5-28]). Multivariate modeling showed that genetic factors also have a substantial influence on fasting glucose levels (51%). However, HbA 1c heritability could not be explained by genes in common with fasting glucose. In the patients with type 1 diabetes, HbA 1c levels were correlated in 33 MZ twins concordant for diabetes (r ‫؍‬ 0.68; P < 0.001) but also in 45 MZ twins discordant for the disease (r ‫؍‬ 0.52; P < 0.001). These significant correlations for HbA 1c in both concordant and discordant pairs indicate a diabetesindependent familial effect. Thus, HbA 1c levels are largely genetically determined and independent of the genes influencing fasting glucose. Even in type 1 diabetes, familial (i.e., diabetes-independent) factors influence protein glycation, implying that familial factors may explain, in part, the risk for microvascular complications, as indicated by high HbA 1c levels.

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...