SIRT1 Activation Promotes β-Cell Regeneration by Activating Endocrine Progenitor Cells via AMPK Signaling-Mediated Fatty Acid Oxidation

Abstract Induction of β-cell regeneration from endogenous cells represents a highly promising strategy in stem cell-based treatment for patients with diabetes. Recently, calorie restriction has been shown to affect the regulation of tissue and cell regeneration, including β cells, via metabolic related mechanisms. Here, we examined the potential utility of sirtuin 1 (SIRT1), a calorie restriction mimetic, for stimulating β-cell regeneration and the underlying mechanisms of such stimulation. The present results showed that SIRT1 activation with SRT1720 promoted β-cell regeneration in streptozotocin (STZ)-induced β-cell-deficient neonatal rats. This beneficial effect involved enhanced activation of neurogenin3 (NGN3)-positive endocrine progenitors from pancreatic ductal cells, rather than an expansion of residual β cells. A dynamic expression profile of SIRT1 was observed in endocrine progenitors both during β-cell regeneration in neonatal rats and in the second transition phase of mouse pancreas development. Consistently, SRT1720 treatment upregulated endocrine progenitor differentiation in cultured pancreatic rudiments. Upregulation of NGN3 by SIRT1 activation was through stimulating AMP-activated protein kinase (AMPK) signaling-mediated fatty acid oxidation (FAO) in human pancreatic progenitor cells; AMPK inhibition abolished these effects. The present findings demonstrate a promotional effect of SIRT1 activation on β-cell restoration and endocrine progenitor differentiation that involves regulation of AMPK signaling-mediated FAO. Stem Cells 2019;37:1416–1428