Gut Microbiota−Tryptophan Metabolism−GLP-1 Axis Participates in β-Cell Regeneration Induced by Dapagliflozin

Abstract

Sodium–glucose cotransporter 2 inhibitors, efficacious antidiabetic agents that have 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 multiomics 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 glucagon-like peptide 1 (GLP-1) production–related gene ( Gcg and Pcsk1) expression and promoted GLP-1 secretion in cultured mouse intestinal L cells, and it increased the supernatant insulin level in primary human islets, which was eliminated by GPR142 antagonist. Transplant 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 levels 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.

Article Highlights

• Sodium–glucose cotransporter 2 inhibitors, novel and efficacious antidiabetic agents, can preserve β-cell mass in type 2 diabetic animals, but the mechanism remains unclear.

• We find that dapagliflozin reshapes gut microbiota, improves microbiotic and plasmatic metabolites related to tryptophan metabolism, and increases glucagon-like peptide 1 (GLP-1) production mediated via tryptophan metabolism. GLP-1−GLP-1 receptor signaling participates in the dapagliflozin-induced β-cell regeneration.

• Our study reveals that the gut microbiota–tryptophan metabolism–GLP-1 axis is a novel mechanism of β-cell regeneration induced by dapagliflozin and provides experimental evidence for its β-cell protection in treating type 2 diabetes.

Graphical Abstract