[en] We investigated inaugural disease phenotype in relation to the presence or absence of diabetes-associated autoantibodies and human leukocyte antigen (HLA) DQ risk genotypes in adult-onset diabetic patients. Blood samples and questionnaires were obtained from 1584 recent-onset Belgian Caucasian patients (age 15-39 yr at diagnosis of primary diabetes) who were recruited by the Belgian Diabetes Registry over an 11-yr period. At clinical diagnosis, antibody-positive patients (n = 1198) were on average younger and had more symptoms, a more acute disease onset, lower body mass index, and random C-peptide levels, but higher insulin needs, glycemia, and prevalence of ketonuria, HLA-DQ, and 5' insulin gene susceptibility genotypes (P < 0.001 vs. antibody-negative patients; n = 386). In antibody-positive patients, these characteristics did not differ according to HLA-DQ genotype. However, in antibody-negative subjects, we found that patients were younger (P = 0.001); had a lower body mass index (P < 0.001), higher insulin needs (P = 0.014), and amylasemia (P = 0.001); and tended to have a higher glycemia and lower C-peptide in the presence of susceptible HLA-DQ genotypes. Differences according to HLA-DQ genotype subsisted after careful age-matching. In conclusion, we found no relation between initial disease phenotype and HLA-DQ genotype in antibody-positive diabetic young adults. In contrast, antibody-negative patients displayed more type I-like features when carrying susceptible HLA-DQ genotypes known to promote the development of antibody-positive diabetes. The overrepresentation of these susceptibility genotypes in antibody-negative patients suggests the existence of an immune-mediated disease process with as yet unidentified immune markers in a subgroup of seronegative patients.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Weets, Ilse; Vrije Universiteit Brussel - VUB > Diabetes Research Center (I.W., B.K., F.C.S., B.V.D.A., M.R., P.D.P., F.K.G.)
Siraux, Valérie; Cliniques Universitaires de Bruxelles - Hôpital Erasme > Department of Endocrinology (V.S., F.F.)
Daubresse, Jean-Claude ; Université de Liège - ULiège > Département des sciences cliniques > Département des sciences cliniques
De Leeuw, Ivo H.; Universitair Ziekenhuis Antwerpen - UZA > Department of Endocrinology (I.H.D.L., L.V.G.)
Féry, Françoise; Cliniques Universitaires de Bruxelles - Hôpital Erasme > Department of Endocrinology (V.S., F.F.)
Keymeulen, Bart; Vrije Universiteit Brussel - VUB > Diabetes Research Center (I.W., B.K., F.C.S., B.V.D.A., M.R., P.D.P., F.K.G.)
Krzentowski, Georges; Centre Hospitalier Universitaire Charleroi > Department of Endocrinology (J.-C.D., G.K.)
Letiexhe, Michel ; Centre Hospitalier Universitaire de Liège - CHU > Maladies infectieuses et médecine interne générale
Mathieu, Chantal; Universitair Ziekenhuizen Leuven - UZ Leuven > Department of Endocrinology (C.M.)
Nobels, Frank; OLV Ziekenhuis Aalst > Department of Endocrinology (F.N.)
Rottiers, Raoul; Universitair Ziekenhuis Gent - UZ > Department of Endocrinology (R.R.)
Scheen, André ; Université de Liège - ULiège > Département des sciences cliniques > Diabétologie, nutrition et maladie métaboliques - Médecine interne générale
Van Gaal, Luc; Universitair Ziekenhuis Antwerpen > Department of Endocrinology (I.H.D.L., L.V.G.)
Schuit, Frans C.; Vrije Universiteit Brussel - VUB > Diabetes Research Center (I.W., B.K., F.C.S., B.V.D.A., M.R., P.D.P., F.K.G.)
Van Der Auwera, Bart; Vrije Universiteit Brussel - VUB > Diabetes Research Center (I.W., B.K., F.C.S., B.V.D.A., M.R., P.D.P., F.K.G.)
Rui, Mao; Vrije Universiteit Brussel - VUB > Diabetes Research Center (I.W., B.K., F.C.S., B.V.D.A., M.R., P.D.P., F.K.G.)
De Pauw, Peter; Vrije Universiteit Brussel - VUB > Diabetes Research Center (I.W., B.K., F.C.S., B.V.D.A., M.R., P.D.P., F.K.G.)
Kaufman, Leonard; Vrije Universiteit Brussel - VUB > Department of Biostatistics (L.K.)
Gorus, F. K.; Vrije Universiteit Brussel - VUB > Diabetes Research Center (I.W., B.K., F.C.S., B.V.D.A., M.R., P.D.P., F.K.G.)
Krolewski A.S., Warram J.H., Rand L.I., Kahn C.R. (1987) Epidemiologic approach to the etiology of type 1 diabetes mellitus and impaired glucose tolerance in adults. N Engl J Med 317:1390-1398.
Leslie D.R.G., Elliott R.B. (1994) Early environmental events as a cause of IDDM. Evidence and implications. Diabetes 43:843-850.
Gorus F.K. (1997) Diabetes registries and early biological markers of insulin-dependent diabetes mellitus. Diabetes Metab Rev 4:247-274.
Östman J., Lernmark Å., Landin-Olsson M., Sundkvist G., Palmer J., Arnqvist H., Blohme G., Lithner F., Littorin B., Nyström L., Schersten B., Wibell L. (1996) Autoimmune (type 1) diabetes in young adults in Sweden. Horm Metab Res 28:348-350.
Mølbak A.G., Christau B., Marner B., Borch-Johnsen K., Nerup J. (1994) Incidence of insulin-dependent diabetes mellitus in age groups over 30 years in Denmark. Diabet Med 11:299-303.
Zimmet P.Z. (1995) The pathogenesis and prevention of diabetes in adults. Diabetes Care 18:1050-1064.
(1997) Report of the Expert Committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 20:1183-1197.
Alberti K.G.M.M., Zimmet P.Z. (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1, Diagnosis and classification of diabetes mellitus: Provisional report of a WHO consultation. Diabet Med 15:539-553.
Gale E.A.M., Gillespie K.M. (2001) Diabetes and gender. Diabetologia 44:3-15.
Karjalainen J., Salmela P., Ilonen J., Surcel H.M., Knip M. (1989) A comparison of childhood and adult type 1 diabetes mellitus. N Engl J Med 320:881-886.
Vandewalle C.L., Decraene T., Schuit F.C., De Leeuw I.H., Pipeleers D.G., Gorus F.K. (1993) Insulin autoantibodies and high titre islet cell antibodies are preferentially associated with the HLA DQA1*0301-DQB*0302 haplotype at clinical onset of type 1 (insulin-dependent) diabetes mellitus before age 10 years, but not at onset between age 10 and 40 years. Diabetologia 36:1155-1162.
Caillat-Zucman S., Garchon H.J., Timsit J., Assan R., Boitard C., Djilali-Saiah I., Bougnères P., Bach J.F. (1992) Age-dependent HLA genetic heterogeneity of type 1 insulin-dependent diabetes mellitus. J Clin Invest 90:2242-2250.
Pipeleers D., Ling Z. (1992) Pancreatic β-cells in insulin-dependent diabetes. Diabetes Metab Rev 8:209-227.
Weets I., Van der Auwera B.J., Schuit F.C., Du Caju M.V., Decochez K., Van Autreve J., De Leeuw I.H., Keymeulen B., Mathieu C., Rottiers R., Dorchy H., Quartier E., Gorus F.K. (2001) Male-to-female excess in diabetes diagnosed in early adulthood is not specific for the immune-mediated form nor is it HLA-DQ restricted: Possible relation to increased body mass index. Diabetologia 44:40-47.
Pozzilli P., Visalli N., Buzzetti R., Cavallo M.G., Marietti G., Hawa M., Leslie R.D. (1998) Metabolic and immune parameters at clinical onset of insulin-dependent diabetes: A population-based study. Metabolism 47:1205-1210.
Turner R., Stratton I., Horton V., Manley S., Zimmet P., Mackay I.R., Shattock M., Bottazzo G.F., Holman R. (1997) UKPDS 25: Autoantibodies to islet cytoplasm and glutamic acid decarboxylase for prediction of insulin requirements in type 2 diabetes. Lancet 350:1288-1293.
Groop L., Bottazzo G.F., Doniach D. (1986) Islet cell antibodies identify latent type 1 diabetes in patients aged 35-75 years at diagnosis. Diabetes 35:237-241.
.
Imagawa A., Hanafusa T., Miyagawa J.-I., Matsuzawa Y. (2000) A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. N Engl J Med 342:301-307.
Carreras G., Mauricio D., Pérez A., De Leiva A. (2000) Can all newly diagnosed subjects without type 1 diabetes-associated autoimmune markers be classified as type 1b diabetic patients?. Diabetes Care 23:1715-1716.
Tiberti C., Buzzetti R., Anastasi E., Dotta F., Vasta M., Petrone A., Cervoni M., Torresi P., Vecci E., Multari G., Di Mario U. (2000) Autoantibody negative new onset type 1 diabetic patients lacking high risk HLA genes in a Caucasian population: Are these type 1b diabetes cases?. Diabetes Metab Res Rev 16:8-14.
Landin-Olsson M., Arnquist H.J., Blohmé G., Littorin B., Lithner F., Nyström L., Schersten B., Sundkvist G., Wibell L., Ostman J., Lernmark A. (1999) Appearance of islet cell autoantibodies after clinical diagnosis of diabetes mellitus. Autoimmunity 29:57-63.
Decochez K., Tits J., Coolens J.-L., Van Gaal L., Krzentowski G., Winnock F., Anckaert E., Weets I., Pipeleers D.G., Gorus F.K. (2000) High frequency of persisting or increasing islet-specific autoantibody levels after diagnosis of insulin-requiring type 1 diabetes presenting before 40 years of age. Diabetes Care 23:838-844.
(1979) Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 28:1039-1057.
Vandewalle C.L., Coeckelberghs M.I., De Leeuw I.H., Du Caju M.V., Schuit F.C., Pipeleers D.G., Gorus F.K. (1997) Epidemiology, clinical aspects, and biology of IDDM patients under age 40 years. Diabetes Care 20:1556-1561.
Vandewalle C., Falorni A., Svanholm S., Lernmark A., Pipeleers D.G., Gorus F.K. (1995) High diagnostic sensitivity of glutamate decarboxylase autoantibodies in insulin-dependent diabetes mellitus with clinical onset between age 20 and 40 years. J Clin Endocrinol Metab 80:846-851.
Vandewalle C., Falorni A., Lernmark A., Goubert P., Dorchy H., Coucke W., Semakula C., Van der Auwera B., Kaufman L., Schuit P.C., Pipeleers D.G., Gorus F.K. (1997) Associations of GAD65- and IA-2-autoantibodies with genetic risk markers in new-onset IDDM patients and their siblings. Diabetes Care 20:1547-1552.
Verge C.F., Stenger D., Bonifacio E., Colman P.G., Pilcher C., Bingley P.J., Eisenbarth G.S. (1998) Combined use of autoantibodies (IA2ab, GADab, IAA, ICA): Combinatorial islet autoantibody workshop. Diabetes 47:1857-1866.
Heimberg H., Nagy Z.P., Somers G., De Leeuw I., Schuit F.C. (1992) Complementation of HLA-DQA and -DQB genes confers susceptibility and protection to insulin-dependent diabetes mellitus. Hum Immunol 320:10-17.
Van der Auwera B.J., Schuit F.C., Lyaruu I., Falorni A., Svanholm S., Vandewalle C.L., Gorus F.K. (1995) Genetic susceptibility for insulin-dependent diabetes mellitus in Caucasians revisited: The importance of diabetes registries in disclosing interactions between HLA-DQ- and insulin gene-linked risk. J Clin Endocrinol Metab 80:2567-2573.
Van der Auwera B., Schuit F.C., Weets I., Ivens A., Van Autreve J., Gorus F.K. (2002) Relative and absolute HLA-DQA1-DQB1-linked risk for developing type 1 diabetes before age 40 years in the Belgian population: Implication for future prevention studies. Hum Immunol 63:40-50.
Livak K.J., Marmaro J., Todd J.A. (1995) Towards fully automated genome-wide polymorphism screening. Nat Genet 9:341-342.
Keymeulen B., Ling Z., Gorus F.K., Delvaux G., Bouwens L., Grupping A., Hendrieckx C., Pipeleers-Marichal M., Van Schravendijk C., Salmela K., Pipeleers D.G. (1998) Implantation of standardized β-cell grafts in a liver segment of IDDM patients: Graft and recipient characteristics in two cases of insulin-independence under maintenance immunosuppression for prior kidney graft. Diabetologia 41:452-460.
Semakula C., Vandewalle C., Van Schravendijk C., Sodoyez J.C., Schuit F.C., Foriers A., Falorni A., Craen M., Decraene P., Pipeleers D.G., Gorus F.K. (1996) Abnormal circulating pancreatic enzyme activities in more than twenty-five percent of recent-onset insulin-dependent diabetic patients: Association of hyperlipasemia with high-titer islet cell antibodies. Pancreas 12:321-333.
Bland J.M., Altman D.G. (1995) Multiple significance tests: The Bonferroni method. BMJ 310:170.
Tuomi T., Groop L., Zimmet P.Z., Rowley M.J., Knowles W., Mackay I.R. (1993) Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease. Diabetes 42:359-363.
Arnqvist H.J., Littorin B., Nyström L., Schersten B., Ostman J., Blohme G., Lithner F., Wibell L. (1993) Difficulties in classifying diabetes at presentation in the young adult. Diabet Med 10:606-613.
Bruno G., De Salvia A., Arcari R., Borra M., Grosso N., Carta Q., Trovati M., Veglio M., Pagano G. (1999) Clinical, immunological, and genetic heterogeneity of diabetes in an Italian population-based cohort of lean newly diagnosed patients aged 30-54 years. Diabetes Care 22:50-55.
Horton V., Stratton I., Bottazzo G.F., Shattock M., Mackay I., Zimmet P., Manley S., Holman R., Turner R. (1999) Genetic heterogeneity of autoimmune diabetes: Age of presentation in adults is influenced by HLA DRB1 and DQB1 genotypes (UKPDS 43). Diabetologia 42:608-616.
Sabbah E., Savola K., Ebeling T., Kulmala P., Vahasalo P., Ilonen J., Salmela P.I., Knip M. (2000) Genetic, autoimmune, and clinical characteristics of childhood and adult-onset type 1 diabetes. Diabetes Care 23:1326-1332.
Ludvigsson J., Samuelsson U., Beauforts C., Deschamps I., Dorchy H., Drash A., Francois R., Herz G., New M., Schober E. (1986) HLA-DR3 is associated with a more slowly progressive form of type 1 (insulin-dependent) diabetes. Diabetologia 29:207-210.
Veijola R., Knip M., Reijonen H., Vahasalo P., Puukka R., Ilonen J. (1995) Effect of genetic risk load defined by HLA DQB1 polymorphism on clinical characteristics of IDDM in children. Eur J Clin Invest 25:106-112.
Winnock F., Christie M.R., Batstra M.R., Aanstoot H.J., Weets I., Decochez K., Jopart P., Nicolaij D., Gorus F.K. (2001) Autoantibodies to a 38 kDa glycosylated islet cell membrane antigen are specific markers of (pre)type 1 diabetes: Association with autoantibodies against IA-2 and islet cell antigens. Diabetes Care 24:1181-1186.
Lernmark Å. (2000) Rapid-onset type 1 diabetes with pancreatic endocrine dysfunction. N Engl J Med 342:344-345.
Pietropaolo M., Becker D.J., LaPorte R.E., Dorman J.S., Riboni S., Rudert W.A., Mazumdar S., Trucco M. (2002) Progression to insulin-requiring diabetes inseronegative prediabetic subjects: The role of two distinct HLA-DQ high-risk haplotypes. Diabetologia 45:66-76.
Piñero-Liloña A., Litonjua P., Aviles-Santa L., Raskin P. (2001) Idiopathic type 1 diabetes in Dallas, Texas. A 5-year experience. Diabetes Care 24:1014-1018.
Lehto M., Wipemo C., Ivarsson S.A., Lindgren C., Lipsanen-Nyman M., Weng J., Wibell L., Widen E., Tuomi T., Groop L. (1999) High frequency of mutation in MODY and mitochondrial genes in Scandinavian patients with familial early-onset diabetes. Diabetologia 42:1131-1137.
Dussoix P., Vaxillaire M., Iynedjian P.B., Tiercy J.M., Ruiz J., Spinas G.A., Berger W., Zahnd G., Froguel P., Philippe J. (1997) Diagnostic heterogeneity of diabetes in lean young adults. Classification based on immunologic and genetic parameters. Diabetes 46:622-631.
Withers D.J., Burks D.J., Towery H.H., Altamuro S.L., Flint C.L., White M.F. (1999) Irs-2 coordinates Igf-1 receptor-mediated β-cell development and peripheral insulin signaling. Nat Genet 23:32-40.
Le Stunff C., Fallin D., Schork N.J., Bougnères P. (2000) The insulin gene VNTR is associated with fasting insulin levels and development of juvenile obesity. Nat Genet 26:444-446.