Association of Ketone Body Levels With Hyperglycemia and Type 2 Diabetes in 9,398 Finnish Men

Author:

Mahendran Yuvaraj1,Vangipurapu Jagadish1,Cederberg Henna2,Stančáková Alena1,Pihlajamäki Jussi3,Soininen Pasi45,Kangas Antti J.4,Paananen Jussi1,Civelek Mete6,Saleem Niyas K.1,Pajukanta Päivi7,Lusis Aldons J.6,Bonnycastle Lori L.8,Morken Mario A.8,Collins Francis S.8,Mohlke Karen L.9,Boehnke Michael10,Ala-Korpela Mika451112,Kuusisto Johanna2,Laakso Markku2

Affiliation:

1. Department of Medicine, University of Eastern Finland, Kuopio, Finland

2. Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland

3. Department of Medicine and Department of Clinical Nutrition, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland

4. Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland

5. Nuclear Magnetic Resonance Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland

6. Department of Human Genetics, Department of Microbiology, Immunology, and Molecular Genetics, and Department of Medicine, University of California, Los Angeles, Los Angeles, California

7. Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California

8. National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland

9. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina

10. Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, Michigan

11. School of Social and Community Medicine, University of Bristol, Bristol, U.K.

12. Unit of General Practice, Oulu University Hospital, Oulu, Finland.

Abstract

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.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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