title: Insulin response dysregulation explains abnormal fat storage and increased risk of diabetes mellitus type 2 in Cohen Syndrome.
abstract: Cohen Syndrome (CS) is a rare autosomal recessive disorder, with defective glycosylation secondary to mutations in the VPS13B gene, which encodes a protein of the Golgi apparatus. Besides congenital neutropenia, retinopathy and intellectual deficiency, CS patients are faced with truncal obesity. Metabolism investigations showed abnormal glucose tolerance tests and low HDL values in some patients, and these could be risk factors for the development of diabetes mellitus and/or cardiovascular complications. To understand the mechanisms involved in CS fat storage, we used two models of adipogenesis differentiation: (i) SGBS pre-adipocytes with VPS13B invalidation thanks to siRNA delivery and (ii) CS primary fibroblasts. In both models, VPS13B invalidation led to accelerated differentiation into fat cells, which was confirmed by the earlier and increased expression of specific adipogenic genes, consequent to the increased response of cells to insulin stimulation. At the end of the differentiation protocol, these fat cells exhibited decreased AKT2 phosphorylation after insulin stimulation, which suggests insulin resistance. This study, in association with the in-depth analysis of the metabolic status of the patients, thus allowed us to recommend appropriate nutritional education to prevent the occurrence of diabetes mellitus and to put forward recommendations for the follow-up of CS patients, in particular with regard to the development of metabolic syndrome. We also suggest replacing the term obesity by abnormal fat distribution in CS, which should reduce the number of inappropriate diagnoses in patients who are referred only on the basis of intellectual deficiency associated with obesity.
authors.affiliation: Génétique des Anomalies du Développement GAD EA4271, Univeristé de Bourgogne Franche-Comté, F-21000 Dijon, France.
authors.forename: Floriane
authors.initials: F
authors.lastname: Limoge
authors.affiliation: Génétique des Anomalies du Développement GAD EA4271, Univeristé de Bourgogne Franche-Comté, F-21000 Dijon, France, FHU TRANSLAD, Département de Génétique, Hôpital d'enfants, CHU Dijon, F-21000 Dijon, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.affiliation: LNC UMR866, INSERM, Université Bourgogne Franche-Comté, F-21000 Dijon, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gautier
authors.affiliation: Service d'Endocrinologie, CHU Bocage, F-21000 Dijon, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Petit
authors.affiliation: Génétique des Anomalies du Développement GAD EA4271, Univeristé de Bourgogne Franche-Comté, F-21000 Dijon, France, FHU TRANSLAD, Département de Génétique, Hôpital d'enfants, CHU Dijon, F-21000 Dijon, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Gautier
authors.affiliation: LNC UMR866, INSERM, Université Bourgogne Franche-Comté, F-21000 Dijon, France.
authors.forename: David
authors.initials: D
authors.lastname: Masson
authors.affiliation: LNC UMR866, INSERM, Université Bourgogne Franche-Comté, F-21000 Dijon, France.
authors.forename: Gaëtan
authors.initials: G
authors.lastname: Jego
authors.affiliation: Génétique des Anomalies du Développement GAD EA4271, Univeristé de Bourgogne Franche-Comté, F-21000 Dijon, France, FHU TRANSLAD, Département de Génétique, Hôpital d'enfants, CHU Dijon, F-21000 Dijon, France.
authors.forename: Salima
authors.initials: S
authors.lastname: El Chehadeh-Djebbar
authors.affiliation: Génétique des Anomalies du Développement GAD EA4271, Univeristé de Bourgogne Franche-Comté, F-21000 Dijon, France, FHU TRANSLAD, Département de Génétique, Hôpital d'enfants, CHU Dijon, F-21000 Dijon, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Marle
authors.affiliation: Génétique des Anomalies du Développement GAD EA4271, Univeristé de Bourgogne Franche-Comté, F-21000 Dijon, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Carmignac
authors.affiliation: LNC UMR866, INSERM, Université Bourgogne Franche-Comté, F-21000 Dijon, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Deckert
authors.affiliation: Service d'Endocrinologie, CHU Bocage, F-21000 Dijon, France.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Brindisi
authors.affiliation: Service de Génétique Clinique, Hôpital Femme Mère Enfant, CHU Lyon, HCL, Lyon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Edery
authors.affiliation: Centre de Référence Maladies Rares Anomalies du Développement et Syndromes Malformatifs Nord, Hôpital Jeanne de Flandres, CHRU Lille, Lille, France and.
authors.forename: Jamal
authors.initials: J
authors.lastname: Ghoumid
authors.affiliation: Department of Clinical Genetics, Oxford Regional Genetics Service, The Churchill Hospital, Oxford, UK.
authors.forename: Edward
authors.initials: E
authors.lastname: Blair
authors.affiliation: LNC UMR866, INSERM, Université Bourgogne Franche-Comté, F-21000 Dijon, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Lagrost
authors.affiliation: Génétique des Anomalies du Développement GAD EA4271, Univeristé de Bourgogne Franche-Comté, F-21000 Dijon, France, FHU TRANSLAD, Département de Génétique, Hôpital d'enfants, CHU Dijon, F-21000 Dijon, France.
authors.forename: Christel
authors.initials: C
authors.lastname: Thauvin-Robinet
authors.affiliation: Génétique des Anomalies du Développement GAD EA4271, Univeristé de Bourgogne Franche-Comté, F-21000 Dijon, France, FHU TRANSLAD, Département de Génétique, Hôpital d'enfants, CHU Dijon, F-21000 Dijon, France, laurence.duplomb@chu-dijon.fr.
authors.forename: Laurence
authors.initials: L
authors.lastname: Duplomb
mesh_terms: D050156:Adipogenesis; D000293:Adolescent; D000328:Adult; D050218:Body Fat Distribution; D002648:Child; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000150:complications / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000209:etiology / Q000503:physiopathology*; D005260:Female; D005385:Fingers / Q000002:abnormalities* / Q000503:physiopathology; D006801:Humans; D007328:Insulin / Q000502:physiology*; D008607:Intellectual Disability / Q000150:complications / Q000503:physiopathology*; D008297:Male; D008831:Microcephaly / Q000150:complications / Q000503:physiopathology*; D008875:Middle Aged; D008954:Models, Biological; D009123:Muscle Hypotonia / Q000150:complications / Q000503:physiopathology*; D009154:Mutation; D009216:Myopia / Q000150:complications / Q000503:physiopathology*; D009765:Obesity / Q000150:complications / Q000503:physiopathology*; D012162:Retinal Degeneration; D012306:Risk; D015398:Signal Transduction; D033921:Vesicular Transport Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: D007328:Insulin; C475722:VPS13B protein, human; D033921:Vesicular Transport Proteins