title: Metabolic signatures of insulin resistance in 7,098 young adults.
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.
authors.affiliation: Computational Medicine Research Group, Institute of Clinical Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland. peter.wyrtz@computationalmedicine.fi
authors.forename: Peter
authors.initials: P
authors.lastname: Würtz
authors.forename: Ville-Petteri
authors.initials: VP
authors.lastname: Mäkinen
authors.forename: Pasi
authors.initials: P
authors.lastname: Soininen
authors.forename: Antti J
authors.initials: AJ
authors.lastname: Kangas
authors.forename: Taru
authors.initials: T
authors.lastname: Tukiainen
authors.forename: Johannes
authors.initials: J
authors.lastname: Kettunen
authors.forename: Markku J
authors.initials: MJ
authors.lastname: Savolainen
authors.forename: Tuija
authors.initials: T
authors.lastname: Tammelin
authors.forename: Jorma S
authors.initials: JS
authors.lastname: Viikari
authors.forename: Tapani
authors.initials: T
authors.lastname: Rönnemaa
authors.forename: Mika
authors.initials: M
authors.lastname: Kähönen
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
authors.forename: Samuli
authors.initials: S
authors.lastname: Ripatti
authors.forename: Olli T
authors.initials: OT
authors.lastname: Raitakari
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Järvelin
authors.forename: Mika
authors.initials: M
authors.lastname: Ala-Korpela
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism*; D004032:Diet; D005215:Fasting / Q000378:metabolism; D005260:Female; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism; D009765:Obesity / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin