Hyperglycemia and a Common Variant of GCKR Are Associated with the Levels of Eight Amino Acids in 9,371 Finnish Men

Objective: Insulin regulates amino acid metabolism. We investigated whether glycemia and 43 genetic risk variants for hyperglycemia/type 2 diabetes affect amino acid levels in a large population-based cohort. Subjects and Methods: A total of 9,371 non-diabetic or newly-diagnosed type 2 diabetic Finnish men from the population-based METSIM Study were studied. Proton NMR spectroscopy was used to measure plasma levels of 8 amino acids. Genotyping of 42 SNPs and mRNA microarray analysis from 200 subcutaneous adipose tissue samples were performed. Results: Increasing fasting and/or 2-hour plasma glucose levels were associated with increasing levels of alanine, valine, leucine, isoleucine, phenylalanine and tyrosine, and decreasing levels of histidine and glutamine. We also found significant correlations between insulin sensitivity (Matsuda ISI) and expression of genes regulating amino acid metabolism. Only one SNP (rs780094 in GCKR) of the 42 risk SNPs for type 2 diabetes or hyperglycemia was significantly associated with the levels of alanine, isoleucine, and glutamine. Conclusions : We observed that the levels of branched-chain, aromatic amino acids and alanine increased and the levels of glutamine and histidine decreased with increasing glycemia. These associations seemed to be mediated by insulin resistance, at least in part. GCKR rs780094 was significantly associated with several amino acids. Total RNA was obtained from subcutaneous fat biopsies from 200 people participating in the METSIM study (4 samples were replicated for a total of 204 arrays).