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

Members of the TGF beta syperfamily, including activins and TGF beta, modulate glucose-stimulated insulin secretion (GSIS) in vitro using rat islets while genetic manipulations that reduce TGF beta 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 beta-cell hyperplasia. These studies suggest that endogenous TGF beta superfamily ligands regulate beta-cell generation and/or function. To test this hypothesis, we examined endogenous TGF beta ligand synthesis and action in isolated rat and mouse islets. We found that activin A, TGF beta 1, 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 TGF beta superfamily ligands in regulating insulin secretion. Endogenous expression of TGF beta 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 TGF beta 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.