Multimodal Kidney Mechanisms of SGLT2 Inhibition in Patients with Type 1 Diabetes

Résumé fourni par la source

Background: SGLT2 inhibitors slow chronic kidney disease progression, but intrarenal mechanisms in type 1 diabetes (T1D) remain unclear. Methods: Single-cell RNA-seq (scRNA-seq) from paired kidney biopsies (subcohort, Fig.) and multiparametric kidney MRI (BOLD R2*) were obtained at baseline and after 16 weeks of treatment with dapagliflozin (dapa) or placebo in youth with T1D and preserved kidney function in a pre-specified ancillary study of the ATTEMPT trial (N=98). Transcriptomic effects were tested with negative binomial mixed models (NBMM) with fixed effects of treatment, visit, their interaction, and within-subject correlation, with FDR<0.05. Transcript changes were regressed against changes in iohexol mGFR, HbA1c and time-in-range (TIR), adjusting for treatment effects within each cell type. An independent external cohort of youth with T1D and healthy controls was used to test whether dapa-responsive transcripts shifted toward healthy-control levels. Results: Dapa reduced GFR, lowered HbA1c, and increased TIR, as previously published. MRI showed increased whole-kidney R2* (p=0.03), consistent with reversal of diabetic medullary hyperoxia (p<0.001). scRNA-seq from 27 biopsies (~214k cells) revealed placebo-controlled shifts across nephron segments, especially PT, TAL, EC, IC, and POD (q<0.001; Fig.). Pseudotime trajectories indicated a shift from stress-prone PT toward healthier PT states. In the external T1D cohort, ~55% of shared significant dapa-responsive transcripts moved toward healthy-control levels. Conclusion: SGLT2 inhibition engages convergent kidney mechanisms in T1D including metabolic reprogramming, vascular quiescence, improved oxygen handling, and acid–base adaptation, providing causal, multimodal evidence for mechanisms underlying kidney protection. Funding: Private Foundation Support

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