Plasma Advanced Glycation End Products Are Associated With Incident Cardiovascular Events in Individuals With Type 2 Diabetes: A Case-Cohort Study With a Median Follow-up of 10 Years (EPIC-NL)

Abstract

Experimental data suggest a role for advanced glycation end products (AGEs) in cardiovascular disease (CVD), particularly in type 2 diabetes (T2DM). However, epidemiological evidence of an association between high plasma AGEs and increased cardiovascular risk remains inconclusive. Therefore, in a case-cohort study comprising 134 cardiovascular case subjects and a random subcohort of 218 individuals (including 65 cardiovascular case subjects), all with T2DM and nested in the European Prospective Investigation into Cancer and Nutrition in the Netherlands (EPIC-NL) study, plasma levels of protein-bound Nε-(carboxymethyl)lysine, Nε-(carboxyethyl)lysine, and pentosidine were measured with liquid chromatography. AGEs were loge-transformed, combined in a z-score, and the association with incident cardiovascular events was analyzed with Cox proportional hazard regression, adapted for case-cohort design (Prentice method). After multivariable adjustment (sex, age, cohort status, diabetes duration, total cholesterol to HDL-cholesterol ratio, smoking, systolic blood pressure, BMI, blood pressure–, cholesterol- and glucose-lowering treatment, prior cardiovascular events, and triglycerides), higher plasma AGE z-scores were associated with higher risk of incident cardiovascular events in individuals without prior cardiovascular events (hazard ratio 1.31 [95% CI: 1.06–1.61]). A similar trend was observed in individuals with prior cardiovascular events (1.37 [0.63–2.98]). In conclusion, high plasma AGEs were associated with incident cardiovascular events in individuals with T2DM. These results underline the potential importance of AGEs in development of CVD.

Glyoxalase biochemistry

“…Connections to vascular diseases, diabetic complications and diabetic neuropathy, and amyloid-type neurodegenerative disease, among other areas, are being investigated (13,15,118). In the area of vascular disease and diabetes, a recent study has reported that increased MG derived AGE appear to be associated with an increased risk of cardiovascular events in type 2 diabetic patients (119). Post-translationally glycated proteins are thought to exert their effects on cells by a receptor-mediated pathway that includes their interaction with a receptor recognizing AGE-modified proteins.…”

Processed meat: the real villain?

“…In addition, higher concentrations were seen in (industrially) processed foods from animal products such as frankfurters, bacon and powdered egg whites, compared with the unprocessed forms (75) . It is well-known that high circulating advanced glycation end products levels are associated with adverse outcomes in diabetes patients (76)(77)(78) , but so far no epidemiological study has evaluated whether dietary advanced glycation end products intake or circulating levels are associated with incident type-2 diabetes.…”

The analysis of advanced glycation endproducts

“…This was in reasonable agreement with data described in literature [36][37][38][39][40][41] . The described method is suitable for studying AGEs in several different human and animal studies [42][43][44][45][46][47][48][49] and is a strong tool to investigate the putative effects of AGEs in the pathophysiology of different diseases.…”

“…AGEs, in our body, can also originate from exogenous sources such as diet and smoking 49,50 . AGEs in foods are formed rapidly during processing at high temperatures, such as grilling, frying, baking or roasting 49,51,52 .…”

“…AGEs in foods are formed rapidly during processing at high temperatures, such as grilling, frying, baking or roasting 49,51,52 . Since the consumption of these processed foods has increased over the past decades 53 , the exposure to dietary AGEs has also increased and may contribute to the development of chronic diseases 27,54,55 .…”