What question did this study set out to answer?

This study aims to identify sex-differential gene expression in proximal tubule cells of young adults with type 2 diabetes.

June 7, 2026

1380-P: Sex Differences in Proximal Tubule Cell Metabolism in Type 2 Diabetes: A Single-Cell Transcriptomic Analysis

Key Points

This study aims to identify sex-differential gene expression in proximal tubule cells of young adults with type 2 diabetes.
Single-cell RNA-sequencing on kidney biopsies from participants with type 2 diabetes (n=13,534 proximal tubule cells)
Analysis of sex-differential expression using NEBULA mixed-effects modeling
Gene Set Enrichment Analysis (GSEA) to identify molecular functions, biological processes, and cellular components.
Males had a significantly higher proportion of adaptive proximal tubule cells compared to females
GSEA revealed female-enriched pathways primarily linked to mitochondrial metabolism
Enhanced electron transport and oxidative phosphorylation observed in female proximal tubule cells.

Abstract

Introduction and Objective: Sex differences in diabetic kidney disease (DKD) are well-established, yet underlying molecular mechanisms remain unclear. We investigated sex-differential gene expression in proximal tubule (PT) cells, the primary site of glucose reabsorption and a driver of DKD pathogenesis, from young adults with T2D to identify pathways contributing to differential disease susceptibility. Methods: Single-cell RNA-sequencing was performed on research kidney biopsies from participants with T2D (A). Analysis focused on PT cells (n=13,534; B), with sex-differential expression analyzed using NEBULA mixed-effects modeling. Gene Set Enrichment Analysis (GSEA) was performed to identify sex-differential molecular functions (MF), biological processes (BP), and cellular components (CC). Normalized Enrichment Scores (NES) with negative values indicate female-enriched pathways; positive values indicate male-enriched pathways. Results: Males had a significantly higher adaptive PT proportion than females (B). GSEA revealed extensive sex dimorphism, with female-enriched pathways predominantly related to mitochondrial metabolism (D, E). Conclusion: PT cells in T2D exhibit pronounced sex differences in mitochondrial metabolism, with females showing enhanced electron transport and oxidative phosphorylation. This mitochondrial signature may represent a protective metabolic program contributing to known sex differences in DKD progression. Disclosure J.D. Weissenkampen: None. Y. Choi: None. H. Hampson: None. M. D'Antonio: None. S. Ramesh: None. M. Sethi: None. K. Tommerdahl: Advisory Panel; Current; Sanofi. J.A. Schaub: Consultant; Ended; Klick. L. Pyle: None. D. van Raalte: Consultant; Current; AstraZeneca. Research Support; Current; AstraZeneca. Consultant; Current; Boehringer Ingelheim International GmbH. Research Support; Current; Boehringer Ingelheim International GmbH. Consultant; Current; Eli Lilly and Company. Research Support; Current; Eli Lilly and Company. Consultant; Current; Merck Current; Merck Current; Novo Nordisk. Research Support; Current; Novo Nordisk. P. Bjornstad: Consultant; Current; Bayer AG, Boehringer Ingelheim International GmbH, Lilly, Novo Nordisk. Funding American Diabetes Association (7-23-ICTST2DY-08; 7-23-ICTST2DY-01); K23 DK116720

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