Oxidative end-products (OxPs) and advanced glycation end-products (AGEs) are long-lived reactive intermediates formed by reactions of reactive oxygen species and chemically reactive sugars with proteins, lipids and nucleic acids. Both are increased in diabetes and are believed to be important contributors to both micro- and macrovascular complications of diabetes. Several clinical and epidemiological studies indicated an association between selective individual AGE/OxPs in blood and cardiovascular risk. However, studies were often small, cross-sectional, used a single AGE or OxP or relatively inaccurate immunoassays, so convincing human data are lacking. A novel high-throughput LC-triple quadrupole approach has been recently developed to measure a panel of AGEs and OxPs concentrations in blood that is comprehensive, precise and can be readily applied to large sample numbers. Using this highly accurate technique, we demonstrated that several baseline plasma AGEs and OxPs (and combinations of them) from the panel were positively associated with long-term progression of coronary and carotid atherosclerosis and with incident CVD in a subset of participants of the Veterans Affairs Diabetes Trial (VADT). Specifically, we found a strong negative association between plasma levels of one of the OxPs, Methionine Sulfoxide (MetSO) and incident CVD events suggesting this unique OxP may offer, or reflect, protection against CVD. We observed many of the same CVD findings (including that for MetSO) in a small case- control subgroup of the Action to Control Cardiovascular Risk in Diabetes (ACCORD). None of the AGE/OxPs were related to concurrent hemoglobin A1c (HbA1c) levels but instead were associated with diabetes duration, consistent with long-term effects of hyperglycemia on these compounds. Furthermore, higher AGEs strongly predicted progression of diabetes kidney disease in our VADT subset, independently of glycemic control and other traditional risk factors of renal disease. These data were consistent previous small studies highlighting that several AGEs were related to renal pathology and its progression in type 2 diabetes. The present proposal builds on these findings and investigates the relationships of MetSO and AGEs and OxPs with diabetes complications diabetes complications in a case-cohort sample of the ACCORD trial.
In Aim 1 we propose to validate an inverse relationship between MetSO and CVD. We will test whether baseline MetSO levels are associated with incident CVD events. We will also explore the relationship between individual AGEs or combined OxP/AGE scores and incident CVD, and whether a combined MetSO/AGE improve CVD risk prediction models.
In Aim 2 we will determine whether AGEs are associated with incident diabetes kidney disease (DKD). We will explore whether individual AGEs or combined AGE scores would improve DKD prediction models. This first large scale and comprehensive evaluation will greatly expand our understanding of the relationships between AGE/OxPs and diabetes complications and their importance in humans, and potentially improve our risk assessment and discrimination models.
The present proposal will utilize a novel high throughput spectrometry assay to investigate the relationships of methionine sulfoxide (MetSO) and advanced glycation endproducts (AGEs) with development of cardiovascular and renal events within type 2 diabetes case-cohort subgroup of the ACCORD trial. This study will provide a definitive understanding of the nature of the relationship of MetSO and AGEs with these common diabetes complications, and whether they may improve prediction of risk compared to standard risk markers. These results may also help guide current and future therapies directed towards lowering levels of MetSO and AGEs.
