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.

中文翻译：

---

肠道菌群-色氨酸代谢-GLP-1轴参与达格列净诱导的β细胞再生

钠-葡萄糖协同转运蛋白 2 (SGLT2) 抑制剂是一种有效的抗糖尿病药物，具有心血管和肾脏益处，可以促进 2 型糖尿病小鼠的胰腺 β 细胞再生。然而，其根本机制仍不清楚。在本研究中，我们旨在利用多组学来鉴定参与达格列净诱导的 β 细胞再生的介质。我们发现达格列净可降低 db/db 小鼠的血糖水平、上调血浆胰岛素水平并增加胰岛面积。达格列净重塑了糖尿病小鼠的肠道微生物群，并调节了与色氨酸代谢相关的微生物和血浆代谢物，尤其是 L-色氨酸。值得注意的是，L-色氨酸上调了 GLP-1 产生相关基因（Gcg 和 Pcsk1）表达的 mRNA 水平，促进了培养的小鼠肠道 L 细胞中的 GLP-1 分泌，并且增加了原代人胰岛中的上清液胰岛素水平，这是被 GPR142 拮抗剂消除。移植达格列净治疗小鼠的粪便微生物群、补充 L-色氨酸或用达格列净治疗上调了 db/db 小鼠的 L-色氨酸、GLP-1 和胰岛素或 C 肽水平，并促进了 β 细胞再生。添加 Exendin 9-39（一种 GLP-1 受体 (GLP-1R) 拮抗剂）或胰腺 Glp1r 敲除会减弱这些有益效果。总之，达格列净治疗 2 型糖尿病小鼠可通过上调 GLP-1 的产生来促进 β 细胞再生，而 GLP-1 的产生是通过肠道微生物群和色氨酸代谢介导的。