151-OR: Metabolomics Profiles Underlying Development of Microvascular Complications in the Diabetes Prevention Project Outcome Study (DPPOS)
Authors: PERNG WEI , SHU RICHARD , NATHAN DAVID M. , LUCHSINGER JOSE A. , GERSZTEN ROBERT E. , MIDDELBEEK ROELAND J.W. , KAHN STEVEN E. , KNOWLER WILLIAM C. , DABELEA DANA , TEMPROSA MARINELLA , RESEARCH GROUP DPP 
Published: June 2024

Objective: We used metabolomics data to identify metabolite profiles predictive of nephropathy, retinopathy, and/or neuropathy over 11-15 y of follow-up in DPPOS, and to assess the extent to which the profiles represent shared v. distinct pathways.
Methods: We applied LASSO to 350 annotated compounds assayed from fasting blood of 1947 participants at baseline (age: 53.1±10.1 y). The models accounted for age, sex, and race. We retained compounds with nonzero estimates from ≥7 of 10 bootstrapped datasets for each outcome.
Results: Five hundred seventy-two participants developed ≥1 outcome during follow-up (277 cases of nephropathy, 194 of retinopathy, and 212 of neuropathy). One hundred thirty-seven metabolites predicted at least one outcome. Of them, 6 metabolites were predictive of all three outcomes, including bilirubin, a byproduct of red blood cell breakdown suppressed in the context of hyperglycemia; serine, for which lower levels are linked to impaired nerve function; and 1-methylhistamine, a biomarker of neurological disorders. Fourteen metabolites were predictive of nephropathy and retinopathy, including some involved in branched chain amino acid (BCAA) metabolism - e.g., 2-AAA, phenylalanine, and kynurenic acid. Thirteen metabolites were predictive of nephropathy and neuropathy, including DMGV, which is implicated in fatty liver progression; and 1,5-AG which is linked to poor glycemic control. Seven metabolites were predictive of neuropathy and retinopathy, including quinolinic acid, a tryptophan metabolite; and UDP-GlcNAc, a nucleotide end-product of glucose metabolism.
Conclusions: Microvascular complications of diabetes share pathophysiology related to hyperglycemia and impaired nerve function. We observed the largest overlap in metabolite predictors of nephropathy and retinopathy, for which several compounds are part of a BCAA metabolic signature implicated in worsening glycemia.

Disclosure
W. Perng: None. R. Shu: None. D.M. Nathan: None. J.A. Luchsinger: Consultant; Merck KGaA. Other Relationship; EMD Serono, Wolters Kluwer Health. R.E. Gerszten: None. R.J.W. Middelbeek: Research Support; Novo Nordisk. S.E. Kahn: Advisory Panel; AltPep, Boehringer-Ingelheim, Eli Lilly and Company, Intarcia Therapeutics, Inc., Merck & Co., Inc., Novo Nordisk A/S. W.C. Knowler: None. D. Dabelea: None. M. Temprosa: None. D. Research Group: None.

Funding
National Instituteof Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) (U01 DK048489, U01 DK048339, U01 DK048377, U01 DK048349, U01DK048381, U01 DK048468, U01 DK048434, U01 DK048485, U01 DK048375, U01 DK048514, U01DK048437, U01 DK048413, U01 DK048411, U01 DK048406, U01 DK048380, U01 DK048397, U01DK048412, U01 DK048404, U01 DK048387, U01 DK048407, U01 DK048443, and U01 DK048400); National Institute on Aging (NIA) of the National Institutes of Health (NIH) (U19AG078558)