SGLT2 inhibitors mitigate kidney tubular metabolic and mTORC1 perturbations in youth onset type 2 diabetes
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PROVIDER: PRJNA912118 | ENA |
REPOSITORIES: ENA
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Project description:Single cell RNA-sequencing analysis allows for a more complete cell-by-cell analysis of the effects of SGLT2 inhibitors on the kidneys of patients with youth onset type 2 diabetes.
2023-01-19 | GSE220939 | GEO
Project description:The molecular mechanisms of sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) remain incompletely understood. Single-cell RNA sequencing and morphometric data were collected from research kidney biopsies donated by young persons with type 2 diabetes (T2D), aged 12 to 21 years, and healthy controls (HCs). Participants with T2D were obese and had higher estimated glomerular filtration rates and mesangial and glomerular volumes than HCs. Ten T2D participants had been prescribed SGLT2i (T2Di[+]) and 6 not (T2Di[-]). Transcriptional profiles showed SGLT2 expression exclusively in the proximal tubular (PT) cluster with highest expression in T2Di(-) patients. However, transcriptional alterations with SGLT2i treatment were seen across nephron segments, particularly in the distal nephron. SGLT2i treatment was associated with suppression of transcripts in the glycolysis, gluconeogenesis, and tricarboxylic acid cycle pathways in PT, but had the opposite effect in thick ascending limb. Transcripts in the energy-sensitive mTORC1-signaling pathway returned toward HC levels in all tubular segments in T2Di(+), consistent with a diabetes mouse model treated with SGLT2i. Decreased levels of phosphorylated S6 protein in proximal and distal tubules in T2Di(+) patients confirmed changes in mTORC1 pathway activity. We propose that SGLT2i treatment benefits the kidneys by mitigating diabetes-induced metabolic perturbations via suppression of mTORC1 signaling in kidney tubules.
| S-EPMC9974101 | biostudies-literature
Project description:Sodium-glucose cotransporter-2 (SGLT2) inhibitors slow progression of diabetic kidney disease, but their intrarenal mechanisms remain unclear, particularly in patients with type 1 diabetes (T1D). In a prespecified ancillary study within the placebo-controlled ATTEMPT trial of dapagliflozin in youth with T1D and well-preserved kidney function (N=98), we integrated sequential kidney biopsies, multiparametric kidney MRI, and proteomics. Single-cell RNA-seq of N=16 baseline and N=11 16-week follow-up biopsies (N=27; 214,415 cells) revealed a coordinated network of metabolic, fibrotic, and inflammatory transcriptional changes across nephron, vascular, and immune compartments. These gene shifts paralleled attenuation of hyperfiltration and improvement in glycemic control (HbA1c and time-in-range), implicating 594 transcripts. MRI indicated a reversal of the medullary hyperoxia characteristic of T1D with dapagliflozin. Urine proteomic profiles echoed the transcriptomic patterns. Together, these multimodal data point to metabolic reprogramming, reduced inflammation, and improved oxygen handling as convergent mechanisms of SGLT2-mediated kidney protection. ClinicalTrials.gov: NCT04333823.
2026-03-12 | GSE316742 | GEO
Project description:Background Youth with type 2 diabetes (T2D) and severe obesity face high risk of diabetic kidney disease, which metabolic bariatric surgery (MBS) can mitigate. This study explores structural and molecular changes in kidneys after vertical sleeve gastrectomy (VSG), a form of MBS. Methods Paired analyses, including metabolic profiling, kidney volume assessment, histological evaluation, and single-cell RNA sequencing (scRNAseq) on kidney biopsies from five youth with T2D and obesity pre- and 12 months post-VSG in the IMPROVE-T2D (Impact of Metabolic surgery on Pancreatic, Renal and cardiOVascular hEalth in youth with T2D) cohort. Circulating proteomics with kidney transcriptomics, were linked using data from an independent cohort of youth with obesity, with or without T2D, undergoing MBS in Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS, n=64). Results Post-VSG, participants lost weight and had improvements in insulin sensitivity and metabolic parameters. Kidney changes included reduced renal hyperfiltration, total kidney volume, mesangial matrix area, and microalbuminuria. scRNAseq in proximal tubule (PT) and thick ascending limb cells indicated repression of glycolysis, gluconeogenesis, and tricarboxylic acid cycle genes, with upregulation of AMP-activated protein kinase (AMPK) and Forkhead box O3 (FOXO3). Decreased metabolic signaling aligned with reduced ribosomal phosphorylated S6K (pS6K), suggesting attenuated mTORC1 activity. JAK-STAT pathway activation in PT was diminished, correlating with lower circulating ligands from Teen-LABS proteomic data. Conclusion MBS/VSG prompts kidney molecular adaptations, providing potential targets for non-surgical interventions against obesity- and diabetes-associated kidney disease.
2026-01-09 | GSE315877 | GEO
Project description:SGLT2 inhibition reverses metabolic and inflammatory kidney signatures in youth with type 1 diabetes
| PRJNA1404116 | ENA
Project description:Effects of SGLT2 inhibitors on gene expression were evaluated in two independent human proximal tubular cell lines using microarray hybridization analysis followed by pathway analysis as well as qPCR- and ELISA-based verification on mRNA and protein level
2019-01-04 | GSE118337 | GEO
Project description:The CANVAS program revealed that the SGLT2 inhibitor canagliflozin increases the risk for lower-limb (minor) amputations in type 2 diabetics about a two-fold. On the contrary, the large RCTs with empagliflozin and dapagliflozin did not demonstrate a similar observation. Thus, a question arises whether the increased risk for minor amputations is associated only with canagliflozin or whether it is a class effect of SGLT2 inhibitors. Vascular disorders including defective angiogenesis are among the leading causes of lower-limb amputations. Therefore, here we examined the effects of empagliflozin, dapagliflozin, and canagliflozin on angiogenesis using zebrafish embryos and HUVECs.
2022-12-31 | GSE191046 | GEO
Project description:SGLT2 inhibitors and zebrafish
| PRJNA789531 | ENA
Project description:Protective effects of SGLT2 inhibitors in human proximal tubular cells
| PRJNA485256 | ENA
Project description:The specific mechanism of sodium-glucose cotransporter 2 (SGLT2) inhibitor in heart failure (HF) needs to be elucidated. In this study, we use SGLT2 global knockout (SGLT2-KO) mice to assess the mechanism of SGLT2 inhibitor on HF. Dapagliflozin ameliorates both myocardial infarction (MI)-and transverse aortic constriction (TAC) -induced HF. Global SGLT2-deficiency doesn’t exert protection against adverse remodeling in both MI- and TAC-induced HF models. Dapagliflozin blurs MI- and TAC-induced HF phenotypes in SGLT2-KO mice. Dapagliflozin causes major changes in cardiac fibrosis and inflammation. Based on single-cell RNA sequencing dapagliflozin causes significant differences in the gene expression profile of macrophages and fibroblasts. Moreover, dapagliflozin directly inhibites macrophage inflammation, thereby suppressing cardiac fibroblasts activation. The cardio-protection of dapagliflozin is blurred in mice treated with a C-C chemokine receptor type 2 (CCR2) antagonist. Taken together the protective effects of dapagliflozin against HF are independent of SGLT2, macrophage inhibition is the main target of dapagliflozin against HF.
2023-11-14 | GSE247062 | GEO