Metabolic Signatures of Insulin Resistance in 7,098 Young Adults
- Peter Würtz1,2,3⇓,
- Ville-Petteri Mäkinen1,4,5,
- Pasi Soininen1,6,
- Antti J. Kangas1,
- Taru Tukiainen1,2,
- Johannes Kettunen2,7,
- Markku J. Savolainen1,8,
- Tuija Tammelin9,
- Jorma S. Viikari10,
- Tapani Rönnemaa10,
- Mika Kähönen11,
- Terho Lehtimäki12,
- Samuli Ripatti2,7,13,
- Olli T. Raitakari14,15,
- Marjo-Riitta Järvelin3,16,17,18 and
- Mika Ala-Korpela1,6,8⇓
- 1Computational Medicine Research Group, Institute of Clinical Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland
- 2Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
- 3Department of Epidemiology and Biostatistics, Imperial College London, London, U.K.
- 4Folkhälsan Research Center, University of Helsinki, Helsinki, Finland
- 5Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
- 6NMR Metabonomics Laboratory, Department of Biosciences, University of Eastern Finland, Kuopio, Finland
- 7Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
- 8Department of Internal Medicine, Clinical Research Center, Biocenter Oulu, University of Oulu, Oulu, Finland
- 9LIKES Research Center for Sport and Health Sciences, Jyväskylä, Finland
- 10Department of Medicine, Turku University Hospital, University of Turku, Turku, Finland
- 11Department of Clinical Physiology, Tampere University Hospital, University of Tampere, Tampere, Finland
- 12Department of Clinical Chemistry, Tampere University Hospital, University of Tampere, Tampere, Finland
- 13Wellcome Trust Sanger Institute, Hinxton, U.K.
- 14Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
- 15Department of Clinical Physiology, Turku University Hospital, University of Turku, Turku, Finland
- 16Department of Children, Young People, and Families, National Institute for Health and Welfare, Helsinki, Finland
- 17Institute of Health Sciences, Biocenter Oulu, University of Oulu, Oulu, Finland
- 18Medical Research Council Health Protection Agency, Centre for Environment and Health, Imperial College London, London, U.K.
- Corresponding authors: Peter Würtz, peter.wyrtz{at}computationalmedicine.fi, and Mika Ala-Korpela, mika.ala-korpela{at}computationalmedicine.fi.
Abstract
Metabolite associations with insulin resistance were studied in 7,098 young Finns (age 31 ± 3 years; 52% women) to elucidate underlying metabolic pathways. Insulin resistance was assessed by the homeostasis model (HOMA-IR) and circulating metabolites quantified by high-throughput nuclear magnetic resonance spectroscopy in two population-based cohorts. Associations were analyzed using regression models adjusted for age, waist, and standard lipids. Branched-chain and aromatic amino acids, gluconeogenesis intermediates, ketone bodies, and fatty acid composition and saturation were associated with HOMA-IR (P < 0.0005 for 20 metabolite measures). Leu, Ile, Val, and Tyr displayed sex- and obesity-dependent interactions, with associations being significant for women only if they were abdominally obese. Origins of fasting metabolite levels were studied with dietary and physical activity data. Here, protein energy intake was associated with Val, Phe, Tyr, and Gln but not insulin resistance index. We further tested if 12 genetic variants regulating the metabolites also contributed to insulin resistance. The genetic determinants of metabolite levels were not associated with HOMA-IR, with the exception of a variant in GCKR associated with 12 metabolites, including amino acids (P < 0.0005). Nonetheless, metabolic signatures extending beyond obesity and lipid abnormalities reflected the degree of insulin resistance evidenced in young, normoglycemic adults with sex-specific fingerprints.
Footnotes
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This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-1355/-/DC1.
- Received September 28, 2011.
- Accepted January 26, 2012.
- © 2012 by the American Diabetes Association.
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