Abstract: TH-PO1205
Multimodal Kidney Mechanisms of SGLT2 Inhibition in Patients with Type 1 Diabetes
Session Information
- Late-Breaking Research Posters
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Choi, Ye Ji, University of Washington, Seattle, Washington, United States
- Bjornstad, Petter, University of Washington, Seattle, Washington, United States
- Narongkiatikhun, Phoom, University of Washington, Seattle, Washington, United States
- Karihaloo, Anil K., Novo Nordisk A/S, Bagsværd, Capital Region of Denmark, Denmark
- Prasad, Pottumarthi V., NorthShore University HealthSystem Research Institute, Evanston, Illinois, United States
- Li, Luping, NorthShore University HealthSystem Research Institute, Evanston, Illinois, United States
- Tommerdahl, Kalie L., University of Washington, Seattle, Washington, United States
- Hodgin, Jeffrey B., University of Michigan, Ann Arbor, Michigan, United States
- Clarke, Antoine, The Hospital for Sick Children, Toronto, Ontario, Canada
- Clarson, Cheril L, London Health Sciences Centre Children's Hospital, London, Ontario, Canada
- Ladd, Patricia E., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- van Raalte, Daniël H., Amsterdam UMC Locatie AMC, Amsterdam, NH, Netherlands
- Heerspink, Hiddo Jan L., Rijksuniversiteit Groningen, Groningen, GR, Netherlands
- Kim, Nan Hee, Korea University Ansan Hospital, Ansan-si, Gyeonggi-do, Korea (the Republic of)
- Nelson, Robert G., University of Washington, Seattle, Washington, United States
- Puelles, Victor G., Aarhus Universitet, Aarhus, Central Denmark Region , Denmark
- Cherney, David, University of Toronto, Toronto, Ontario, Canada
- Pyle, Laura, University of Washington, Seattle, Washington, United States
- Mahmud, Farid H., The Hospital for Sick Children, Toronto, Ontario, Canada
- Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
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