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Annieke C G van Baar Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands

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Andrei Prodan Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands

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Camilla D Wahlgren Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark

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Steen S Poulsen Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Filip K Knop Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Albert K Groen Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands
Department of Laboratory Medicine, University of Groningen, University Medical Center, Groningen, the Netherlands

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Jacques J Bergman Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands

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Max Nieuwdorp Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands
Department of Internal Medicine, VUMC Free University, Amsterdam, the Netherlands
Wallenberg Laboratory, Sahlgrenska Hospital, University of Gothenburg, Gothenburg, Sweden

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Evgeni Levin Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands
Horaizon BV, Delft, the Netherlands

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Background

Enteroendocrine cells are essential for the regulation of glucose metabolism, but it is unknown whether they are associated with clinical features of metabolic syndrome (MetS) and fasting plasma metabolites.

Objective

We aimed to identify fasting plasma metabolites that associate with duodenal L cell, K cell and delta cell densities in subjects with MetS with ranging levels of insulin resistance.

Research design and methods

In this cross-sectional study, we evaluated L, K and delta cell density in duodenal biopsies from treatment-naïve males with MetS using machine-learning methodology.

Results

We identified specific clinical biomarkers and plasma metabolites associated with L cell and delta cell density. L cell density was associated with increased plasma metabolite levels including symmetrical dimethylarginine, 3-aminoisobutyric acid, kynurenine and glycine. In turn, these L cell-linked fasting plasma metabolites correlated with clinical features of MetS.

Conclusions

Our results indicate a link between duodenal L cells, plasma metabolites and clinical characteristics of MetS. We conclude that duodenal L cells associate with plasma metabolites that have been implicated in human glucose metabolism homeostasis. Disentangling the causal relation between L cells and these metabolites might help to improve the (small intestinal-driven) pathophysiology behind insulin resistance in human obesity.

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