Association of Ketone Body Levels With Hyperglycemia and Type 2 Diabetes in 9,398 Finnish Men
- Yuvaraj Mahendran1,
- Jagadish Vangipurapu1,
- Henna Cederberg2,
- Alena Stančáková1,
- Jussi Pihlajamäki3,
- Pasi Soininen4,5,
- Antti J. Kangas4,
- Jussi Paananen1,
- Mete Civelek6,
- Niyas K. Saleem1,
- Päivi Pajukanta7,
- Aldons J. Lusis6,
- Lori L. Bonnycastle8,
- Mario A. Morken8,
- Francis S. Collins8,
- Karen L. Mohlke9,
- Michael Boehnke10,
- Mika Ala-Korpela4,5,11,12,
- Johanna Kuusisto2 and
- Markku Laakso2⇑
- 1Department of Medicine, University of Eastern Finland, Kuopio, Finland
- 2Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
- 3Department of Medicine and Department of Clinical Nutrition, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
- 4Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland
- 5Nuclear Magnetic Resonance Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland
- 6Department of Human Genetics, Department of Microbiology, Immunology, and Molecular Genetics, and Department of Medicine, University of California, Los Angeles, Los Angeles, California
- 7Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
- 8National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
- 9Department of Genetics, University of North Carolina, Chapel Hill, North Carolina
- 10Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, Michigan
- 11School of Social and Community Medicine, University of Bristol, Bristol, U.K.
- 12Unit of General Practice, Oulu University Hospital, Oulu, Finland.
- Corresponding author: Markku Laakso, .
We investigated the association of the levels of ketone bodies (KBs) with hyperglycemia and with 62 genetic risk variants regulating glucose levels or type 2 diabetes in the population-based Metabolic Syndrome in Men (METSIM) study, including 9,398 Finnish men without diabetes or newly diagnosed type 2 diabetes. Increasing fasting and 2-h plasma glucose levels were associated with elevated levels of acetoacetate (AcAc) and β-hydroxybutyrate (BHB). AcAc and BHB predicted an increase in the glucose area under the curve in an oral glucose tolerance test, and AcAc predicted the conversion to type 2 diabetes in a 5-year follow-up of the METSIM cohort. Impaired insulin secretion, but not insulin resistance, explained these findings. Of the 62 single nucleotide polymorphisms associated with the risk of type 2 diabetes or hyperglycemia, the glucose-increasing C allele of GCKR significantly associated with elevated levels of fasting BHB levels. Adipose tissue mRNA expression levels of genes involved in ketolysis were significantly associated with insulin sensitivity (Matsuda index). In conclusion, high levels of KBs predicted subsequent worsening of hyperglycemia, and a common variant of GCKR was significantly associated with BHB levels.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-1363/-/DC1.
- Received October 1, 2012.
- Accepted March 28, 2013.
- © 2013 by the American Diabetes Association.
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