TGF-β Signaling in Pancreatic Islet β Cell Development and Function

Abstract

Pancreatic islet beta cells (β-cells) synthesize and secrete insulin in response to rising glucose levels and thus are a prime target in both major forms of diabetes. Type 1 diabetes ensues due to autoimmune destruction of β-cells. On the other hand, the prevailing insulin resistance and hyperglycemia in type 2 diabetes (T2D) elicits a compensatory response from β-cells that involves increases in β-cell mass and function. However, the sustained metabolic stress results in β-cell failure, characterized by severe β-cell dysfunction and loss of β-cell mass. Dynamic changes to β-cell mass also occur during pancreatic development that involves extensive growth and morphogenesis. These orchestrated events are triggered by multiple signaling pathways, including those representing the transforming growth factor β (TGF-β) superfamily. TGF-β pathway ligands play important roles during endocrine pancreas development, β-cell proliferation, differentiation, and apoptosis. Furthermore, new findings are suggestive of TGF-β's role in regulation of adult β-cell mass and function. Collectively, these findings support the therapeutic utility of targeting TGF-β in diabetes. Summarizing the role of the various TGF-β pathway ligands in β-cell development, growth and function in normal physiology, and during diabetes pathogenesis is the topic of this mini-review.

Keywords: TGF-β; development; diabetes; function; islets; pancreas; β cells.

Figure 1.

Presumptive role of the TGF-β superfamily in pancreas organogenesis and lineage specification. At E8.5 (rodent)/CS9 (human) signals from the notochord, including activin, initiate development of pancreatic buds. BMP signals reportedly exert both negative (dashed, red line) and positive (solid green arrow) effects on pancreatic development. Initial pancreatic bud outgrowth occurs between E9-E9.5/CS13. Around E12.5/CS19, multipotent “tip” and “trunk” domains get established. During the secondary transition (E12.5/CS20 and later), the “tip” domain gives rise to exocrine acinar cells, whereas the “trunk” domain gives rise to duct and endocrine cells. TGF-β1 and activin promote endocrine differentiation and repress exocrine differentiation. Follistatin, an antagonist of activin, promotes exocrine cell differentiation and reduces differentiation of endocrine cells. Established interactions between molecules are indicated by solid lines with green arrows indicating positive regulation and red dash lines indicating negative regulation.

Figure 2.

Schematic of in vitro differentiation from hPSC into INS+ cells. Timeline indicates days in culture to progress through the different stages of differentiation when cultured in the presence of TGF-β signaling ligands (activin) and inhibitors (SB431542 or ALK5i).