Abstract: FR-PO0533
Single-Cell RNA Sequencing Dissociates the Kidney Transcriptional Signatures of Obesity and Type 1 Diabetes in Young Persons, Potentially Supporting Combined Glycemic and Adiposity-Directed Therapy
Session Information
- CKM: Clinical - Trials, Epidemiology, and Biomarkers
October 23, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Cardiovascular-Kidney-Metabolic Health
- 602 Cardiovascular-Kidney-Metabolic Health: Clinical
Authors
- Choi, Ye Ji, University of Washington, Seattle, Washington, United States
- Leidholt, Savanah L., University of Washington, Seattle, Washington, United States
- Tommerdahl, Kalie L., University of Washington, Seattle, Washington, United States
- Goodrich, Jesse Allen, University of California Los Angeles, Los Angeles, California, United States
- Nelson, Robert G., University of Washington, Seattle, Washington, United States
- Miller, Kristen, University of Washington, Seattle, Washington, United States
- Ramesh, Shivani, University of Washington, Seattle, Washington, United States
- D'Antonio, Matteo, University of Washington, Seattle, Washington, United States
- Schaub, Jennifer A., University of Michigan, Ann Arbor, Michigan, United States
- Hodgin, Jeffrey B., University of Michigan, Ann Arbor, Michigan, United States
- Menon, Rajasree, University of Michigan, Ann Arbor, Michigan, United States
- McCown, Phillip J., University of Michigan, Ann Arbor, Michigan, United States
- Eddy, Sean, University of Michigan, Ann Arbor, Michigan, United States
- Alakwaa, Fadhl, University of Michigan, Ann Arbor, Michigan, United States
- Nair, Viji, University of Michigan, Ann Arbor, Michigan, United States
- Naik, Abhijit S., University of Michigan, Ann Arbor, Michigan, United States
- Otto, Edgar A., University of Michigan, Ann Arbor, Michigan, United States
- Weissenkampen, James Dylan, University of Washington, Seattle, Washington, United States
- Smith, Cathy, University of Michigan, Ann Arbor, Michigan, United States
- Brosius, Chip, The University of Arizona College of Science, Tucson, Arizona, United States
- Karihaloo, Anil K., Novo Nordisk, Lexington, Massachusetts, United States
- Pyle, Laura, University of Washington, Seattle, Washington, United States
- de Boer, Ian, University of Washington, Seattle, Washington, United States
- Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
- Bjornstad, Petter, University of Washington, Seattle, Washington, United States
Background
Obesity is increasingly prevalent in young persons with type 1 diabetes (T1D) and associates with accelerated kidney disease, but whether obesity acts through distinct mechanisms or amplifies T1D-driven kidney injury is unclear.
Methods
We performed single-cell RNA sequencing on kidney biopsies from young persons with T1D and healthy controls (HC). Participants were categorized by BMI/BMI%ile as normal-weight (NW), overweight (OW), and obese (OB). Differential expression was computed per cell-type using negative binomial mixed models with two contrasts: T1D-NW vs HC (T1D-contrast) and T1D-OB+OW vs T1D-NW (adiposity-contrast). GSEA and effect-size concordance classified signals as T1D-specific, adiposity-specific, amplified, or reversed across proximal tubule, thick ascending limb, principal cells, intercalated cells, endothelial cells, and immune cells.
Results
Participants included 49 with T1D (22 NW/22 OW/5 OB) and 12 HC; mean age 23.4±3.3 years; 59% female. Across all cell-types, 98% of significant transcriptional perturbations uniquely associated with either T1D or adiposity, but not both. Adiposity-contrast GSEA showed suppressed oxidative phosphorylation (NES -2.6 to -3.5; padj <0.001 across four cell-types), myelocytomatosis (MYC) targets, mTORC1 signaling, DNA repair, and adipogenesis. The T1D-contrast was dominated by elevated interferon-α and -γ responses (NES +1.8 to +3.1; padj <0.001 across all cell-types), with inflammatory response and complement enrichment in immune cells. Several inflammatory pathways were elevated in the T1D-contrast but suppressed in the adiposity-contrast, including MYC targets which was fully restored to HC levels in immune cells, while IFN-α/γ signaling in endothelial cells was only partially restored.
Conclusion
Obesity in T1D youth drives kidney transcriptional programs largely independent of T1D-mediated injury, predominantly bioenergetic suppression in tubular and endothelial cells. Findings support adjunctive anti-obesity therapies alongside insulin-focused glycemic management.