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)