Gut Microbiota-Tryptophan Metabolism-GLP-1 Axis Participates in ß-Cell Regeneration Induced by Dapagliflozin.
Diabetes
; 73(6): 926-940, 2024 Jun 01.
Article
em En
| MEDLINE
| ID: mdl-38471012
ABSTRACT
Sodium-glucose cotransporter 2 inhibitors, efficacious antidiabetic agents that have cardiovascular and renal benefits, can promote pancreatic ß-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 ß-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 ß-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 ß-cell regeneration by upregulating GLP-1 production, which is mediated via gut microbiota and tryptophan metabolism.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Regeneração
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Triptofano
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Compostos Benzidrílicos
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Células Secretoras de Insulina
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Peptídeo 1 Semelhante ao Glucagon
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Microbioma Gastrointestinal
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Glucosídeos
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Diabetes
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China
País de publicação:
Estados Unidos