Pörksen S et al. (2010), Disease progression and search for monogenic di...

XB-ART-42085

BMC Endocr Disord 2010 Sep 23;10:16. doi: 10.1186/1472-6823-10-16.

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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 LB , Nielsen L , Louise Max Andersen M , Sandal T , de Wet H , Schwarcz E , Aman J , Swift P , Kocova M , Schönle EJ , de Beaufort C , Hougaard P , Ashcroft F , Molven A , Knip M , Mortensen HB , Hansen L , Njølstad PR , Hvidøre Study Group on Childhood Diabetes .

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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.

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Species referenced: Xenopus
Genes referenced: abcc8 gad1.2 hnf1a hnf4a ins kcnj11 kcnj21 ptprn

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References [+] :

Aguilera, Clinical characteristics, beta-cell function, HLA class II and mutations in MODY genes in non-paediatric subjects with Type 1 diabetes without pancreatic autoantibodies. 2005, Pubmed

Aguilera, Clinical characteristics, beta-cell function, HLA class II and mutations in MODY genes in non-paediatric subjects with Type 1 diabetes without pancreatic autoantibodies. 2005, Pubmed
Babenko, Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. 2006, Pubmed
Bjørkhaug, Hepatocyte nuclear factor-1 alpha gene mutations and diabetes in Norway. 2003, Pubmed
Colombo, Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus. 2008, Pubmed
Fajans, Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. 2001, Pubmed
Flanagan, Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood. 2007, Pubmed
Gloyn, Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. 2004, Pubmed , Xenbase
Lampasona, Zinc transporter 8 antibodies complement GAD and IA-2 antibodies in the identification and characterization of adult-onset autoimmune diabetes: Non Insulin Requiring Autoimmune Diabetes (NIRAD) 4. 2010, Pubmed
Molven, Mutations in the insulin gene can cause MODY and autoantibody-negative type 1 diabetes. 2008, Pubmed
Mortensen, New definition for the partial remission period in children and adolescents with type 1 diabetes. 2009, Pubmed
Nielsen, Impact of IDDM2 on disease pathogenesis and progression in children with newly diagnosed type 1 diabetes: reduced insulin antibody titres and preserved beta cell function. 2006, Pubmed
Njølstad, Neonatal diabetes mellitus due to complete glucokinase deficiency. 2001, Pubmed
Pearson, Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. 2006, Pubmed , Xenbase
Powell, Glutamic acid decarboxylase autoantibody assay using 125I-labelled recombinant GAD65 produced in yeast. 1996, Pubmed
Proks, A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes. 2006, Pubmed , Xenbase
Raeder, A hepatocyte nuclear factor-4 alpha gene (HNF4A) P2 promoter haplotype linked with late-onset diabetes: studies of HNF4A variants in the Norwegian MODY registry. 2006, Pubmed
Rubio-Cabezas, Testing for monogenic diabetes among children and adolescents with antibody-negative clinically defined Type 1 diabetes. 2009, Pubmed
Sabbah, Diabetes-associated autoantibodies in relation to clinical characteristics and natural course in children with newly diagnosed type 1 diabetes. The Childhood Diabetes In Finland Study Group. 1999, Pubmed
Sagen, Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy. 2004, Pubmed
Sandal, The spectrum of ABCC8 mutations in Norwegian patients with congenital hyperinsulinism of infancy. 2009, Pubmed
Savola, IA-2 antibodies--a sensitive marker of IDDM with clinical onset in childhood and adolescence. Childhood Diabetes in Finland Study Group. 1998, Pubmed
Støy, Insulin gene mutations as a cause of permanent neonatal diabetes. 2007, Pubmed
Williams, A novel micro-assay for insulin autoantibodies. 1997, Pubmed
Yamagata, Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1). 1996, Pubmed
Yamagata, Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). 1996, Pubmed
Zung, Glibenclamide treatment in permanent neonatal diabetes mellitus due to an activating mutation in Kir6.2. 2004, Pubmed

	Figure 1. Comparison of disease course in autoantibody-negative and autoantibody-positive children: A: 12 months after disease onset, the residual beta cell function in autoantibody-negative patients was twofold higher than in autoantibody-positive patients (p = 0.002). B: Autoantibody-negative patients had significantly higher proinsulin release 12 months after disease diagnosis than autoantibody-positive subjects (P = 0.01). C: The blood glucose change (90 minutes value minus fasting value) during meal-stimulation differed significantly between autoantibody-negative and autoantibody-positive patients 12 months after disease onset (P = 0.004). D: 12 months after diagnosis autoantibody-negative patients received about 0.15 IU/kg/day less insulin than autoantibody-positive subjects (P = 0.02). E: Autoantibody-negative subjects had 0.8% lower IDAA1c than autoantibody-positive patients (P = 0.02).
	Figure 2. Tolbutamide response in SUR1-R1530C. Whole-cell currents recorded from Xenopus oocytes coexpressing Kir6.2 and either SUR1 (WT) or SUR1-R1530C in response to voltage steps of +20 mV from a holding potential of -10 mV. Bars indicate the times of application of 3 mmol/l azide or 0.5 mmol/l tolbutamide.
	Figure 3. Tolbutamide response in SUR1-R1530C. Mean steady-state whole-cell K-ATP currents (as indicated) evoked by a voltage step from -10 to -30 mV before (rest; grey bars) and after application of 3 mmol/l azide (grey bars) and in the presence of 3 mmol/l azide plus 0.5 mmol/l tolbutamide (black bars). Four oocytes were used for each experiment. *P < 0.05against control (t-test).