Sodium-glucose cotransporter 2 inhibitors facilitate cell phenotype conversion of alpha cells through progenitors to beta cells by activating Ppargc1α in diabetic mice

BACKGROUND: Sodium-glucose cotransporter 2 inhibitor (SGLT2i) improves beta-cell function in animals and humans with diabetes. Herein, we aimed to investigate the effects of SGLT2i on beta-cell regeneration, trace the origin of regenerated beta cells, and reveal the potential mechanism. METHODS: Type 2 and type 1 diabetic mice were treated with canagliflozin (10 mg/kg), dapagliflozin (1 mg/kg), or vehicle. Islet morphology was evaluated to investigate beta-cell regeneration. Inducible pancreatic neurogenin 3 (Ngn3) + progenitor lineage-tracing mice and alpha-cell lineage-tracing mice were used to trace the origin of regenerated cells. Mouse and human islets, alpha cells, and beta cells were incubated with dapagliflozin (12.5 μmol/L) or vehicle. Insulin and glucagon-like peptide-1 (GLP-1) release, gene expression, and RNA sequencing analysis were performed to clarify the direct actions of SGLT2i and to screen potential targets. Alpha cells were transfected with peroxisome proliferator-activated receptor-γ coactivator 1α ( Ppargc1α ) plasmid or with Ppargc1α siRNA, followed by incubation with or without dapagliflozin to confirm the effects of Ppargc1α in alpha-cell phenotype conversion. RESULTS: SGLT2i increased islet and beta-cell areas in type 2 diabetic mice and showed a similar trend in type 1 diabetic mice. SGLT2i induced alpha-cell dedifferentiation into Ngn3 + progenitors and promoted progenitor differentiation toward beta cells. In cultured diabetic mouse and human islets and in stressed alpha cells, SGLT2i increased supernatant insulin and active GLP-1 levels, downregulated alpha-cell-specific marker expression, and upregulated the expression of endocrine progenitor- and beta-cell-specific markers, including prohormone convertase 1/3. Although dapagliflozin did not affect beta cells directly, it affected alpha cells (457 upregulated and 235 downregulated genes). Ppargc1α, a coactivator participating in oxidative phosphorylation, was identified as a potential target. By using overexpression and knockdown, we confirmed that Ppargc1α participated in SGLT2i-induced regulation of alpha-cell phenotype conversion. CONCLUSION: Alpha-cell regression to progenitors and progenitor differentiation toward beta cells represent a novel pathway for beta-cell neogenesis induced by SGLT2i in diabetes, with Ppargc1α playing a role in this process.