Prävalenz und Bedeutung der diabetes-spezifischen Autoantikörper GADA, IA-2A und IAA zum Zeitpunkt der Manifestation eines Typ-1-Diabetes bei 341 Kindern und Jugendlichen

Zusammenfassung

Ziel dieser Arbeit war die Charakterisierung eines großen Patientenkollektivs von Kindern und Jugendlichen mit Typ-1-Diabetes (T1D) in Deutschland hinsichtlich der Prävalenz einzelner und multipler Diabetes-spezifischer Autoantikörper zum Zeitpunkt der Manifestation der Erkrankung. 341 Kinder und Jugendliche (53,1 % Knaben) mit T1D-Manifestation im Alter von 8,9 ± 4,2 Jahren (Bereich 0-17 Jahre) nahmen im Zeitraum von 1989 bis 2004 an dieser Auswertung teil. Die T1D-spezifischen Autoantikörper GADA, IA-2A und IAA wurden mittels Radioimmunoassay (Medipan, Berlin-Dahlewitz, Deutschland) innerhalb der ersten 12 Wochen nach T1D-Manifestation bestimmt. 73 % der Patienten waren positiv für IA-2A, 72 % für GADA und 46 % für IAA. Die überwiegende Mehrheit der Patienten (92 %) hatte mindestens einen erhöhten T1D-spezifischen Autoantikörper, während nur 8 % keine Autoantikörper aufwiesen. Knaben sowie jüngere Kinder waren für IAA signifikant häufiger positiv als Mädchen (p < 0,01) bzw. ältere Kinder (p < 0,05). GADA-positive Patienten waren bei T1D-Manifestation älter als GADA-negative Patienten (p < 0,001). Insgesamt waren 80 % der über 12-Jährigen positiv für GADA, während dies nur bei 57 % der unter 6-Jährigen der Fall war (p < 0,001). Diese Ergebnisse zeigen, dass bei mehr als 90 % der Patienten mit Typ-1-Diabetes diabetes-spezifische Autoantikörper bereits zum Zeitpunkt der Manifestation nachweisbar sind. Somit ist die T1D-AAK-Bestimmung weiterhin eine wichtige diagnostische Untersuchung, um den Typ-1-Diabetes frühzeitig zu erkennen und ihn von anderen Diabetesformen im Kindes- und Jugendalter abzugrenzen.

Abstract

Aim of this study was to assess the prevalence of diabetes-specific autoantibodies in a large German cohort of children and adolescents at the time of diagnosis of type 1 diabetes (T1D). A total of 341 patients (53.1 % male) diagnosed with T1D between 1989 and 2004 (mean age 8.9 ± 4.2 years, range 0-17 years) participated in the study. The T1D-specific autoantibodies GADA, IA-2A and IAA were determined by radioimmunoassay (Medipan, Berlin-Dahlewitz, Germany) within twelve weeks from T1D onset. 73 % of patients were positive for IA-2A, 72 % for GADA and 46 % for IAA. The vast majority of patients (92 %) had at least one antibody, while 8 % were negative for all three antibodies. Boys and younger children were more frequently positive for IAA than girls (p < 0.01) or older children (p < 0.05), respectively. GADA positive patients were older at T1D onset than those without GADA (p < 0.001). These results indicate that more than 90 % of young patients with T1D are positive for diabetes-specific antibodies at the time of clinical diagnosis of the disease. Thus, determination of these antibodies is an important tool for an early diagnosis and differentiation of type 1 diabetes from other diabetes forms in childhood and adolescence.

Typ-1-Diabetes - Kinder - Jugendliche - GADA - IAA - IA-2A - Altersunterschiede

type 1 diabetes - GADA - IAA - IA-2A - children - adolescents - age differences

Literatur

• 1 Bottazzo G F, Florin-Christensen A, Doniach D. Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies.  Lancet. 1974;  30 1279-1283
• 2 Gillespie K M. Type 1 diabetes: pathogenesis and prevention.  CMAJ. 2006;  175 165-170
• 3 Baekkeskov S, Warnock G, Christie M et al. Revelation of specificity of 64 K autoantibodies in IDDM serums by high-resolution 2-D gel electrophoresis. Unambiguous identification of 64 K target antigen.  Diabetes. 1989;  38 1133-1141
• 4 Achenbach P, Warncke K, Reiter J et al. Stratification of type 1 diabetes risk on the basis of islet autoantibody characteristics.  Diabetes. 2004;  53 384-389
• 5 Lan M S, Wasserfall C, Maclaren N K et al. IA-2A, a transmembrane protein of the protein tyrosine phosphatise family, is a major autoantigen in insulin-dependent diabetes mellitus.  Proc Natl Acad Sci USA. 1996;  93 6367-6370
• 6 Leslie R D, Atkinson M A, Notkins A L. Autoantigens IA-2A and GADA in type 1 (insulin-dependent) diabetes.  Diabetologia. 1999;  42 3-14
• 7 EURODIAB ACE Study Group . Variation and trends in incidence of childhood diabetes in Europe.  Lancet. 2000;  356 1690
• 8 Seissler J, de Sonnaville J J, Morgenthaler N G et al. Immunological heterogeneity in type 1 diabetes: presence of distinct autoantibody patterns in patients with acute onset and slowly progressive disease.  Diabetologia. 1998;  41 891-897
• 9 Verge C F, Howard N J, Rowley M J et al. Anti-glutamate decarboxylase and other antibodies at the onset of childhood IDDM: a population-based study.  Diabetologia. 1994;  37 1113-1120
• 10 Ziegler A G, Hummel M, Schenker M et al. Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes: the 2-year analysis of the German BABYDIAB study.  Diabetes. 1999;  48 460-468
• 11 Schmidt K D, Valer C, Leslie R D. Autoantibodies in type 1 diabetes.  Clinica Chimica Acta. 2005;  354 35-40
• 12 Blu D -F, Erlander M G, Hitz B C et al. Two human glutamate decarboxylases, 65-kD GADA and 67-kD GADA, are each encoded by a single gene.  Proc Natl Acad Sci. 1992;  89 2115-2119
• 13 Lühder F, Woltanski K P, Mauch L et al. Detection of autoantibodies to the 65-kD isoform of glutamate decarboxylase by radioimmunoassay.  Eur J Endocrinol. 1994;  130 575-580
• 14 Kordonouri O, Meyer K, Egerer K et al. Prevalence of 20 S proteasome, anti-nuclear and thyroid antibodies in young patients at onset of type 1 diabetes mellitus and the risk of autoimmune thyroiditis.  JPEM. 2004;  17 975-981
• 15 Atkinson M A, Kaufman D L, Newman D et al. Islet cell cytoplasmatic autoantibody reactivity to glutamate decarboxylase in insulin-dependent diabetes.  J Clin Invest. 1993;  91 350-356
• 16 Decochez K, DeLeeuw I C, Keymeulen B et al. IA-2A autoantibodies predict impending type I diabetes in siblings of patients. Belgian Diabetes Registry.  Diabetologia. 2002;  45 1658-1666
• 17 Kobayashi T, Tanaka S, Okubo M et al. Unique epitopes of glutamic acid decarboxylase autoantibodies in slowly progressive type 1 diabetes.  J Clin Endocrinol Metab. 2003;  88 4768-4775
• 18 Lohmann T, Hawa M, Leslie R D et al. Immune reactivity to glutamic acid decarboxylase 65 in Stiff-Man Syndrome and Type 1 diabetes.  Lancet. 2000;  356 31-35
• 19 Yu L, Robles D T, Abiru N et al. Early expression of antiinsulin antibodies of humans and NOD mouse: evidence for early determination of subsequent diabetes.  Proc Natl Acad Aci USA. 2000;  97 1701-1706
• 20 Palmer J P. Insulin autoantibodies: their role in the pathogenesis of IDDM.  Diabetes Metab Rev. 1987;  3 1005-1015
• 21 Vandewalle C L, Decraene T, Schuit F C et al. Insulin autoantibodies and high titre islet cell antibodies are preferentially associated with the HLA DQA1*0301-DQB1*0302 haplotype at clinical type 1 diabetes mellitus before age 10 years, but not at onset between age 10 and 40 years. The Belgian Diabetes Registry.  Diabetologia. 1993;  36 1155-1162
• 22 Vardi P, Ziegler A G, Mathews J H et al. Concentration of insulin autoantibodies at onset of type 1 diabetes. Inverse log-linear correlation with age.  Diabetes Care. 1988;  11 736-739
• 23 Bingley P J, Bonifacio E, Williams A J et al. Predicition of IDDM in the general popluation: strategies based on combinations of autoantibody marker.  Diabetes. 1997;  46 1701-1710
• 24 Ziegler A G, Rabl W, Albert E. Insulin autoantibodies and islet cell antibodies in recently appearing diabetes mellitus type 1. Association with age of manifestation and HLA phenotype.  Dtsch Med Wochenschr. 1991;  116 1737-1741
• 25 Kordonouri O, Hartmann R, Grüters-Kieslich A et al. Age-specific levels of diabetes-related GADA and IA-2A antibodies in healthy children and adults.  J Pediatr Endocrinol Metab. 2002;  15 47-52
• 26 Irvine W J, Gray R S, McCallum C J. Pancreatic islet-cell antibody as a marker for asymptomatic and latent diabetes and prediabetes.  Lancet. 1976;  2 1097-1102
• 27 Decochez K, Truyen I, van der Auwera B et al. Combined positivity for HLA DQ2 / DQ8 and IA-2A antibodies defines populations at high-risk of developing type I diabetes.  Diabetologia. 2005;  48 687-694
• 28 Verge C F, Stenger D, Bonifacio E et al. Combined use of autoantibodies (IA-2A autoantibody, GADA autoantibody, insulin autoantibody, cytoplasmatic islet cell antibodies) in type diabetes: Combinatorial Islet Autoantibody Workshop.  Diabetes. 1998;  47 1857-1866
• 29 Seissler J, Amann J, Mauch L et al. Prevalence of autoantibodies to the 65- and 67- kDa isoforms of glutamate decarboxylase in insulin-dependent diabetes mellitus.  J Clin Invest. 1993;  92 1394-1399
• 30 Ludvigsson J, Hellström S. Autoantibodies in relation to residual insulin secretion in children with IDDM.  Diabetes Research and Clinical Practice. 1997;  35 81-89
• 31 Winter W E, Harris N, Schatz D. Type 1 diabetes islet autoantibody markers.  Diabetes Technol Ther. 2002;  4 817-839
• 32 Sabbah E, Savola K, Ebeling T et al. Genetic, autoimmune, and clinical characteristics of childhood and adult-onset type 1 diabetes.  Diabetes Care. 2000;  23 1326-1332
• 33 Sabbah E, Savola K, Kulmala P et al. Diabetes-associated autoantibodies in relation to clinical characteristics and natural course in children with newly diagnosed type 1 diabetes.  J Clin Endocrinol Metab. 1999;  84 1534-1539
• 34 Mandrup-Poulsen T R. Auto-antibodies against glutamic acid decarboxylase and diabetes.  Ugeskr Laeger. 2007;  169 300-304
• 35 Chang Y H, Shiau M Y, Tsai S T et al. Autoantibodies against IA-2A, GADA, and topoisomerase II in type 1 diabetic patients.  Biochem Biophys Res Commun. 2004;  320 802-809
• 36 Bilbao J R, Rica I, Vasquez J A et al. Influence of sex and age at onset on autoantibodies against insulin, GADA65, IA2 in recent onset type 1 diabetic patients.  Hormone Research. 2000;  54 181-185
• 37 Zimmet P Z, Elliott R B, Mackay I R et al. Autoantibodies to glutamic acid decarboxylase and insulin in islet cell antibody positive presymptomatic type 1 diabetes mellitus: frequency and segregation by age and gender.  Diabet Med. 1994;  11 866-871
• 38 Karvonen M, LaPorte R, Viik-Kajander M et al. Incidence of childhood type 1 diabetes worldwide.  Diabetes Care. 2000;  23 1516-1526
• 39 Serreze D V, Chen Y G. Of mice and men: use of animal models to identify possible interventions for the prevention of autoimmune type 1 diabetes in humans.  Trends in Immunology. 2005;  26 603-607
• 40 Ludvigsson J, Vaarala O, Forsander G et al. GAD65-vaccination preserves residual insulin secretion in children and adolescents with recent onset type 1 diabetes: Results of a randomized controlled phase II trial.  Pediatr Diab. 2007;  8 (Suppl 7) 14