American Diabetes Association
DB 230553_Supplementary Materials-proofed[AU].pdf (3.37 MB)

Gut microbiota-tryptophan metabolism-GLP-1 axis participates in β-cell regeneration induced by dapagliflozin

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Version 2 2024-05-23, 15:19
Version 1 2024-03-12, 18:48
posted on 2024-05-23, 15:19 authored by Yafei Jiang, Jin Yang, Li Xia, Tianjiao Wei, Xiaona Cui, Dandan Wang, Zirun Jin, Xiafang Lin, Fei Li, Kun Yang, Shan Lang, Ye Liu, Jing Hang, Zhe Zhang, Tianpei Hong, Rui Wei

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 work was supported by the special fund of the National Clinical Key Specialty Construction Program, P. R. China (2023), the National Natural Science Foundation of China (82270843, 82170875, 82070319, 82100885, 82200908 and 82271611), the Natural Science Foundation of Beijing (7232198 and 7222216), Clinical Medicine Plus X-Young Scholars Project of Peking University (PKU2023LCXQ025), Talent Project of Clinical Key Project of Peking University Third Hospital and Tianjin Municipal Human Resources and Social Security Bureau (XB202011). The funding sources had no role in study design, collection, analysis and interpretation of data, writing of the report, and decision to submit the article for publication.


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