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Molecular Biology

Metabolic profiling of tissue-specific insulin resistance in human obesity: results from the Diogenes study and the Maastricht Study

International Journal of Obesity volume 44, pages 1376–1386 (2020)Cite this article

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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.

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Fig. 1: Standardized beta’s (95% CI) of associations between HIRI and metabolites.
Fig. 2: Standardized beta’s (95% CI) of associations between MISI and metabolites.

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Acknowledgements

The present study and the work of NV were supported through a grant from the Maastricht University Medical Center+. The Diogenes Study was supported by the European Commission, Food Quality, and Safety Priority of the Sixth Framework Program (FP6-2005-513946). The Maastricht Study was supported by the European Regional Development Fund via OP-Zuid, the Province of Limburg, the Dutch Ministry of Economic Affairs (grant 31O.041), Stichting De Weijerhorst (Maastricht, the Netherlands), the Pearl String Initiative Diabetes (Amsterdam, the Netherlands), the Cardiovascular Center (CVC, Maastricht, the Netherlands), Cardiovascular Research Institute Maastricht (CARIM, Maastricht, the Netherlands), School for Public Health and Primary Care (CAPHRI, Maastricht, the Netherlands), School for Nutrition, Toxicology and Metabolism (NUTRIM, Maastricht, the Netherlands), Stichting Annadal (Maastricht, the Netherlands), Health Foundation Limburg (Maastricht, the Netherlands) and by unrestricted grants from Janssen-Cilag B.V. (Tilburg, the Netherlands), Novo Nordisk Farma B.V. (Alphen aan den Rijn, the Netherlands), and Sanofi-Aventis Netherlands B.V. (Gouda, the Netherlands). The study sponsors were not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication.

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Author notes

  1. These authors contributed equally: Ellen E. Blaak, Ilja C.W. Arts

Authors and Affiliations

  1. Department of Epidemiology, Maastricht University, Maastricht, The Netherlands

    Nicole Vogelzangs, Simone J. P. M. Eussen & Ilja C. W. Arts

  2. Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, The Netherlands

    Nicole Vogelzangs & Ilja C. W. Arts

  3. CARIM School for Cardiovascular Diseases, Maastricht University & Maastricht University Medical Centre, Maastricht, The Netherlands

    Nicole Vogelzangs, Carla J. H. van der Kallen, Marleen M. J. van Greevenbroek, Nicolaas C. Schaper, Ronald M. A. Henry, Simone J. P. M. Eussen, Coen D. A. Stehouwer & Ilja C. W. Arts

  4. Department of Internal Medicine, Maastricht University, Maastricht, The Netherlands

    Carla J. H. van der Kallen, Marleen M. J. van Greevenbroek, Nicolaas C. Schaper, Ronald M. A. Henry & Coen D. A. Stehouwer

  5. Department of Human Biology, Maastricht University, Maastricht, The Netherlands

    Birgitta W. van der Kolk, Johan W. E. Jocken, Gijs H. Goossens, Wim H. M. Saris & Ellen E. Blaak

  6. NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands

    Birgitta W. van der Kolk, Johan W. E. Jocken, Gijs H. Goossens, Wim H. M. Saris & Ellen E. Blaak

  7. CAPHRI School for Care and Public Health Research, Maastricht University, Maastricht, The Netherlands

    Simone J. P. M. Eussen

  8. Nestlé Institute of Health Sciences, Lausanne, Switzerland

    Armand Valsesia

  9. Netherlands Metabolomics Centre, Leiden, The Netherlands

    Thomas Hankemeier

  10. Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark

    Arne Astrup

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  1. Nicole Vogelzangs
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Correspondence to Nicole Vogelzangs.

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Conflict of interest

AV is full-time employee at Nestlé Institute of Health Sciences SA. WHMS reports having received research support from several food companies, such as Nestlé, DSM, Unilever, Nutrition et Sante, and Danone as well as Pharmaceutical companies, such as GSK, Novartis, and Novo Nordisk; he is an unpaid scientific advisor for the International Life Science Institute, ILSI Europe. AA reports grants and personal fees from McCain Foods, personal fees from Dutch Beer Knowledge Institute, the Netherlands, personal fees from Gelesis, personal fees from Novo Nordisk, Denmark, outside the submitted work, and royalties received for the book first published in Danish as Verdens Bedste Kur (Politiken; Copenhagen, Denmark), and subsequently published in Dutch as Het beste dieet ter wereld (Kosmos Uitgevers; Utrecht/Antwerpen, the Netherlands), in Spanish as Plan DIOGENES para el control del peso. La dieta personalizada inteligente (Editorial Evergra ́ficas; Léon, Spain), and in English as World’s Best Diet (Penguin, Australia). EEB receives grant support from food industry, such as DSM, Danone, Friesland Campina, Avebe, and Sensus, partly within the context of public–private consortia and has received funding from pharmaceutical companies like Novartis. She is involved in several task forces/expert groups related to the International Life Science Institute, ILSI Europe. All other authors report no possible conflicts of interest.

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Vogelzangs, N., van der Kallen, C.J.H., van Greevenbroek, M.M.J. et al. Metabolic profiling of tissue-specific insulin resistance in human obesity: results from the Diogenes study and the Maastricht Study. Int J Obes 44, 1376–1386 (2020). https://doi.org/10.1038/s41366-020-0565-z

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