SAD-A, a downstream mediator of GLP-1 signaling, promotes the phosphorylation of Bad S155 to regulate in vitro β-cell functions.

Abstract The incretin hormone GLP-1 reduces β-cell failure in patients with type 2 diabetes. Previous studies demonstrated that GLP-1 activates SAD-A, a member of the AMPK family, to regulate glucose-stimulated secretion (GSIS), but the underlying mechanisms of SAD-A regulation of β-cell functions remain poorly understood. Here, we propose that activation of SAD-A by GLP-1 promotes the phosphorylation of Bad S155, which in turn positively affects GSIS and β-cell survival. Bad therefore appears to be a downstream molecule of a SAD-A pathway that mediates the GLP-1-triggered reduction in β-cell failure. Knockdown of endogenous SAD-A expression significantly exacerbated in vitro β-cell dysfunction under lipotoxic conditions and promoted lipotoxicity-induced apoptosis, whereas overexpression of SAD-A inhibited β-cell apoptosis. SAD-A silencing increased ER stress and inhibited the autophagic flux, which contributed to β-cell apoptosis. Thus, SAD-A appears to function as a downstream molecule of GLP-1 signaling that results in Bad S155 phosphorylation. This phosphorylation might therefore be involved in the GLP-1-linked protection against β-cell dysfunction and apoptosis. Highlights • SAD-A is activated by the incretin hormone GLP-1 in pancreatic β-cell. • SAD-A promotes the phosphorylation of Bad S155. • SAD-A regulates the GSIS of β-cell. • SAD-A mediates the lipotoxicity-induced β-cell apoptosis. [ABSTRACT FROM AUTHOR]