421-P: Methylglyoxal-Derived Advanced Glycation End Products Are Prognostic Biomarkers for Diabetic Complications and Drivers of Endothelial Dysfunction

Abstract

Diabetic kidney disease (DKD) affects over 30% of individuals with T1D, significantly increasing mortality risk in this population. Canonical tools to predict DKD such as glomerular filtration rate (GFR) or albumin excretion rate (AER) alone may not be sufficient to predict disease risk, as they often do not become apparent until significant kidney damage has already occurred. Therefore, there is an unmet need to identify additional clinically useful biomarkers to predict DKD risk. Methylglyoxal (MG) is an abundant, reactive electrophile produced during metabolic flux from glycolysis and protein and lipid metabolism. MG covalently modifies macromolecules such as DNA, RNA, and protein forming MG-advanced glycation end products (MG-AGEs). Both MG and MG-AGEs have been correlated with diabetes and cancer, but the ability of nucleoside MG-AGEs to predict DKD risk has not been examined. Using a novel mass spectrometry method, we measured levels of MG-AGEs in patient urinary samples collected from the DCCT/EDIC study and found MG-AGEs independently predicted DKD risk up to 16 years pre-diagnosis. This association was more significant than the association of AER, GFR, or HbA1c with DKD. In DKD, endothelial cells (ECs) become dysfunctional, which contributes to the development of the disease. To understand the extent to which MG-AGEs impact EC dysfunction, we synthesized pure MG-AGEs and exposed human umbilical vein endothelial cells (HUVECS) to these compounds. We found MG-AGEs activated pathways associated with the receptor for AGEs (RAGE) and EC dysfunction as evidenced by increased leukocyte adhesion, oxidative stress, pro-inflammatory gene expression, and NFkB activation. This suggests that MG-AGEs are not only predictive of DKD, but may also contribute to EC dysfunction preceding disease. Disclosure S.Lai: None. E.D.J.Lopez gonzalez: None. S.Shuck: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (X01DK118575); National Institutes of Health (1R21DK127285); Wanek Family Project to Cure T1D; Diabetes Complications Consortium