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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	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).