-cells from progenitors in adults. Soluble antagonists of these ligands also appear to have important roles in regulating ligand activity to maintain homeostasis. These studies suggest that the coordinated activity of several TGFβ ligands might have important regulatory actions in adult β-cells and raise the possibility of developing new therapies for diabetes based on using agonists or antagonists of these ligands. TGFβ family, β-cells and diabetesThe recent obesity epidemic in the US and other developed countries has contributed to an increased incidence of insulin resistance and diabetes, resulting in a more urgent search for novel therapeutic approaches. Loss of β-cell number and/or function results in reduced ability to control blood glucose concentrations, hyperglycemia, and diabetes -a process often exacerbated by peripheral insulin resistance that requires ever increasing insulin output from remaining β-cells. Indeed, recent GWAS studies have identified a number of genetic polymorphisms associated with increased diabetes risk, the majority of which implicate genes important for proper β-cell function. [1][2][3]. The critical nature of functional β-cells to glucose control has focused research on finding new sources for β-cells for transplantation or on factors that can lead to enhanced β-cell function and/or mass. Recent studies suggest that several members of the TGFβ family of growth factors might fill this role under normal physiological conditions and thus, might also be exploited to develop new therapies for diabetes. Although these growth factors are most widely known for their critical roles in development and tissue specification [4], more recent evidence suggests they also mediate numerous actions in adults involving homeostatic control of normal physiological processes, as well as roles in pathology, such as cancer [5]. Although potential actions of some TGFβ family members in glucose regulation were suggested more than 20 years ago, a specific role for a subset of these ligands has been only recently described, including regulation of glucose homeostasis in peripheral tissues and modulation of β-cell function (Table 1).In this review, we examine data from both in vitro and in vivo approaches supporting a role for TGFβ family ligands in glucose homeostasis in adults. These actions of TGFβ family © 2010 Elsevier Ltd. All rights reserved.Corresponding Author: Schneyer, A. (alan.schneyer@bhs.org). This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting,...

Differential synthesis and action of TGFβ superfamily ligands in mouse and rat islets

“…Another contributing factor to the More recently, several members of this superfamily, including activin, TGFβ and BMP4 have been shown to modulate β-cell proliferation and/or function and thus glucose homeostasis in adults. 5,7,11,17,21 However, most of the in vivo studies utilize mouse models due to their accessibility for genetic modifications whereas most in vitro studies utilize rat and occasionally human islets to examine TGFβ ligand function. Thus, interpretation of the mechanisms whereby genetic manipulation of TGFβ family signaling in mice alters glucose metabolism, that is, whether the actions are direct on islets or indirect via peripheral tissues, depends on how closely the actions of this family are aligned among the two rodent species.…”

“…We included additional ligands, such as GDF11, BMP4 and BMP7 that had been shown through in vivo genetic studies to influence pancreatic development and/or regulate glucose homeostasis in mice. 5,6 Surprisingly, none of the tested TGFβ family ligands altered insulin secretion in mouse islets in low glucose, including those that were active on rat islets. (Fig.…”

“…4 A number of TGFβ superfamily members, including activins A and B, TGFβ1, GDF11 and BMP4, along with their receptors and Smad second messengers, have been identified in islets and/or β-cells. 5 Recent in vivo studies using genetically altered mice have identified roles for these ligands in regulating adult islet function and/or β-cell proliferation. 5,6 For example, genetic manipulations that blocked…”

“…5 Recent in vivo studies using genetically altered mice have identified roles for these ligands in regulating adult islet function and/or β-cell proliferation. 5,6 For example, genetic manipulations that blocked…”

ActivinB Is Induced in Insulinoma To Promote Tumor Plasticity through a β-Cell-Induced Dedifferentiation

“…Although activinA and activinB are expressed in pancreatic islets, their presence in ␤ cells is still debated (20)(21)(22). Nevertheless, transgenic mouse models have confirmed roles for these ligands in adult islets and in ␤-cell proliferation (23,24). Interestingly, activinA decreases the expression of mature ␤-cell genes, highlighting a possible contribution of activins to ␤-cell dedifferentiation and islet plasticity (25).…”