Introduction & Objective: Renal hypermetabolism in youth-onset T2D presents a critical area of study due to potential metabolic implications. Prior kidney biopsy research indicated upregulated metabolic pathways, such as the TCA cycle and oxidative phosphorylation, in the proximal tubules of patients with T2D. However, the functional impact of these transcriptomic changes remains unclear. This study aims to evaluate oxidative metabolism in youth with obesity and T2D, and its clinical implications, using C-11 acetate PET scans.

Methods: This study involved 18 youths with obesity and T2D, and 11 normal weight controls (NWC). We employed C-11 acetate PET scans to measure cortical and medullary oxidative rates (k2), and cortical perfusion (F). Statistical analyses focused on comparing these rates between the two groups, along with spearman correlations between oxidative rates and urinary albumin-to-creatinine ratio (UACR).

Results: Youths with obesity and T2D exhibited significantly higher cortical (0.21 [0.15, 0.34] vs. 0.17 [0.14, 0.22] min-1, p=0.002) and medullary (0.20 [0.16, 0.35] vs. 0.14 [0.11, 0.18] min-1, p<0.0001) oxidative rates compared to NWC. Cortical perfusion was lower in the T2D group, but medullary perfusion did not differ significantly. The ratio of cortical and medullary K2/F was higher in T2D, indicating a metabolic mismatch. Additionally, higher oxidative rate (k2) and cortical k2/F ratio correlated with UACR (r: 0.41, p=0.038; r: 0.47, p=0.014, respectively).

Conclusion: The study demonstrates a pronounced elevation in oxidative metabolism and a notable mismatch between oxidative metabolism and perfusion in youths with obesity and T2D, compared to NWC. This is associated with increased albuminuria. These findings corroborate the transcriptional changes observed in kidney biopsies, particularly in the transcripts of TCA and oxidative phosphorylation, underscoring the functional relevance of these molecular alterations.

Disclosure

M. Leroux: None. Y. Choi: None. N. Nguyen: None. L. Pyle: None. K.L. Tommerdahl: None. G. Richard: Research Support; Eli Lilly and Company. D. Blondin: None. D. van Raalte: Consultant; Eli Lilly and Company. Research Support; Eli Lilly and Company, Boehringer-Ingelheim. Consultant; Boehringer-Ingelheim. Research Support; Merck & Co., Inc. Advisory Panel; Merck & Co., Inc. Consultant; Bayer Inc. P. Bjornstad: Consultant; AstraZeneca, Boehringer-Ingelheim. Advisory Panel; Lilly Diabetes, Novo Nordisk, Bayer Inc., Horizon Therapeutics plc.

Funding

NIH/NIDDK

© 2024 by the American Diabetes Association
2024
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