Emerging technologies allow the high-throughput profiling of metabolic status from a blood specimen (metabolomics). We investigated whether metabolite profiles could predict the development of diabetes. Among 2,422 normoglycemic individuals followed for 12 years, 201 developed diabetes. Amino acids, amines, and other polar metabolites were profiled in baseline specimens using liquid chromatography-tandem mass spectrometry. Cases and controls were matched for age, body mass index and fasting glucose. Five branched-chain and aromatic amino acids had highly-significant associations with future diabetes: isoleucine, leucine, valine, tyrosine, and phenylalanine. A combination of three amino acids predicted future diabetes (>5-fold higher risk for individuals in top quartile). The results were replicated in an independent, prospective cohort. These findings underscore the potential importance of amino acid metabolism early in the pathogenesis of diabetes, and suggest that amino acid profiles could aid in diabetes risk assessment.

An increased plasma homocysteine level is a strong, independent risk factor for the development of dementia and Alzheimer's disease.

Background-Vitamin

Background-Vitamin D is crucial for maintaining musculoskeletal health. Recently, vitamin D insufficiency has been linked to a number of extraskeletal disorders, including diabetes, cancer, and cardiovascular disease. Determinants of circulating 25-hydroxyvitamin D (25-OH D) include sun exposure and dietary intake, but its high heritability suggests that genetic determinants may also play a role.

Background Methylenetetrahydrofolate reductase (MTHFR) synthesizes 5-methyltetrahydrofolate, the major carbon donor in remethylation of homocysteine to methionine. A common MTHFR mutation, an alanine-to-valine substitution, renders the enzyme thermolabile and may cause elevated plasma levels of the amino acid homocysteine.

Background-Consumption of soft drinks has been linked to obesity in children and adolescents, but it is unclear whether it increases metabolic risk in middle-aged individuals. Methods and Results-We related the incidence of metabolic syndrome and its components to soft drink consumption in participants in the Framingham Heart Study (6039 person-observations, 3470 in women; mean age 52.9 years) who were free of baseline metabolic syndrome. Metabolic syndrome was defined as the presence of Ն3 of the following: waist circumference Ն35 inches (women) or Ն40 inches (men); fasting blood glucose Ն100 mg/dL; serum triglycerides Ն150 mg/dL; blood pressure Ն135/85 mm Hg; and high-density lipoprotein cholesterol Ͻ40 mg/dL (men) or Ͻ50 mg/dL (women).

DNA methylation, an essential epigenetic feature of DNA that modulates gene expression and genomic integrity, is catalyzed by methyltransferases that use the universal methyl donor S-adenosyl-L-methionine. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate (5-methyl-THF), the methyl donor for synthesis of methionine from homocysteine and precursor of S-adenosyl-L-methionine. In the present study we sought to determine the effect of folate status on genomic DNA methylation with an emphasis on the interaction with the common C677T mutation in the MTHFR gene. A liquid chromatography͞MS method for the analysis of nucleotide bases was used to assess genomic DNA methylation in peripheral blood mononuclear cell DNA from 105 subjects homozygous for this mutation (T͞T) and 187 homozygous for the wild-type (C͞C) MTHFR genotype. The results show that genomic DNA methylation directly correlates with folate status and inversely with plasma homocysteine (tHcy) levels (P < 0.01). T͞T genotypes had a diminished level of DNA methylation compared with those with the C͞C wild-type (32.23 vs.62.24 ng 5-methylcytosine͞g DNA, P < 0.0001). When analyzed according to folate status, however, only the T͞T subjects with low levels of folate accounted for the diminished DNA methylation (P < 0.0001). Moreover, in T͞T subjects DNA methylation status correlated with the methylated proportion of red blood cell folate and was inversely related to the formylated proportion of red blood cell folates (P < 0.03) that is known to be solely represented in those individuals. These results indicate that the MTHFR C677T polymorphism influences DNA methylation status through an interaction with folate status.

The fortification of enriched grain products with folic acid was associated with a substantial improvement in folate status in a population of middle-aged and older adults.