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

Abstract

Members of the TGFβ superfamily, including activins and TGFβ, modulate glucose-stimulated insulin secretion (GSIS) in vitro using rat islets while genetic manipulations that reduce TGFβ superfamily signaling in vivo in mice produced hypoplastic islets and/or hyperglycemia. Moreover, deletion of Fstl3, an antagonist of activin and myostatin, resulted in enlarged islets and β-cell hyperplasia. These studies suggest that endogenous TGFβ superfamily ligands regulate β-cell generation and/or function. To test this hypothesis, we examined endogenous TGFβ ligand synthesis and action in isolated rat and mouse islets. We found that activin A, TGFβ1, and myostatin treatment enhanced rat islet GSIS but none of the ligands tested enhanced GSIS in mouse islets. However, follistatin inhibited GSIS, consistent with a role for endogenous TGFβ superfamily ligands in regulating insulin secretion. Endogenous expression of TGF∆ superfamily members was different in rat and mouse islets with myostatin being highly expressed in mouse islets and not detectable in rats. These results indicate that TGFβ superfamily members directly regulate islet function in a species-specific manner while the ligands produced by islets differ between mice and rats. The lack of in vitro actions of ligands on mouse islets may be mechanical or result from species-specific actions of these ligands.