MITOCHONDRIAL DYSFUNCTION DEFINES A POPULATION OF YOUNG PEOPLE WITH TYPE 1 DIABETES AT RISK OF KIDNEY DISEASE

JM FORBES1,2, NB FLEMMING1,2, DA MCCARTHY1, K BOOT3, N DE SILVA4, LA GALLO1,2, J NISBETT4, A MORTON4, S TEASDALE4, DR THORBURN5, A RUSSELL6, N ISBEL6, D JOHNSON6, G MORAHAN7, T JONES8, J COUPER9, K DONAGHUE10, MP HODSON2,11, T O’MOORE-SULLIVAN4

1Mater Research Institute – The University of Queensland, TRI, Brisbane, Queensland; Schools of 2Biomedical Sciences, Medicine and Pharmacy, The University of Queensland, St Lucia, Qld; 3David Serisier Respiratory Biobank and 4Diabetes and Endocrine Centre, Mater Health Service, Brisbane, Qld; 5Murdoch Children’s Research Institute, Melbourne, Victoria; 6Metro South Health, Brisbane, Qld; 7Harry Perkins Institute of Medical Research, Perth, WA; 8Telethon Kid’s Institute, Perth, WA; 9Women’s and Children’s Hospital, Adelaide, SA; 10Children’s Hospital at Westmead, Sydney, NSW 11Metabolomics Australia, The University of Queensland, St Lucia, Queensland; 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=9.8×10-5; vs lower, P=2×10-16). 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.

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The ASM is hosted by Australian and New Zealand Society of Nephrology.

The aims of the Society are to promote and support the study of the kidney and urinary tract in health and disease, and to ensure the highest professional standards for the practice of nephrology in Australia and New Zealand.

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