Multi-omics correlates of insulin resistance and circadian parameters mapped directly from human serum

Article Article scientifique Article Multi-omics correlates of insulin resistance and circadian parameters mapped directly from human serum eng 2024-08-28 author Du Ngoc-Hien 0009-0007-3525-8094 Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland. author Sinturel Flore Department of Surgery, Division of Thoracic and Endocrine Surgery, University Hospitals of Geneva, Geneva, Switzerland.,Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Institute of Genetics and Genomics of Geneva (iGE3), Geneva, Switzerland.,Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 796363 author Nowak Nora Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland. author Gosselin Pauline Department of Surgery, Division of Thoracic and Endocrine Surgery, University Hospitals of Geneva, Geneva, Switzerland.,Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Institute of Genetics and Genomics of Geneva (iGE3), Geneva, Switzerland.,Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Department and Division of Primary Care Medicine, University Hospitals of Geneva, Geneva, Switzerland. 804518 author Saini Camille Department of Surgery, Division of Thoracic and Endocrine Surgery, University Hospitals of Geneva, Geneva, Switzerland.,Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Institute of Genetics and Genomics of Geneva (iGE3), Geneva, Switzerland.,Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Department and Division of Primary Care Medicine, University Hospitals of Geneva, Geneva, Switzerland. 510657 author Guessous Idris Department and Division of Primary Care Medicine, University Hospitals of Geneva, Geneva, Switzerland. 760565 Médecine de premier recours hospitalo-universitaire (MPRHU) author Jornayvaz François 0000-0001-9425-3137 Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Department of Medicine, Division of Endocrinology, Diabetes, Nutrition, and Therapeutic Education of Patient, University Hospitals of Geneva, Geneva, Switzerland. 641037 Département de médecine (DEMED) author Philippe Jacques Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Department of Medicine, Division of Endocrinology, Diabetes, Nutrition, and Therapeutic Education of Patient, University Hospitals of Geneva, Geneva, Switzerland. 26481 Décanat et administration de la faculté de médecine (ADMED) author Rey Guillaume Institute of Genetics and Genomics of Geneva (iGE3), Geneva, Switzerland.,Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 901120 author Dermitzakis Emmanouil Institute of Genetics and Genomics of Geneva (iGE3), Geneva, Switzerland.,Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 542683 author Zenobi Renato Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland. author Dibner Charna 0000-0002-4188-803X Department of Surgery, Division of Thoracic and Endocrine Surgery, University Hospitals of Geneva, Geneva, Switzerland.,Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Institute of Genetics and Genomics of Geneva (iGE3), Geneva, Switzerland.,Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 583541 Département de chirurgie (CHIRU) author Brown Steven A Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland. 5487-5504 10.1111/ejn.16486 39205434 0953-816X https://onlinelibrary.wiley.com/doi/10.1111/ejn.16486 While it is generally known that metabolic disorders and circadian dysfunction are intertwined, how the two systems affect each other is not well understood, nor are the genetic factors that might exacerbate this pathological interaction. Blood chemistry is profoundly changed in metabolic disorders, and we have previously shown that serum factors change cellular clock properties. To investigate if circulating factors altered in metabolic disorders have circadian modifying effects, and whether these effects are of genetic origin, we measured circadian rhythms in U2OS cell in the presence of serum collected from diabetic, obese or control subjects. We observed that circadian period lengthening in U2OS cells was associated with serum chemistry that is characteristic of insulin resistance. Characterizing the genetic variants that altered circadian period length by genome-wide association analysis, we found that one of the top variants mapped to the E3 ubiquitin ligase MARCH1 involved in insulin sensitivity. Confirming our data, the serum circadian modifying variants were also enriched in type 2 diabetes and chronotype variants identified in the UK Biobank cohort. Finally, to identify serum factors that might be involved in period lengthening, we performed detailed metabolomics and found that the circadian modifying variants are particularly associated with branched chain amino acids, whose levels are known to correlate with diabetes and insulin resistance. Overall, our multi-omics data showed comprehensively that systemic factors serve as a path through which metabolic disorders influence circadian system, and these can be examined in human populations directly by simple cellular assays in common cultured cells. GWAS Circadian rhythms Insulin resistance Obesity and type 2 diabetes Serum metabolomics Humans Insulin Resistance / physiology Circadian Rhythm / physiology Male Diabetes Mellitus, Type 2 / blood Diabetes Mellitus, Type 2 / genetics Diabetes Mellitus, Type 2 / metabolism Female Genome-Wide Association Study Middle Aged Metabolomics / methods Cell Line, Tumor Ubiquitin-Protein Ligases / genetics Ubiquitin-Protein Ligases / metabolism Obesity / blood Obesity / genetics Adult Multiomics Dewey 612 Dewey 613 Dewey 616 Dewey 617 Dewey 576.5 Swiss National Science Foundation Interactions between the human circadian clock, diabetes, and metabolic syndrome 160741 CH Programmes Swiss National Science Foundation Roles of the circadian oscillator in pancreatic islet function, failure and regeneration 166700 CH Projects Swiss National Science Foundation Roles of the pancreatic islet cell-specific circadian oscillators in metabolic regulation in physiology and type 2 diabetes 184708 CH Projects 57 Département de chirurgie 222 134 Département de physiologie cellulaire et métabolisme 21C 219 Institut universitaire de médecine de famille et de l'enfance 22A93 56 Département de médecine 221 135 Département de médecine génétique et développement 21D false 913 Endocrinologie et horloge circadienne 948 1263 MASLD/MASH et résistance à l'insuline 997 1313 Médecine de 1er recours 1020 https://doi.org/10.5281/zenodo.10598274 https://doi.org/10.5281/zenodo.10605035 EJN. European journal of neuroscience 60 7 a49158de-bb45-4cdc-b667-772bbd48e13c Article (Published version) Public file.pdf 1376764 application/pdf CC BY-NC-ND-4.0 065b0a1e4764c480a8fcc0ecb5d77afb40175513b911526a8d0c80f9410178e2 openAccess Faculté de médecine / Section de médecine clinique / Département de chirurgie Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme Faculté de médecine / Section de médecine clinique / Département de santé et médecine communautaires / Institut de médecine de premier recours / Institut universitaire de médecine de famille et de l'enfance Faculté de médecine / Section de médecine clinique / Département de médecine Faculté de médecine / Section de médecine fondamentale / Département de médecine génétique et développement

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