Metabolic Signatures of Insulin Resistance in 7,098 Young Adults

• DOI: 10.2337/db11-1355
• Publication Date: 2012-04-18T05:57:30Z
• Authors: Peter Würtz; Ville-Petteri Mäk...; Pasi Soininen; Antti J. Kangas; Taru Tukiainen; Johannes Kettunen; Markku J. Savolainen; Tuija Tammelin; Jorma S. Viikari; Tapani Rönnemaa; Mika Kähönen; Terho Lehtimäki; Samuli Ripatti; Olli T. Raitakari; Marjo-Riitta Järv...; Mika Ala-Korpela
• Keywords: Adult; Blood Glucose; Male; 0301 basic medicine; HOMEOSTASIS; LOCI; 610; PROTEIN; MECHANISMS; Endocrinology & Metabolism; 03 medical and health sciences; 616; Homeostasis; Humans; Insulin; Obesity; GENOME-WIDE ASSOCIATION; 11 Medical and Health Sciences; ta999; Metabolic Syndrome; 2. Zero hunger; Science & Technology; CARDIOVASCULAR RISK; DIABETES-MELLITUS; HUMANS; Fasting; ta3121; Diet; 3. Good health; FASTING PLASMA-GLUCOSE; Metabolism; OBESITY; Female; Insulin Resistance; Life Sciences & Biomedicine

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.