Attenuated kidney oxidative metabolism in young adults with type 1 diabetes

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Abstract

BACKGROUND In type 1 diabetes (T1D), impaired insulin sensitivity may contribute to the development of diabetic kidney disease (DKD) through alterations in kidney oxidative metabolism.METHODS Young adults with T1D (n = 30) and healthy controls (HCs) (n = 20) underwent hyperinsulinemic-euglycemic clamp studies, MRI, 11C-acetate PET, kidney biopsies, single-cell RNA-Seq, and spatial metabolomics to assess this relationship.RESULTS Participants with T1D had significantly higher glomerular basement membrane (GBM) thickness compared with HCs. T1D participants exhibited lower insulin sensitivity and cortical oxidative metabolism, correlating with higher insulin sensitivity. Proximal tubular transcripts of TCA cycle and oxidative phosphorylation enzymes were lower in T1D. Spatial metabolomics showed reductions in tubular TCA cycle intermediates, indicating mitochondrial dysfunction. The Slingshot algorithm identified a lineage of proximal tubular cells progressing from stable to adaptive/maladaptive subtypes, using pseudotime trajectory analysis, which computationally orders cells along a continuum of states. This analysis revealed distinct distribution patterns between T1D and HCs, with attenuated oxidative metabolism in T1D attributed to a greater proportion of adaptive/maladaptive subtypes with low expression of TCA cycle and oxidative phosphorylation transcripts. Pseudotime progression associated with higher HbA1c, BMI, and GBM, and lower insulin sensitivity and cortical oxidative metabolism.CONCLUSION These early structural and metabolic changes in T1D kidneys may precede clinical DKD.TRIAL REGISTRATION ClinicalTrials.gov NCT04074668.FUNDING University of Michigan O’Brien Kidney Translational Core Center grant (P30 DK081943); CROCODILE studies by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (P30 DK116073), Juvenile Diabetes Research Foundation (JDRF) (2-SRA-2019-845-S-B), Boettcher Foundation, Intramural Research Program at NIDDK and Centers for Disease Control and Prevention (CKD Initiative) under Inter-Agency Agreement #21FED2100157DPG.

Authors

Ye Ji Choi, Gabriel Richard, Guanshi Zhang, Jeffrey B. Hodgin, Dawit S. Demeke, Yingbao Yang, Jennifer A. Schaub, Ian M. Tamayo, Bhupendra K. Gurung, Abhijit S. Naik, Viji Nair, Carissa Birznieks, Alexis MacDonald, Phoom Narongkiatikhun, Susan Gross, Lynette Driscoll, Maureen Flynn, Kalie Tommerdahl, Kristen J. Nadeau, Viral N. Shah, Tim Vigers, Janet K. Snell-Bergeon, Jessica Kendrick, Daniel H. van Raalte, Lu-Ping Li, Pottumarthi Prasad, Patricia Ladd, Bennett B. Chin, David Z. Cherney, Phillip J. McCown, Fadhl Alakwaa, Edgar A. Otto, Frank C. Brosius, Pierre Jean Saulnier, Victor G. Puelles, Jesse A. Goodrich, Kelly Street, Manjeri A. Venkatachalam, Aaron Ruiz, Ian H. de Boer, Robert G. Nelson, Laura Pyle, Denis P. Blondin, Kumar Sharma, Matthias Kretzler, Petter Bjornstad