Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies

Pörksen, S.; Laborie, L. B.; Nielsen, L.; Louise Max Andersen, M.; Sandal, T.; de Wet, H.; Schwarcz, E.; Åman, J.; Swift, P.; Kocova, M.; Schönle, E. J.; De Beaufort, Carine; Hougaard, P.; Ashcroft, F.; Molven, A.; Knip, M.; Mortensen, H. B.; Hansen, L.; Njølstad, P. R.

doi:10.1186/1472-6823-10-16

Reference : Disease progression and search for monogenic diabetes among children with new onset t...


	Document type :	Scientific journals : Article
	Discipline(s) :	Human health sciences : Multidisciplinary, general & others
	To cite this reference:	http://hdl.handle.net/10993/27181

Title :	Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies
Language :	English
Author, co-author :	Pörksen, S. [Department of Pediatrics, Glostrup Hospital and University of Copenhagen, Copenhagen, Denmark]
	Laborie, L. B. [Department of Clinical Medicine, University of Bergen, Bergen, Norway, Department of Pediatrics, Haukeland University Hospital, Bergen, Norway]
	Nielsen, L. [Department of Pediatrics, Glostrup Hospital and University of Copenhagen, Copenhagen, Denmark]
	Louise Max Andersen, M. [Department of Pediatrics, Glostrup Hospital and University of Copenhagen, Copenhagen, Denmark]
	Sandal, T. [Department of Clinical Medicine, University of Bergen, Bergen, Norway, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway, Gade Institute, University of Bergen, Bergen, Norway]
	de Wet, H. [Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom]
	Schwarcz, E. [Department of Pediatrics, University Hospital Ørebro, Ørebro, Sweden]
	Åman, J. [Department of Pediatrics, University Hospital Ørebro, Ørebro, Sweden]
	Swift, P. [Department of Pediatrics, Leicester Royal Infirmery Children's Hospital, Leicester, United Kingdom]
	Kocova, M. [Department of Endocrinology and Genetics, Paediatric Clinic, Skopje, Macedonia]
	Schönle, E. J. [Department of Pediatrics, University Childrens Hospital, Zurich, Switzerland]
	De Beaufort, Carine [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
	Hougaard, P. [Department of Biostatistics, University of Southern Denmark, Odense, Denmark]
	Ashcroft, F. [Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom]
	Molven, A. [Gade Institute, University of Bergen, Bergen, Norway]
	Knip, M. [Department of Pediatrics, Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland]
	Mortensen, H. B. [Department of Pediatrics, Glostrup Hospital and University of Copenhagen, Copenhagen, Denmark]
	Hansen, L. [Department of Pediatrics, Glostrup Hospital and University of Copenhagen, Copenhagen, Denmark]
	Njølstad, P. R. [Department of Clinical Medicine, University of Bergen, Bergen, Norway, Department of Pediatrics, Haukeland University Hospital, Bergen, Norway]
Publication date :	2010
Journal title :	BMC Endocrine Disorders
Volume :	10
Peer reviewed :	Yes (verified by ORBi^lu)
ISSN :	14726823
Keywords :	[en] ABC transporter ; Xenopus ; disease progression ; monogenic diabetes ; type 1 diabetes ; ICA ; GAD ; IA-2 ; antibodies
Abstract :	[en] Background: To investigate disease progression the first 12 months after diagnosis in children with type 1 diabetes negative (AAB negative) for pancreatic autoantibodies [islet cell autoantibodies(ICA), glutamic acid decarboxylase antibodies (GADA) and insulinoma-associated antigen-2 antibodies (IA-2A)]. Furthermore the study aimed at determining whether mutations in KCNJ11, ABCC8, HNF1A, HNF4A or INS are common in AAB negative diabetes.Materials and methods: In 261 newly diagnosed children with type 1 diabetes, we measured residual β-cell function, ICA, GADA, and IA-2A at 1, 6 and 12 months after diagnosis. The genes KCNJ11, ABCC8, HNF1A, HNF4A and INS were sequenced in subjects AAB negative at diagnosis. We expressed recombinant K-ATP channels in Xenopus oocytes to analyse the functional effects of an ABCC8 mutation.Results: Twenty-four patients (9.1%) tested AAB negative after one month. Patients, who were AAB-negative throughout the 12-month period, had higher residual β-cell function (P = 0.002), lower blood glucose (P = 0.004), received less insulin (P = 0.05) and had lower HbA1c(P = 0.02) 12 months after diagnosis. One patient had a heterozygous mutation leading to the substitution of arginine at residue 1530 of SUR1 (ABCC8) by cysteine. Functional analyses of recombinant K-ATP channels showed that R1530C markedly reduced the sensitivity of the K-ATP channel to inhibition by MgATP. Morover, the channel was highly sensitive to sulphonylureas. However, there was no effect of sulfonylurea treatment after four weeks on 1.0-1.2 mg/kg/24 h glibenclamide.Conclusion: GAD, IA-2A, and ICA negative children with new onset type 1 diabetes have slower disease progression as assessed by residual beta-cell function and improved glycemic control 12 months after diagnosis. One out of 24 had a mutation in ABCC8, suggesting that screening of ABCC8 should be considered in patients with AAB negative type 1 diabetes. © 2010 Pörksen et al; licensee BioMed Central Ltd.
Permalink :	http://hdl.handle.net/10993/27181
DOI :	10.1186/1472-6823-10-16

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