title: Carriers of loss-of-function mutations in EXT display impaired pancreatic beta-cell reserve due to smaller pancreas volume.
abstract: Exotosin (EXT) proteins are involved in the chain elongation step of heparan sulfate (HS) biosynthesis, which is intricately involved in organ development. Loss of function mutations (LOF) in EXT1 and EXT2 result in hereditary exostoses (HME). Interestingly, HS plays a role in pancreas development and beta-cell function, and genetic variations in EXT2 are associated with an increased risk for type 2 diabetes mellitus. We hypothesized that loss of function of EXT1 or EXT2 in subjects with hereditary multiple exostoses (HME) affects pancreatic insulin secretion capacity and development. We performed an oral glucose tolerance test (OGTT) followed by hyperglycemic clamps to investigate first-phase glucose-stimulated insulin secretion (GSIS) in HME patients and age and gender matched non-affected relatives. Pancreas volume was assessed with magnetic resonance imaging (MRI). OGTT did not reveal significant differences in glucose disposal, but there was a markedly lower GSIS in HME subjects during hyperglycemic clamp (iAUC HME: 0.72 [0.46-1.16] vs. controls 1.53 [0.69-3.36] nmol·l-1·min-1, p<0.05). Maximal insulin response following arginine challenge was also significantly attenuated (iAUC HME: 7.14 [4.22-10.5] vs. controls 10.2 [7.91-12.70] nmol·l-1·min-1 p<0.05), indicative of an impaired beta-cell reserve. MRI revealed a significantly smaller pancreatic volume in HME subjects (HME: 72.0±15.8 vs. controls 96.5±26.0 cm3 p = 0.04). In conclusion, loss of function of EXT proteins may affect beta-cell mass and insulin secretion capacity in humans, and render subjects at a higher risk of developing type 2 diabetes when exposed to environmental risk factors.
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Sophie J
authors.initials: SJ
authors.lastname: Bernelot Moens
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Hans L
authors.initials: HL
authors.lastname: Mooij
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: H Carlijne
authors.initials: HC
authors.lastname: Hassing
authors.affiliation: Department of Paediatrics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Janine K
authors.initials: JK
authors.lastname: Kruit
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Julia J
authors.initials: JJ
authors.lastname: Witjes
authors.affiliation: Department of Orthopaedics, LUMC, Leiden, the Netherlands.
authors.forename: Michiel A J
authors.initials: MA
authors.lastname: van de Sande
authors.affiliation: Department of Radiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Aart J
authors.initials: AJ
authors.lastname: Nederveen
authors.affiliation: Department of Cellular and Molecular Medicine, UC San Diego, San Diego, California, United States of America.
authors.forename: Ding
authors.initials: D
authors.lastname: Xu
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands; Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Geesje M
authors.initials: GM
authors.lastname: Dallinga-Thie
authors.affiliation: Department of Cellular and Molecular Medicine, UC San Diego, San Diego, California, United States of America.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Esko
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Erik S G
authors.initials: ES
authors.lastname: Stroes
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands; Department of Cellular and Molecular Medicine, UC San Diego, San Diego, California, United States of America; Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Max
authors.initials: M
authors.lastname: Nieuwdorp
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005097:Exostoses, Multiple Hereditary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005947:Glucose / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D000099065:Exostosin 2; D000099058:Exostosin 1
chemical_list: D007328:Insulin; D017351:N-Acetylglucosaminyltransferases; D000099058:Exostosin 1; D000099065:Exostosin 2; D005947:Glucose