# Role of Methionine Sulfoxide and Advanced Glycation Endproducts in Cardiovascular and Renal Complications of Type 2 Diabetes

> **NIH NIH R21** · ARIZONA VETERANS RESEARCH AND EDUCATION FOUNDATION · 2020 · $106,147

## Abstract

Abstract
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 t...

## Key facts

- **NIH application ID:** 10022163
- **Project number:** 5R21HL150268-02
- **Recipient organization:** ARIZONA VETERANS RESEARCH AND EDUCATION FOUNDATION
- **Principal Investigator:** Juraj Koska
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $106,147
- **Award type:** 5
- **Project period:** 2019-09-20 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10022163

## Citation

> US National Institutes of Health, RePORTER application 10022163, Role of Methionine Sulfoxide and Advanced Glycation Endproducts in Cardiovascular and Renal Complications of Type 2 Diabetes (5R21HL150268-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10022163. Licensed CC0.

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