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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