Higher Plasma Methylglyoxal Levels Are Associated With Incident Cardiovascular Disease in Individuals With Type 1 Diabetes: A 12-Year Follow-up Study

Abstract

Methylglyoxal (MGO), a major precursor for advanced glycation end products, is increased in diabetes. In diabetic rodents, inhibition of MGO prevents cardiovascular disease (CVD). Whether plasma MGO levels are associated with incident CVD in people with type 1 diabetes is unknown. We included 159 individuals with persistent normoalbuminuria and 162 individuals with diabetic nephropathy (DN) from the outpatient clinic at Steno Diabetes Center. We measured MGO at baseline and recorded fatal and nonfatal CVD over a median follow-up of 12.3 years (interquartile range 7.6-12.5 years). Data were analyzed by Cox regression, with adjustment for sex, age, HbA, DN, diabetes duration, smoking, systolic blood pressure, antihypertensive medication, and BMI. During follow-up, 73 individuals suffered at least one CVD event (36 fatal and 53 nonfatal). Higher MGO levels were associated with total, fatal, and nonfatal incident CVD (hazard ratios [HRs] 1.47 [95% CI 1.13-1.91], 1.42 [1.01-1.99], and 1.46 [1.08-1.98], respectively). We observed a similar trend for total mortality (HR 1.24 [0.99-1.56]). This study shows for the first time in our knowledge that plasma MGO levels are associated with cardiovascular events in individuals with type 1 diabetes. MGO may explain, at least in part, the increased risk for CVD in type 1 diabetes.

Higher Plasma Methylglyoxal Levels Are Associated With Incident Cardiovascular Disease and Mortality in Individuals With Type 2 Diabetes

“…This is the first study demonstrating an association between plasma MGO levels and incident CVD in type 2 diabetes. Our current findings are largely in line with our recent report on associations between plasma MGO, GO, and 3-DG levels and incident CVD in type 1 diabetes (11). A major difference from our previous study is that, in the current study, we found that adjustment for markers of CKD attenuated associations between MGO and GO and cardiovascular mortality as well as incident total CVD and ischemic heart disease.…”

“…These findings may suggest a causal role of MGO in diabetes complications. Indeed, we recently found that higher levels of MGO are associated with incident CVD in individuals with type 1 diabetes (11). However, it is unclear whether these findings also apply to type 2 diabetes.…”

Non-standard AGE4 epitopes that predict polyneuropathy independently of obesity can be detected by slot dot-blot immunoassay

“…28 Elevated concentrations of MGO in serum have previously been shown in diabetes 20 and held responsible for inducing maladaptive responses in the vasculature. 29 Similarly, MGO has been linked with diabetic complications, increasing risk of cardiovascular events and mortality, 31 as well as impairing bone regeneration in patients with diabetes. 32 Mechanistically, MGO has been shown to interfere with the platelet-derived growth factor B/platelet-derived growth factor receptor β (PDGFB/PDGFRβ) axis in smooth muscle cells and fibroblasts through formation of CML and CEL adducts on the PDGFB receptor.…”

Skin Autofluorescence–Indicated Advanced Glycation End Products as Predictors of Cardiovascular and All‐Cause Mortality in High‐Risk Subjects: A Systematic Review and Meta‐analysis

“…Conflicting results have been reported from measurement of AGE levels in plasma and concern the ability of AGEs to predict cardiovascular events or cardiovascular mortality, even though most recent works support such a predictive role 7. Changes in levels of plasma RAGEs have also been associated indirectly with increased risk of cardiovascular disease (CVD),8 namely, heart failure9 and coronary heart disease 10…”