A surrogate of Roux-en-Y gastric bypass (the enterogastro anastomosis surgery) regulates multiple beta-cell pathways during resolution of diabetes in ob/ob mice
Chloé Amouyal,
Julien Castel,
Claudiane Guay,
Amélie Lacombe,
Jessica Denom,
Stéphanie Migrenne-Li,
Christine Rouault,
Florian Marquet,
Eleni Georgiadou,
Theodoros Stylianides,
Serge Luquet,
Hervé Le Stunff,
Raphael Scharfmann,
Karine Clément,
Guy A. Rutter,
Olivier Taboureau,
Christophe Magnan,
Romano Regazzi,
Fabrizio Andreelli
Affiliations
Chloé Amouyal
Sorbonne Université, INSERM, Nutrition and Obesities; Systemic approaches (NutriOmics), Paris, France; AP-HP, Pitié-Salpêtrière Hospital, Diabetology department, F-75013 Paris, France
Julien Castel
Université de Paris, BFA, UMR 8251, CNRS, F-75013 Paris, France
Claudiane Guay
Department of Fundamental Neurosciences, University of Lausanne, Rue du Bugnon 9, CH-1005, Lausanne, Switzerland
Amélie Lacombe
PreclinICAN, Institute of Cardiometabolism and Nutrition, Paris, France
Jessica Denom
Université de Paris, BFA, UMR 8251, CNRS, F-75013 Paris, France
Stéphanie Migrenne-Li
Université de Paris, BFA, UMR 8251, CNRS, F-75013 Paris, France
Christine Rouault
Sorbonne Université, INSERM, Nutrition and Obesities; Systemic approaches (NutriOmics), Paris, France
Florian Marquet
Sorbonne Université, INSERM, Nutrition and Obesities; Systemic approaches (NutriOmics), Paris, France
Eleni Georgiadou
Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
Theodoros Stylianides
Loughborough University, Loughborough, UK
Serge Luquet
Université de Paris, BFA, UMR 8251, CNRS, F-75013 Paris, France
Hervé Le Stunff
Université de Paris, BFA, UMR 8251, CNRS, F-75013 Paris, France
Raphael Scharfmann
Université de Paris, Cochin Institute, Inserm U1016, Paris 75014, France
Karine Clément
Sorbonne Université, INSERM, Nutrition and Obesities; Systemic approaches (NutriOmics), Paris, France; APHP, Pitié-Salpêtrière Hospital, Nutrition department, F-75013 Paris, France
Guy A. Rutter
Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK; Lee Kong Chian School of Medicine, Nan Yang Technological University, Singapore
Olivier Taboureau
Université de Paris, BFA, Team CMPLI, Inserm U1133, CNRS UMR 8251, Paris, France.
Christophe Magnan
Université de Paris, BFA, UMR 8251, CNRS, F-75013 Paris, France
Romano Regazzi
Department of Fundamental Neurosciences, University of Lausanne, Rue du Bugnon 9, CH-1005, Lausanne, Switzerland; Department of Biomedical Sciences, University of Lausanne, Rue du Bugnon 7, CH-1005 Lausanne, Switzerland
Background: Bariatric surgery is an effective treatment for type 2 diabetes. Early post-surgical enhancement of insulin secretion is key for diabetes remission. The full complement of mechanisms responsible for improved pancreatic beta cell functionality after bariatric surgery is still unclear. Our aim was to identify pathways, evident in the islet transcriptome, that characterize the adaptive response to bariatric surgery independently of body weight changes. Methods: We performed entero-gastro-anastomosis (EGA) with pyloric ligature in leptin-deficient ob/ob mice as a surrogate of Roux-en-Y gastric bypass (RYGB) in humans. Multiple approaches such as determination of glucose tolerance, GLP-1 and insulin secretion, whole body insulin sensitivity, ex vivo glucose-stimulated insulin secretion (GSIS) and functional multicellular Ca2+-imaging, profiling of mRNA and of miRNA expression were utilized to identify significant biological processes involved in pancreatic islet recovery. Findings: EGA resolved diabetes, increased pancreatic insulin content and GSIS despite a persistent increase in fat mass, systemic and intra-islet inflammation, and lipotoxicity. Surgery differentially regulated 193 genes in the islet, most of which were involved in the regulation of glucose metabolism, insulin secretion, calcium signaling or beta cell viability, and these were normalized alongside changes in glucose metabolism, intracellular Ca2+ dynamics and the threshold for GSIS. Furthermore, 27 islet miRNAs were differentially regulated, four of them hubs in a miRNA-gene interaction network and four others part of a blood signature of diabetes resolution in ob/ob mice and in humans. Interpretation: Taken together, our data highlight novel miRNA-gene interactions in the pancreatic islet during the resolution of diabetes after bariatric surgery that form part of a blood signature of diabetes reversal. Funding: European Union's Horizon 2020 research and innovation programme via the Innovative Medicines Initiative 2 Joint Undertaking (RHAPSODY), INSERM, Société Francophone du Diabète, Institut Benjamin Delessert, Wellcome Trust Investigator Award (212625/Z/18/Z), MRC Programme grants (MR/R022259/1, MR/J0003042/1, MR/L020149/1), Diabetes UK (BDA/11/0004210, BDA/15/0005275, BDA 16/0005485) project grants, National Science Foundation (310030–188447), Fondation de l'Avenir.
