Level of an Advanced Glycated End Product Is Genetically Determined

Abstract

Reducing sugars react with amino groups in proteins, lipids, and nucleic acids to produce advanced glycation end products (AGEs), including N ⑀ -carboxymethyl lysine (CML), which have been implicated in oxidative stress and vascular damage. The aim of this study was to determine whether genetic factors influence serum CML levels in normal subjects. We performed a classical twin study of CML in healthy nondiabetic female twins, 39 monozygotic and 45 dizygotic pairs, aged 21-74 years. Serum CML levels were estimated by enzymelinked immunosorbent assay. Twin correlations (r) for serum CML levels were higher in monozygotic (r ‫؍‬ 0.71) compared with dizygotic (r ‫؍‬ 0.50) twin pairs, suggesting a substantial genetic effect and confirmed by quantitative genetic model fitting. Additive genetic effects (heritability) explained 74% (95% CI 58 -84) of population variance in CML. Heritability (%) of fasting glucose (51%) and HbA 1c (62%) could not explain CML heritability, which was not associated with them. CML levels are, therefore, predominantly genetically determined and independent of genes influencing fasting glucose or HbA 1c . Thus familial, largely genetic factors influence AGE implicating these glycoxidation products in the genetic contribution to macro-and microvascular disease. Diabetes 52: [2441][2442][2443][2444] 2003 T he formation of advanced glycation end products (AGEs) by glycation and oxidation alters the functional property of matrix proteins and mediates sustained cellular changes by binding to AGE ligands (1). AGE formation has been implicated in widespread pathology, including the macro-and microvascular complications of diabetes (1-4). Factors determining AGEs in normal physiology are unclear. Tissue levels of AGE increase with age (5). The formation of AGEs is predominantly endogenous, but these products can also be derived from exogenous sources such as food and tobacco smoke (6,7). The nonenzymatic glycation of food leads to browning through the formation of AGE, which is known as the Maillard reaction (6). Heat-treated food contains substantial AGEs, which can promote inflammatory responses (6 -8). Since the predominant source of AGEs is endogeneous, AGE levels may be genetically determined.The heterogeneity of AGEs implies that many products could be measured to estimate AGE formation. Of them, pentosidine and N ⑀ -carboxymethyl lysine (CML) are the best characterized, and CML can serve as a biomarker of oxidative stress resulting from sugar and lipid oxidation (8 -10). An assay for CML detects levels in normal and diabetic sera, and increased levels have been associated with diabetes and renal dysfunction (11). Since AGEs, including CML, are potentially important metabolic products, we aimed to determine whether population variation in CML levels could be due to genetic factors. We therefore studied a cohort of healthy nondiabetic female monozygotic and dizygotic twins to determine the impact of genetic and environmental factors on serum CML levels. Table 1 shows the characteristics of th...

Effects of Sevelamer on HbA1c, Inflammation, and Advanced Glycation End Products in Diabetic Kidney Disease

“…This has also been shown in mouse models (4). Finally, a study of monozygotic and dizygotic twins and northern European children revealed that environmental AGEs, likely from the diet, are important in the development of type 1 diabetes mellitus (D. Leslie, unpublished observations) (12).…”

DETERMINATION OF ADVANCED GLYCATION (AGEs) AND LIPOXIDATION (ALEs) END PRODUCTS IN FOODS AND BIOLOGICAL SYSTEMS: ADVANCES, CHALLENGES AND PERSPECTIVES

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Glycation: Implication in Perceived Age and Dermatology

“…Glycated collagen has been shown to accumulate at a rate of 3.7% per year (36), percentage highly infl uenced by environmental factors such as diet and smoking (37). Moreover, studies conducted on healthy twins, both monozygotic and heterozygotic, concluded that circulating AGEs level's are genetically determined (38).…”