Hyperglycemia and a Common Variant of GCKR Are Associated With the Levels of Eight Amino Acids in 9,369 Finnish Men

  1. Markku Laakso1
  1. 1Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
  2. 2Department of Human Genetics, the Department of Microbiology, Immunology and Molecular Genetics, and the Department of Medicine, University of California, Los Angeles, Los Angeles, California
  3. 3Computational Medicine Research Group, Institute of Clinical Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland
  4. 4Nuclear Magnetic Resonance Metabonomics Laboratory, Laboratory of Chemistry, Department of Biosciences, University of Eastern Finland, Kuopio, Finland
  5. 5Departments of Medicine and Clinical Nutrition, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
  6. 6National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
  7. 7Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan
  8. 8Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
  9. 9Department of Internal Medicine and Biocenter Oulu, Clinical Research Center, University of Oulu, Oulu, Finland.
  1. Corresponding author: Markku Laakso, markku.laakso{at}


We investigated the association of glycemia and 43 genetic risk variants for hyperglycemia/type 2 diabetes with amino acid levels in the population-based Metabolic Syndrome in Men (METSIM) Study, including 9,369 nondiabetic or newly diagnosed type 2 diabetic Finnish men. Plasma levels of eight amino acids were measured with proton nuclear magnetic resonance spectroscopy. Increasing fasting and 2-h plasma glucose levels were associated with increasing levels of several amino acids and decreasing levels of histidine and glutamine. Alanine, leucine, isoleucine, tyrosine, and glutamine predicted incident type 2 diabetes in a 4.7-year follow-up of the METSIM Study, and their effects were largely mediated by insulin resistance (except for glutamine). We also found significant correlations between insulin sensitivity (Matsuda insulin sensitivity index) and mRNA expression of genes regulating amino acid degradation in 200 subcutaneous adipose tissue samples. Only 1 of 43 risk single nucleotide polymorphisms for type 2 diabetes or hyperglycemia, the glucose-increasing major C allele of rs780094 of GCKR, was significantly associated with decreased levels of alanine and isoleucine and elevated levels of glutamine. In conclusion, the levels of branched-chain, aromatic amino acids and alanine increased and the levels of glutamine and histidine decreased with increasing glycemia, reflecting, at least in part, insulin resistance. Only one single nucleotide polymorphism regulating hyperglycemia was significantly associated with amino acid levels.

  • Received October 5, 2011.
  • Accepted March 2, 2012.

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