Sodium-glucose co-transporter 2 (SGLT2) inhibitor, an efficacious anti-diabetic agent, which has cardiovascular and renal benefits, can promote pancreatic β-cell regeneration in type 2 diabetic mice. However, the underlying mechanism remains unclear. In this study, we aimed to use multi-omics to identify the mediators involved in β-cell regeneration induced by dapagliflozin. We showed that dapagliflozin lowered blood glucose level, upregulated plasma insulin level, and increased islet area in db/db mice. Dapagliflozin reshaped gut microbiota, and modulated microbiotic and plasmatic metabolites related to tryptophan metabolism, especially L-tryptophan, in the diabetic mice. Notably, L-tryptophan upregulated the mRNA level of GLP-1 production-related genes (Gcg and Pcsk1) expression and promoted GLP-1 secretion in cultured mouse intestinal L-cells, and it increased supernatant insulin level in primary human islets, which was eliminated by GPR142 antagonist. Transplantation of fecal microbiota from dapagliflozin-treated mice, supplementation of L-tryptophan or treatment with dapagliflozin upregulated L-tryptophan, GLP-1, and insulin or C-peptide level, and promoted β-cell regeneration in db/db mice. Addition of exendin 9-39, a GLP-1 receptor (GLP-1R) antagonist, or pancreatic Glp1r knockout diminished these beneficial effects. In summary, treatment with dapagliflozin in type 2 diabetic mice promotes β-cell regeneration by upregulating GLP-1 production, which is mediated via gut microbiota and tryptophan metabolism.

This article contains supplementary material online at https://doi.org/10.2337/figshare.25375459.

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