Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies
<p style="text-align:justify;"> <b>Background:</b> 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 a...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
BioMed Central
2010
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| _version_ | 1797050252053708800 |
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| author | Pörksen, S Laborie, L Nielsen, L Louise Max Andersen, M Sandal, T De Wet, H Schwarcz, E Aman, J Swift, P Kocova, M Schönle, E de Beaufort, C Hougaard, P Ashcroft, F Molven, A Knip, M Mortensen, H Hansen, L Njølstad, P |
| author_facet | Pörksen, S Laborie, L Nielsen, L Louise Max Andersen, M Sandal, T De Wet, H Schwarcz, E Aman, J Swift, P Kocova, M Schönle, E de Beaufort, C Hougaard, P Ashcroft, F Molven, A Knip, M Mortensen, H Hansen, L Njølstad, P |
| author_sort | Pörksen, S |
| collection | OXFORD |
| description | <p style="text-align:justify;"> <b>Background:</b> 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.<br/><br/> <b>Materials and methods:</b> 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.<br/><br/> <b>Results:</b> 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.<br/><br/> <b>Conclusion:</b> 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. </p> |
| first_indexed | 2024-03-06T18:02:25Z |
| format | Journal article |
| id | oxford-uuid:0042e2d8-e412-4270-8103-5691b55064a8 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:02:25Z |
| publishDate | 2010 |
| publisher | BioMed Central |
| record_format | dspace |
| spelling | oxford-uuid:0042e2d8-e412-4270-8103-5691b55064a82022-03-26T08:28:31ZDisease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 AntibodiesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:0042e2d8-e412-4270-8103-5691b55064a8EnglishSymplectic Elements at OxfordBioMed Central2010Pörksen, SLaborie, LNielsen, LLouise Max Andersen, MSandal, TDe Wet, HSchwarcz, EAman, JSwift, PKocova, MSchönle, Ede Beaufort, CHougaard, PAshcroft, FMolven, AKnip, MMortensen, HHansen, LNjølstad, P <p style="text-align:justify;"> <b>Background:</b> 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.<br/><br/> <b>Materials and methods:</b> 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.<br/><br/> <b>Results:</b> 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.<br/><br/> <b>Conclusion:</b> 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. </p> |
| spellingShingle | Pörksen, S Laborie, L Nielsen, L Louise Max Andersen, M Sandal, T De Wet, H Schwarcz, E Aman, J Swift, P Kocova, M Schönle, E de Beaufort, C Hougaard, P Ashcroft, F Molven, A Knip, M Mortensen, H Hansen, L Njølstad, P Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies |
| title | Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies |
| title_full | Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies |
| title_fullStr | Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies |
| title_full_unstemmed | Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies |
| title_short | Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies |
| title_sort | disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ica gad and ia 2 antibodies |
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