Oral Virtual Presentation (Virtual only) ESA-SRB-ANZBMS 2021

Mitochondrial dysfunction aligns with risk for diabetic kidney disease in youth with type 1 diabetes (#166)

Mitchell A Sullivan 1 , Domenica A McCarthy 1 , Nicole Flemming 1 , Preeti Chandrashekar 1 , Amelia K Fotheringham 1 , Rani Whiddett 1 , Neisha D'Silva 2 , Janelle Nisbet 2 , Adam Morton 3 , Stephanie Teasdale 2 , Nicolle Isbel 3 , Timothy Jones 4 , Jennifer Couper 5 , Grant Morahan 6 , David R Thorburn 7 , Mark Harris 8 , David W Johnson 3 , Andrew Cotterill 8 , Helen Barrett 2 , Trisha O'Moore-Sullivan 2 , Kim Donaghue 9 , Josephine M Forbes 1
  1. Mater Research Institute - The University of Queensland, Brisbane, QLD, Australia
  2. Mater Young Adults Health Centre, Mater Misericordiae Ltd, Brisbane, QLD, Australia
  3. Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
  4. Telethon Kid's Institute, Perth, WA, Australia
  5. Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia
  6. The Harry Perkins Institute of Medical Research, University of Western Australia, Perth, WA, Australia
  7. Brain and Mitochondrial Research, Murdoch Children's Research Institute, Melbourne, VIC, Australia
  8. Children's Health Queensland, Brisbane, QLD, Australia
  9. Univeristy of Sydney, Sydney, NSW, Australia

Background

Growing evidence demonstrates that diabetic kidney disease (DKD) begins as early as adolescence, with the highest tertile of urinary albumin-to-creatinine ratio (uACR) being identified as those individuals at elevated risk. The best-pactise regimens used to combat DKD in adults have proven ineffective in Phase III clinical trials, indicating that in early T1D other factors may confer the risk of DKD.

This study tested the hypothesis that mitochondrial dysfunction in adolescents with T1D may contribute to an increased risk in developing DKD.

Methods

This cross-sectional cohort study recruited 100 young adults with T1D. Mean uACR was determined and the cohort was then divided into the low-risk group (uACR <1.16 mg/mmol; n=66) and the high-risk group for DKD and CVD (uACR ≥1.17; n=34).

Peripheral blood mononuclear cells (PBMCs) from all participants were isolated and their mitochondrial to nuclear DNA ratios were determined. A Seahorse mitochondrial stress test was also performed.  Flow cytometry was used to quantify circulating T cells.

Primary proximal tubule epithelial cells (PTECs) were treated with the serum of the participants and the mitochondrial density and levels of SGLT2 and Collagen IV were measured using flow cytometry.

Results

PBMCs from the high-risk group had a higher oxygen consumption rate but lower basal respiration (P=0.01) and ATP-linked respiration (P=0.03). There was a negative correlation between the number of CD3+ T cells and the PBMC mitochondrial to nuclear DNA ratio in both the low-risk group (slope = -3.5; P=0.045) and the high-risk group (slope = -5.2; P=0.0022). PTECS exposed to the plasma of high-risk patients had a trend towards increased mitochondria (P=0.08) and had statistically significant increases in Collogen IV (P=0.049) and SGLT2 levels (P=0.01).

Conclusion

Young adults with T1D at high risk for DKD and CVD have signs of changed mitochondrial function and possess altered proportions of circulating T cells.