Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2017

Mitochondrial dysfunction defines a population of young people with type 1 diabetes at risk of kidney disease (#34)

Josephine M Forbes 1 , Nicole Flemming 1 , Domenica McCarthy 1 , Kristof Boot 2 , Neisha D'Silva 3 , Linda Gallo 1 , Janelle Nisbett 3 , Adam Morton 3 , Stephanie Teasedale 3 , David Thorburn 4 , Anthony Russell 5 , Nicolle Isbel 6 , David Johnson 6 , Grant Morahan 7 , Mark Harris 1 , Tim Jones 8 , Jenny Couper 9 , Kim Donaghue 10 , Mark Hodson 11 , Trisha O'Moore-Sullivan 3
  1. Mater Research Institute - The University of Queensland, Brisbane, QLD, Australia
  2. David Serisier Biobank, Mater Health Service, Brisbane, QLD, Australia
  3. Mater Young Adult Health Centre, Mater Health Service, Brisbane, QLD, Australia
  4. Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC, Australia
  5. Diabetes and Endocrinology, Metro South Health, Brisbane, QLD, Australia
  6. Metro South and Ipswich Nephrology and Transplant Service, Metro South Health, Brisbane, QLD, Australia
  7. Harry Perkins Institute of Medical Research, University of Western Australia, Perth, WA, Australia
  8. Telethon Kid’s Institute, Perth, WA, Australia
  9. Women’s and Children’s Hospital, Adelaide, SA, Australia
  10. Children’s Hospital at Westmead, Sydney, NSW, Australia
  11. Metabolomics Australia, The University of Queensland, Brisbane, QLD, Australia

Aim: The objective of this study was to examine the relationships between mitochondrial and renal function in young people with Type 1 diabetes (T1D).

Background: Recent evidence suggests that kidney disease in T1D develops much earlier than previously appreciated. In adolescents with type 1 diabetes (T1D), the highest tertile of urinary albumin-to-creatinine ratio (uACR), predicts renal and cardiovascular disease risk.

Methods: A cross-sectional cohort of young adults with T1D was recruited [n=100; 20.0±2.8 yrs; M:F-54:46, HbA1c-66.1(12.3) mmol/mol; diabetes duration-10.7±5.2 yrs; BMI-24.5(5.3) kg/m2]. Mean uACR tertiles (3 morning urine samples) were used to divide the study population. Lower (uACR ≤0.66 mg/mmol; n=33) and middle (uACR 0.67-1.16; n=33) tertiles were defined as having low-moderate risk and those in the upper tertile (uACR ≥1.17; n=34) as high risk of future DKD. Mitochondrial function in circulating leukocytes and urinary metabolomics were performed.

Results: Participants had hyperfiltration [CKDEPI eGFR, 135.0(13.8) ml/min/m2) and individuals in the upper tertile of uACR had the highest median eGFR (P <0.031 vs low risk tertile; age, gender and diabetes duration adjusted). In a generalized linear model which included HbA1c, BMI, diabetes duration, sex and age, a significant inverse relationship was identified between eGFR-CKDEPI and logACR in the upper tertile, which was not seen in lower risk tertiles (vs middle, P=9.8x10-5; vs lower, P=2x10-16). Mitochondrial function (ATP dependent respiration) in circulating leukocytes, was decreased in individuals in the higher uACR tertile (P=0.008). Multivariate modelling of urinary metabolites identified a signature which separated the upper uACR tertile from the lower risk tertiles.

Conclusions: Young individuals with type 1 diabetes and higher risk of DKD have mitochondrial dysfunction and an inverse relationship between GFR and uACR.

  1. 1. Marcovecchio ML, Woodside J, Jones T, Daneman D, Neil A, Prevost T, Dalton RN, Deanfield J, Dunger DB; AdDIT Investigators.. Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT): urinary screening and baseline biochemical and cardiovascular assessments. Diabetes Care. 2014;37(3):805-13. doi: 10.2337/dc13-1634. Epub 2013 Nov 6.PMID:24198300.
  2. 2. Maftei O, Pena AS, Sullivan T, Jones TW, Donaghue KC, Cameron FJ, Davis E, Cotterill A, Craig ME, Gent R, Dalton N, Daneman D, Dunger D, Deanfield J, Couper JJ; AdDIT Study Group. Early atherosclerosis relates to urinary albumin excretion and cardiovascular risk factors in adolescents with type 1 diabetes: Adolescent type 1 Diabetes cardio-renal Intervention Trial (AdDIT). Diabetes Care. 2014 Nov;37(11):3069-75. doi: 10.2337/dc14-0700. Epub 2014 Jul 28. PMID:25071076