SGLT2 inhibition modulates metabolic, vascular, and inflammatory molecular markers in the kidney in youth with type 1 diabetes

Sodium-glucose cotransporter-2 (SGLT2) inhibitors slow diabetic kidney disease progression, but their intrarenal mechanisms remain incompletely understood, particularly in type 1 diabetes (T1D), where kidney protection has not been definitively established. ATTEMPT (NCT04333823) was a placebo-controlled trial in which 98 youth (ages 12 to 21) with T1D and hyperfiltration were randomized 1:1 to dapagliflozin (5 milligrams) or placebo for 16 weeks. Participants underwent sequential kidney biopsies, multiparametric kidney MRI, and plasma and urine proteomics. The sequential research kidney biopsies were performed on adults 18 years or older at one of three sites (baseline n = 16, follow-up n = 11). Single-cell RNA sequencing of 214,415 cells across 27 biopsies revealed coordinated transcriptional shifts across nephron, vascular, and immune compartments. In the proximal tubule, the primary site of SGLT2 expression, dapagliflozin down-regulated glycolysis, gluconeogenesis, and oxidative stress markers. Endothelial cells showed reduced profibrotic and inflammatory gene expression with increased protective factors. Podocytes demonstrated enhanced cytoskeletal reinforcement and suppressed interferon signaling. These molecular changes paralleled clinical improvements, including attenuation of hyperfiltration, improved glycemic control, and normalization of medullary oxygenation. Trajectory analyses revealed dapagliflozin shifted tubular cells from injury-prone toward healthier phenotypes. Cross-cohort comparison against healthy controls showed that more than 55% of dapagliflozin-responsive genes shifted toward healthy control expression patterns. Urine proteomics mirrored tissue changes with decreased injury markers and increased protective proteins. These convergent molecular mechanisms, metabolic reprogramming, dampened inflammation, and normalized oxygen handling provide hypothesis-generating mechanistic insights into potential kidney-protective mechanisms of SGLT2 inhibitor therapy in youth with T1D.

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Journal
Science Translational Medicine
Published
2026-07-22
DOI
https://doi.org/10.1126/scitranslmed.aee1005
Primary Topic
Chronic Kidney Disease and Diabetes
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article
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article

SGLT2 inhibition modulates metabolic, vascular, and inflammatory molecular markers in the kidney in youth with type 1 diabetes

Jenny E. Kanter, Pottumarthi V. Prasad, Kelly Street, Karin Bornfeldt et al.
Science Translational Medicine
Chronic Kidney Disease and Diabetes
article

SGLT2 inhibition modulates metabolic, vascular, and inflammatory molecular markers in the kidney in youth with type 1 diabetes

Jenny E. Kanter, Pottumarthi V. Prasad, Kelly Street, Karin Bornfeldt, Carissa Birznieks, Viji Nair, Jennifer A. Schaub, Fadhl Alakwaa, Phillip J. McCown, Hiddo J.L. Heerspink, Ye Ji Choi, Ian H. de Boer, Petter Bjornstad, Cathy Smith, Victor G. Puelles, Katherine R. Tuttle, Antoine Clarke, Farid H. Mahmud, Nan Hee Kim, Jesse A. Goodrich, Laura L. Pyle, Hailey Hampson, Edgar A. Otto, Jairo A Pinzón-Cortés, Long Yuan, Abhijit S. Naik, Kalie L. Tommerdahl, Matthias Kretzler, P.C. Ladd, Rajasree Menon, Tomáš Vaisar, Jeffrey B. Hodgin, Robert G. Nelson, Cheril Clarson, Sean Eddy, Sarah A. van Eeghen, Anil Karihaloo, MANINDERPAL SETHI, Kelly R. Bergmann, David Z. I. Cherney, Daniël H. van Raalte, Dylan Weissenkampen, Jacqueline Curtis, Lu-Ping Li, Yesmino Elia, Phoom Narongkiatikhun, Matteo D’Antonio, Shivani Ramesh
article en

Abstract

Sodium-glucose cotransporter-2 (SGLT2) inhibitors slow diabetic kidney disease progression, but their intrarenal mechanisms remain incompletely understood, particularly in type 1 diabetes (T1D), where kidney protection has not been definitively established. ATTEMPT (NCT04333823) was a placebo-controlled trial in which 98 youth (ages 12 to 21) with T1D and hyperfiltration were randomized 1:1 to dapagliflozin (5 milligrams) or placebo for 16 weeks. Participants underwent sequential kidney biopsies, multiparametric kidney MRI, and plasma and urine proteomics. The sequential research kidney biopsies were performed on adults 18 years or older at one of three sites (baseline n = 16, follow-up n = 11). Single-cell RNA sequencing of 214,415 cells across 27 biopsies revealed coordinated transcriptional shifts across nephron, vascular, and immune compartments. In the proximal tubule, the primary site of SGLT2 expression, dapagliflozin down-regulated glycolysis, gluconeogenesis, and oxidative stress markers. Endothelial cells showed reduced profibrotic and inflammatory gene expression with increased protective factors. Podocytes demonstrated enhanced cytoskeletal reinforcement and suppressed interferon signaling. These molecular changes paralleled clinical improvements, including attenuation of hyperfiltration, improved glycemic control, and normalization of medullary oxygenation. Trajectory analyses revealed dapagliflozin shifted tubular cells from injury-prone toward healthier phenotypes. Cross-cohort comparison against healthy controls showed that more than 55% of dapagliflozin-responsive genes shifted toward healthy control expression patterns. Urine proteomics mirrored tissue changes with decreased injury markers and increased protective proteins. These convergent molecular mechanisms, metabolic reprogramming, dampened inflammation, and normalized oxygen handling provide hypothesis-generating mechanistic insights into potential kidney-protective mechanisms of SGLT2 inhibitor therapy in youth with T1D.

Science Translational MedicineVol. 18(859)
University of Southern California (US), Joslin Diabetes Center (US), University Health Network (CA), Children’s Minnesota - St. Paul Hospital (US), University Medical Center Groningen (NL), Providence Regional Medical Center Everett (US), Johns Hopkins University (US), Universität Hamburg (DE), Novo Nordisk (Denmark) (DK), University of Washington (US), Aarhus University (DK), University of Michigan (US), Johns Hopkins Medicine (US), London Health Sciences Centre (CA), Hospital for Sick Children (CA), Inland Northwest Health Services (US), Aarhus University Hospital (DK), Ansan University (KR), Children's Hospital Colorado (US), Novo Nordisk (United States) (US), Amsterdam Neuroscience (NL), University Medical Center Hamburg-Eppendorf (DE), Seattle Children's Hospital (US), Michigan Medicine (US), Children's Minnesota (US), Hamburg Institut (Germany) (DE), Advanced Imaging Research (United States) (US), Chiang Mai University (TH), University of Colorado Anschutz Medical Campus (US), University of Amsterdam (NL), University of Colorado Denver (US), Providence Health & Services (US)
Good health and well-being
Openalex Percentile: Top 8%
Chronic Kidney Disease and Diabetes
DOISourceOpenAlex
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