317-OR: Metabolomic Analyses Identify Novel Predictors of Diabetic Kidney Disease in Youth-Onset Type 2 Diabetes
Authors: PYLE LAURA , VIGERS TIMOTHY B. , EL GHORMLI LAURE , DE BOER IAN , NELSON ROBERT G. , WAIKAR SUSHRUT , HEERSPINK HIDDO L. , WHITE NEIL , TOMMERDAHL KALIE L. , LAFFEL LORI M. , SHAH AMY S. , DREWS KIMBERLY , RYDER JUSTIN R. , GUBITOSI-KLUG ROSE , SHARMA KUMAR , BJORNSTAD PETTER 
Published: June 2023

Background: Diabetic kidney disease (DKD) develops by young adulthood in up to 50% of people with youth-onset type 2 diabetes (Y-T2D), increasing risk of dialysis and premature death. Understanding mechanisms responsible for early DKD is key to management and prevention; accordingly, we sought to identify metabolite signatures of DKD in Y-T2D.
Methods: We measured 57 metabolites in 374 baseline plasma and urine samples from the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study, using mass spectrometry with a targeted ZipChip based assay. Urine albumin-to-creatinine ratio (UACR) was assessed annually for up to 15 years. Incident moderate and severe albuminuria were defined as UACR ≥30 and ≥300 mg/g, respectively, on ≥2 of 3 measures. We evaluated prediction of moderate and severe albuminuria in separate Cox proportional hazards models adjusted for HbA1c, triglycerides, systolic blood pressure, and estimated insulin sensitivity. Urine metabolites were normalized by urine creatinine.
Results: Participants were 14±2 years of age, 37% male; 43% developed either moderate or severe albuminuria. Four urine metabolites predicted time to moderate albuminuria, while 8 urine metabolites predicted time to severe albuminuria, with 3 metabolites in common: 2-hydroxybutyric acid (moderate: HR: 0.82 per 1 SD [95% CI 0.70, 0.96]; severe: 0.70 [0.55, 0.88]), glycine (moderate: 0.81 [0.69, 0.94]; severe: 0.62 [0.45, 0.85]), citric acid (moderate: 0.78 [0.67, 0.91]; severe: 0.76 [0.58, 0.99]). Four plasma metabolites predicted time to moderate albuminuria and severe albuminuria, such as glutamic acid for moderate albuminuria (1.23 [1.03, 1.47]) and citric acid for severe albuminuria (1.39 [1.09, 1.77]).
Conclusion: Higher urine metabolites involved in mitigating oxidative stress (glycine), glomerular epithelial cell injury (2-hydroxybutyric acid) and preserving mitochondrial function (citrate) predicted lower risk of albuminuria in Y-T2D.

Disclosure
L.Pyle: None. L.M.Laffel: Advisory Panel; Medtronic, Lilly Diabetes, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Roche Diagnostics, Provention Bio, Inc., Consultant; Dexcom, Inc., Janssen Pharmaceuticals, Inc., Medscape. A.S.Shah: None. K.Drews: None. J.R.Ryder: None. R.Gubitosi-klug: None. K.Sharma: Advisory Panel; Reata Pharmaceuticals, Inc., Otsuka America Pharmaceutical, Inc. P.Bjornstad: Advisory Panel; AstraZeneca, Novo Nordisk, Lilly, Horizon Therapeutics plc, Boehringer Ingelheim (Canada) Ltd., LG Chem, Consultant; Bayer Inc., Bristol-Myers Squibb Company. T.B.Vigers: None. L.El ghormli: None. I.De boer: Advisory Panel; AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Boehringer Ingelheim International GmbH, Otsuka America Pharmaceutical, Inc., Bayer Inc., Consultant; George Clinical, Gilead Sciences, Inc., Medscape, Research Support; Dexcom, Inc. R.G.Nelson: None. S.Waikar: None. H.L.Heerspink: Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Bayer Inc., Eli Lilly and Company, Chinook Therapeutics Inc., CSL Behring, Gilead Sciences, Inc., George Clinical, Merck & Co., Inc., Janssen Research & Development, LLC, Traveere Pharmaceuticals, Novo Nordisk. N.White: None. K.L.Tommerdahl: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (U01DK61242)