Ellen E Blaak1,2, Ilja C W Arts3,4,5, Nicole Vogelzangs6,7,8, Carla J H van der Kallen5,9, Marleen M J van Greevenbroek5,9, Birgitta W van der Kolk1,2, Johan W E Jocken1,2, Gijs H Goossens1,2, Nicolaas C Schaper5,9, Ronald M A Henry5,9, Simone J P M Eussen3,5,10, Armand Valsesia11, Thomas Hankemeier12, Arne Astrup13, Wim H M Saris1,2, Coen D A Stehouwer5,9. 1. Department of Human Biology, Maastricht University, Maastricht, The Netherlands. 2. NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands. 3. Department of Epidemiology, Maastricht University, Maastricht, The Netherlands. 4. Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, The Netherlands. 5. CARIM School for Cardiovascular Diseases, Maastricht University & Maastricht University Medical Centre, Maastricht, The Netherlands. 6. Department of Epidemiology, Maastricht University, Maastricht, The Netherlands. n.vogelzangs@maastrichtuniversity.nl. 7. Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, The Netherlands. n.vogelzangs@maastrichtuniversity.nl. 8. CARIM School for Cardiovascular Diseases, Maastricht University & Maastricht University Medical Centre, Maastricht, The Netherlands. n.vogelzangs@maastrichtuniversity.nl. 9. Department of Internal Medicine, Maastricht University, Maastricht, The Netherlands. 10. CAPHRI School for Care and Public Health Research, Maastricht University, Maastricht, The Netherlands. 11. Nestlé Institute of Health Sciences, Lausanne, Switzerland. 12. Netherlands Metabolomics Centre, Leiden, The Netherlands. 13. Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
Abstract
BACKGROUND: Recent evidence indicates that insulin resistance (IR) in obesity may develop independently in different organs, representing different etiologies toward type 2 diabetes and other cardiometabolic diseases. The aim of this study was to investigate whether IR in the liver and IR in skeletal muscle are associated with distinct metabolic profiles. METHODS: This study includes baseline data from 634 adults with overweight or obesity (BMI ≥ 27 kg/m2) (≤65 years; 63% women) without diabetes of the European Diogenes Study. Hepatic insulin resistance index (HIRI) and muscle insulin sensitivity index (MISI), were derived from a five-point OGTT. At baseline 17 serum metabolites were identified and quantified by nuclear-magnetic-resonance spectroscopy. Linear mixed model analyses (adjusting for center, sex, body mass index (BMI), waist-to-hip ratio) were used to associate HIRI and MISI with these metabolites. In an independent sample of 540 participants without diabetes (BMI ≥ 27 kg/m2; 40-65 years; 46% women) of the Maastricht Study, an observational prospective population-based cohort study, 11 plasma metabolites and a seven-point OGTT were available for validation. RESULTS: Both HIRI and MISI were associated with higher levels of valine, isoleucine, oxo-isovaleric acid, alanine, lactate, and triglycerides, and lower levels of glycine (all p < 0.05). HIRI was also associated with higher levels of leucine, hydroxyisobutyrate, tyrosine, proline, creatine, and n-acetyl and lower levels of acetoacetate and 3-OH-butyrate (all p < 0.05). Except for valine, these results were replicated for all available metabolites in the Maastricht Study. CONCLUSIONS: In persons with obesity without diabetes, both liver and muscle IR show a circulating metabolic profile of elevated (branched-chain) amino acids, lactate, and triglycerides, and lower glycine levels, but only liver IR associates with lower ketone body levels and elevated ketogenic amino acids in circulation, suggestive of decreased ketogenesis. This knowledge might enhance developments of more targeted tissue-specific interventions to prevent progression to more severe disease stages.
BACKGROUND: Recent evidence indicates that insulin resistance (IR) in obesity may develop independently in different organs, representing different etiologies toward type 2 diabetes and other cardiometabolic diseases. The aim of this study was to investigate whether IR in the liver and IR in skeletal muscle are associated with distinct metabolic profiles. METHODS: This study includes baseline data from 634 adults with overweight or obesity (BMI ≥ 27 kg/m2) (≤65 years; 63% women) without diabetes of the European Diogenes Study. Hepatic insulin resistance index (HIRI) and muscle insulin sensitivity index (MISI), were derived from a five-point OGTT. At baseline 17 serum metabolites were identified and quantified by nuclear-magnetic-resonance spectroscopy. Linear mixed model analyses (adjusting for center, sex, body mass index (BMI), waist-to-hip ratio) were used to associate HIRI and MISI with these metabolites. In an independent sample of 540 participants without diabetes (BMI ≥ 27 kg/m2; 40-65 years; 46% women) of the Maastricht Study, an observational prospective population-based cohort study, 11 plasma metabolites and a seven-point OGTT were available for validation. RESULTS: Both HIRI and MISI were associated with higher levels of valine, isoleucine, oxo-isovaleric acid, alanine, lactate, and triglycerides, and lower levels of glycine (all p < 0.05). HIRI was also associated with higher levels of leucine, hydroxyisobutyrate, tyrosine, proline, creatine, and n-acetyl and lower levels of acetoacetate and 3-OH-butyrate (all p < 0.05). Except for valine, these results were replicated for all available metabolites in the Maastricht Study. CONCLUSIONS: In persons with obesity without diabetes, both liver and muscle IR show a circulating metabolic profile of elevated (branched-chain) amino acids, lactate, and triglycerides, and lower glycine levels, but only liver IR associates with lower ketone body levels and elevated ketogenic amino acids in circulation, suggestive of decreased ketogenesis. This knowledge might enhance developments of more targeted tissue-specific interventions to prevent progression to more severe disease stages.
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