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Carriers of loss-of-function mutations in EXT display impaired pancreatic beta-cell reserve due to smaller pancreas volume. - PubMed - NCBI
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PLoS One. 2014 Dec 26;9(12):e115662. doi: 10.1371/journal.pone.0115662. eCollection 2014.

Carriers of loss-of-function mutations in EXT display impaired pancreatic beta-cell reserve due to smaller pancreas volume.

Author information

1
Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
2
Department of Paediatrics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
3
Department of Orthopaedics, LUMC, Leiden, the Netherlands.
4
Department of Radiology, Academic Medical Center, Amsterdam, the Netherlands.
5
Department of Cellular and Molecular Medicine, UC San Diego, San Diego, California, United States of America.
6
Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands; Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
7
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.

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.

PMID:
25541963
PMCID:
PMC4277348
DOI:
10.1371/journal.pone.0115662
[Indexed for MEDLINE]
Free PMC Article
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