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

Mar 12, 2024Diabetes

Gut bacteria and tryptophan metabolism linked to GLP-1 in helping insulin-producing cell growth triggered by Dapagliflozin

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Abstract

Dapagliflozin treatment in type 2 diabetic mice resulted in increased islet area and plasma insulin levels.

Blood glucose levels were lowered in db/db mice treated with dapagliflozin.
Dapagliflozin reshaped gut microbiota and altered metabolites related to tryptophan metabolism.
L-tryptophan increased the expression of genes associated with glucagon-like peptide 1 (GLP-1) production and enhanced GLP-1 secretion in cultured mouse intestinal cells.
Transplantation of fecal microbiota from dapagliflozin-treated mice or l-tryptophan supplementation promoted β-cell regeneration and increased insulin levels in db/db mice.
GLP-1 receptor antagonism diminished the beneficial effects of dapagliflozin on β-cell regeneration.

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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.

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

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