Islet-cell antibodies and beta-cell function in insulin-dependent diabetics

Diabetologia S. Madsbad 1 G. F. Bottazzo 1 A. G. Cudworth 1 B. D e a n 1 O. K. Faber 1 C. Binder 0 1 0 Present address: Steno Memorial Hospital , Gentofte , Denmark 1 Hvidore Hospital , Klampenborg , Denmark; Department of Immunology, The Middlesex Hospital Medical School and Department of Medicine, St. Bartholomew's Hospital , London, England S u m m a r y . Residual insulin secretion and islet-cell antibodies w e r e studied in 399 insulin-dependent diabetics with age at onset of b e t w e e n 1 0 - 1 9 . 9 years (248 patients) or 3 0 - 3 9 . 9 years (151 patients). W e found the prevalence of islet-cell antibodies to b e i n d e p e n d e n t of residual beta-cell function as m e a s - u r e d by s e r u m C - p e p t i d e and age at onset. T h e cause and role of the persistence of islet-cell antibodies in insulin-dependent diabetics r e m a i n obscure. I n s u l i n - d e p e n d e n t diabetics; beta-cell function; islet-cell antibodies - A g o o d deal of evidence has n o w accumulated conc e m i n g the possible aetiological role of b o t h h u m o r a l [ 1, 2, 3, 4, 5 ] and cell m e d i a t e t d i m m u n i t y [ 6, 7, 8, 9 ] in insulin-dependent diabetes. Islet-cell antibodies ( I C A ) were first d e m o n strated in 1974 [ 1 ] in patients with polyendocrine a u t o i m m u n e disease. T h e precise n a t u r e and location of the antigen remains to b e elucidated, but it is a cytoplasmic c o m p o n e n t c o m m o n to all four types of islet-cells [ 10 ]. T h e m a j o r i t y of patients h a v e I C A at the time of onset of diabetes, but after 10 years of disease only 5 - 1 5 % are still positive [ 11, 12, 13, 14 ]. W e h a v e also f o u n d that the prevalence of residual beta-cell function was almost 100% during the first two years of disease, and a b o u t 15% after 10 years of diabetes [15 ]. If the beta-cell is the antigenic stimulus to I C A - p r o d u c t i o n , patients with residual beta-cell function would h a v e a higher p r e v a l e n c e of I C A than those without beta-cells and hence n o possibility for antibody stimulation. In o n e such study it was shown that only one out of 13 insulin-dependent patients with circulating I C A had d e m o n s t r a b l e beta-cell function [ 16 ]. T h e p u r p o s e of the p r e s e n t study was to evaluate w h e t h e r an association exists b e t w e e n residual b e t a cell function and I C A in a larger population of insulin-dependent diabetics with onset of disease between the age of 1 0 - 1 9 , or 3 0 - 3 9 respectively, i. e. a ten y e a r span in each case. T h e difference in age at onset was chosen because of a previously d e m o n strated direct relationship b e t w e e n age at onset and prevalence of p r e s e r v e d beta-cell function [ 15 ]. Materials and Methods Study Population The study population (399 patients) was part of a larger series previously described [ 15 ]. It comprised 248 diabetic patients with age at onset 10-19, and 151 patients with age at onset 30-39. The average duration of diabetes was 16 years (range 0-52) in the early onset group and 13 years (range 0--42) in the late onset group. Patients were considered insulin-dependent if insulin treatment was started for initial hyperglycaemia with ketonuria, or became necessary within the first year after diagnosis. None of the patients were taking drugs known to influence immune response. Twenty patients had other endocrine or autoimmune disorders: Five had myxoedema, one with postadrenalectomy adrenocortical insufficiency, two with thyroiditis of which one also had pernicious anaemia, a further two with pernicious anaemia, and ten with previous or actual thyrotoxicosisof whichone had concommitantpernicious anemia. Patients with pancreatic disorders in addition to diabetes mellitus were excluded from the study. All patients gave informed consent to the investigation. Methods Residual beta-cell function was assessed by the C-peptide immunoreactivity (CPR) obtained followingstimulation with 1 mg of glucagon or breakfast [ 17 ]. CPR was determined employing - ICA -ICA -ICA ~ .,cA ;; + ICA -~ a, y~ 0 ICA "-'1 I Cl - ICA ",ICA ',I~II § - ICA AGE OF ONSET 30-39.9 YEARS - ICA ici l N-ICA AGE OF ONSET 10-19.9 YEARS - ICA -- ICA -ICA .,ci+ICA i antibody M 1230 [ 18 ], and residual beta-cell function was considered present when CPR in plasma was equal to or exceeded 0.06 pmol/ml, which is the detection limit of the assay. Islet-cell antibodies were detected by the indirect immunofluorescence test on undiluted serum as previously described [ 1 ]. All probability values were derived by use of the chi-squared test. Results Residual beta-cell function was present in 54 patients (21.7%) with early onset diabetes and in 61 (40.4%) with late onset (p < 0.01). The prevalence was almost 100 per cent during the first 2 years of disease and thereafter lower in diabetics with early onset and up to 15 years of disease (Fig. (...truncated)