Clinical Chemistry 43: 2358-2363, 1997;
(Clinical Chemistry. 1997;43:2358-2363.)
© 1997 American Association for Clinical Chemistry, Inc.
Protein tyrosine phosphatase-like protein IA2-antibodies plus glutamic acid decarboxylase 65 antibodies (GADA) indicates autoimmunity as frequently as islet cell antibodies assay in children with recently diagnosed diabetes mellitus
Henrik Borg1,a,
Per Fernlund2 and
Göran Sundkvist1
Departments of
1
Endocrinology and
2
Clinical Chemistry, University of Lund, Malmö University Hospital, S-205 05 Malmö, Sweden
a Address correspondence to this author, at: Wallenberg Laboratory, Entrance 46, 2nd Fl., Malmö University Hospital, S-205 05 Malmö, Sweden. Fax +46 40 337041; e-mail Henrik.Borg{at}medforsk.mas.lu.se
 |
Abstract
|
|---|
Islet cell antibodies (ICA), the classical autoimmunity marker for
insulin-dependent diabetes mellitus (IDDM), are detected in ~85% of
children with recently diagnosed diabetes. Because the ICA assay is
semiquantitative and difficult to standardize, alternative assays are
needed. When glutamic acid decarboxylase 65 (GAD 65) was discovered as
a major islet antigen, the measurement of antibodies to GAD 65 (GADA)
was considered a good alternative to ICA. Recently, however, we showed
that 1 in 3 ICA-positive diabetic patients do not have GADA. Now,
antibodies against the protein tyrosine phosphatase-like protein IA2
(IA2-ab) have been detected in IDDM. To find out whether measurements
of IA2-ab combined with those of GADA could detect autoimmunity to the
same extent as ICA, we have measured all three kinds of antibodies
(using radioligand binding assays for IA2-ab and GADA) in 100 recently
diagnosed diabetic and 100 control children: ICA were found in 87,
IA2-ab in 69, and GADA in 66 of the 100 diabetic patients, whereas in
the 100 control children ICA were found in 2, IA2-ab in 1, and GADA in
3. Among the 87 ICA-positive patients, 45 (52%) had both IA2-ab and
GADA, 21 (24%) had only IA2-ab, and 16 (18%) had only GADA, whereas 5
(6%) lacked both IA2-ab and GADA. Among the 13 ICA-negative patients,
1 (8%) had both IA2-ab and GADA, 2 (15%) had only IA2-ab, and 4
(31%) had only GADA. Thus, 6 of the 100 patients had neither ICA,
IA2-ab, nor GADA. Combining the IA2-ab and GADA assays gave positive
results for autoimmunity in 89 of the 100 patients, compared with 87 by
the ICA assay. The combination of the IA2-ab and GADA assays appears to
be an effective alternative to the ICA assay.
|
Introduction
|
|---|
Insulin-dependent diabetes mellitus
(IDDM)1
is an autoimmune disease in which destruction of the
insulin-producing ß-cells leads to a loss of endogenous insulin
secretion and thereby a lifelong need for insulin treatment. Islet cell
antibodies (ICA, antibodies reacting against the islets of Langerhans)
constitute a well-known autoimmune marker of IDDM, which may be
detected in 85% of children at the time of diagnosis of the disease
(1). The antigens reactive in the ICA assay were unknown
until 1990, when glutamic acid decarboxylase 65 (GAD 65) antibodies
(GADA) were discovered as another autoimmune marker of IDDM
(2). GAD 65 was first thought to be the main ICA antigen,
but absorption studies with GAD 65 have shown that GAD 65 is not the
only antigen in the ICA reactions (3)—in agreement with
our recent demonstration that only 2 of 3 ICA-positive sera from
diabetic patients contain GADA (4). The antigen or
antigens reacting with the remaining ICA-positive sera (about
one-third) therefore remain to be found. Antibodies against a protein
tyrosine phosphatase-like protein, IA2, have recently been demonstrated
in diabetic patients (5)(6)(7)(8)(9)(10). The aim of this study was to
find out whether the assays of GADA and of antibodies against IA2
(IA2-ab) together could detect autoimmunity to the same extent as ICA
assays in children with recently diagnosed diabetes. If so, the
combination of IA2-ab and GADA assays could be used instead of the
indirect immunofluorescence ICA assay, which is semiquantitative and
difficult to standardize.
|
Materials and Methods
|
|---|
subjects
Patients' samples were collected consecutively from 100 children
with recently diagnosed diabetes mellitus. All were Caucasians, 47 were
girls, and their mean ± SD ages were 9 ± 4 years (range
1–15 years). The samples were obtained from 97 of the patients within
2 weeks of diagnosis. An equal number of control samples were collected
from 100 subjects randomly selected from 1031 apparently healthy school
children (11). Of these, 49 were girls and their mean
± SD ages were 11 ± 2 years (range 7–13 years).
reagents
A cDNA (IA2ic) coding for the intracellular domain of IA2
(beginning at amino acid 606), obtained by courtesy of Michael R.
Christie (Kings College, London, UK), was provided as an insert in the
BamHI restriction site in the pSP64 Poly(A) plasmid vector
(Promega) with the coding strand downstream of the SP6 promoter. The
construction of the cDNA has been described elsewhere (5).
Competent Escherichia coli 
DH5 cells were transformed
with the vector, and minipreps of the plasmid were done with routine
methods (12). The plasmid DNA obtained was checked by
cutting with BamHI restriction enzyme, which gave a fragment
of the expected size (1230 bp), and by sequencing with a
vector-specific primer (SP6 primer; DNA Technology, Aarhus, Denmark).
The sequence obtained was the same as the published cDNA sequence for
human tyrosine phosphatase IA2/PTP (Genbank accession L18983)
(13) except for a G2072A substitution, a change that
should give an Ala to Thr substitution in the expressed protein. TNT
Coupled Reticulocyte Lysate System was obtained from Promega, RNAsin
from Appligene (Illkirch, France),
L-[35S]methionine (>1000 kCi/mol) from
Amersham, Protein A–Sepharose CL-4B from Pharmacia, and a Multiscreen
96-well filtration system from Millipore. Buffers used in the IA2-ab
and GADA assays were "plain" buffer (NaCl 150 mmol/L, Tris 20
mmol/L, pH 7.4, and NaN3 2 g/L), coating buffer (plain
buffer plus bovine serum albumin, 10 g/L), and washing buffer (plain
buffer plus bovine serum albumin, 1 g/L, and Tween 20, 1.5 mL/L).
assay methods
In the IA2-ab assay, 35S-labeled human
recombinant IA2 was synthesized by in vitro transcription–translation
with a circular pSP64 poly(A) vector with IA2ic insert and TNT Coupled
Reticulocyte Lysate System. The yield of the translation product,
determined by trichloroacetic acid precipitation, was between 10% and
20% of the total [35S]methionine added. The translation
product was not separated from the remaining free
[35S]methionine. Overnight incubations with the
35S-labeled IA2 were made at 4 °C in duplicates for each
sample. Two aliquots from each incubation were incubated with Protein
A–Sepharose on a 96-well filtration plate to collect immunocomplexes.
The filter bottom of each well was punched into a scintillation bottle,
and the radioactivity was counted (Wallac 1410; Pharmacia). Sera from
three blood donors served as negative controls, and plasma from a
patient with a high concentration of IA2-ab diluted in negative control
serum served as a positive control. The controls were kept as
single-use aliquots at -20 °C. The results are presented as an
IA2-ab index: 100 x (u - n)/(p - n), where u = CPM of
the unknown sample, n = CPM of the negative control, p = CPM
of the positive control, and CPM = the mean activity (counts/min)
of all four measurements for a sample.
The IA2-ab assay has been evaluated in the Juvenile Diabetes Foundation
(JDF) First Proficiency evaluation, showing a 100% diagnostic
sensitivity and specificity (24 samples evaluated). The
imprecision of the IA2-ab assay was monitored by including in each run
two control samples, one with a low and one with a high concentration
of IA2-ab. The imprecision (total), estimated by analysis of variance
of the pooled values for the controls, was 19% at the low
concentration and 12% at the high.
GADA were determined by a radioligand assay based on
[35S]methionine-labeled human recombinant in vitro
transcribed–translated GAD 65 (4). Evaluation of this
assay in the International Diabetes Workshop GADA65 Proficiency Program
(No. 2) showed 100% sensitivity and specificity. The imprecision
(total) was 17% at the low concentration and 19% at the high.
ICA were determined by a prolonged immunofluorescence assay as
previously described in detail (14). Four pancreata were
used in the study. The detection limit (cutoff limit for abnormality)
was 2 JDF units for pancreas 1 (used for 75 patients), 4 JDF units for
pancreas 2 (used for 21 patients), 6 JDF units for pancreas 3 (used for
4 patients), and 3 JDF units for pancreas 4 (used for the control
subjects). In the latest (No. 12) International Diabetes Workshop
proficiency test for ICA, our assay showed a sensitivity of 86% and a
specificity of 100%. The imprecision (total) of our ICA assay was 34%
at 36 JDF units.
statistics
The nonparametric Mann–Whitney's test was used to analyze
differences in antibody values between patient and control groups, the
nonparametric Kruskal–Wallis test to analyze differences in antibody
values between patient groups, and the nonparametric Spearman test
(rs) to analyze the degree of correlation
between the different antibodies. ROC curves and logistic regression
analysis were performed with the SAS 6.10/OS/2 Warp Connect software.
Data are presented as median ± interquartile range, if not stated
otherwise.
|
Results
|
|---|
The results obtained by the IA2-ab and the GADA assays are shown
in Fig. 1
. In both assays, there were pronounced differences
(P <0.0001) in the results between the patients and the
controls (IA2-ab, 37.4 ± 118.7 vs 0.3 ± 0.5; GADA,
11.0 ± 36.2 vs 1.2 ± 2.1). The cutoff limits for the IA2-ab
(IA2-ab index = 1.0), and GADA assay (GADA index = 4.5) were
determined nonparametrically as the 97.5% percentile. Results above
the cutoff limits were considered positive. One control subject gave
results regarded as outliers, which were excluded; this boy had high
IA2-ab (IA2-ab index = 144.1), GADA (GADA index = 40.1), and
ICA (192 JDF) concentrations and later developed diabetes.
View larger version (20K):
[in this window]
[in a new window]
|
Figure 1. Results of measurements of IA2-ab (left) and
GADA (right) in 100 diabetic and 100 control children.
The horizontal bars indicate the cutoff values (IA2-ab
index = 1.0 and GADA index = 4.5). The inserts show
expanded y-axis scales near the cutoffs.
|
|
ICA were found in 87, IA2-ab in 69, and GADA in 66 of the 100 patients.
IA2-ab and GADA seemed to be complementary; only half of the
ICA-positive patients (45 of 87, 52%) had both IA2-ab and GADA, but as
many as 21 of 87 (24%) ICA-positive patients had only IA2-ab, and 16
of 87 (18%) ICA-positive patients had only GADA. Nevertheless, 5 of 87
(6%) ICA-positive patients lacked both IA2-ab and GADA. Among the 13
ICA-negative patients, 1 (8%) had both IA2-ab and GADA, 2 (15%) had
only IA2-ab, and 4 (31%) had only GADA. Six of the 100 patients had
neither ICA, IA2-ab, nor GADA. Among the 100 control subjects, 1 had
ICA, IA2-ab, and GADA (the "outlier"), 1 had only ICA, none had
only IA2-ab, and 2 had only GADA (Table 1
). Combining the results of all three assays showed that 94 of
the 100 patients had at least one sign of humoral autoimmunity. If only
the IA2-ab and GADA assays were used, 89 of the 100 patients were
positive for humoral autoimmunity, i.e., a frequency almost the same as
with the ICA assay (87 of 100).
Figure 2
shows the ROC curves obtained for the IA2-ab, GADA, and ICA
assays, and for a combination of the IA2-ab and GADA assays made by
logistic regression analysis, with the sensitivities determined from
the results for the diabetic children (n = 100) and the
specificities from the control children (n = 99; excluding the
outlier). The areas (±SE) under the curves for the different assays
were 0.80 ± 0.03 (IA2-ab), 0.87 ± 0.03 (GADA), 0.93 ±
0.02 (ICA), and 0.90 ± 0.03 (IA2-ab and GADA combined). Table 2
gives the sensitivities, based on logistic regression analysis,
for different combinations of the assays at some clinically relevant
specificities. As Fig. 2
and Table 2
demonstrate, the sensitivity of
the combination of IA2-ab and GADA assays corresponded well to that of
the ICA assay.
View larger version (13K):
[in this window]
[in a new window]
|
Figure 2. ROC curves for IA2-ab (—), GADA (– – –), ICA
(... .), and a combination of IA2-ab and GADA made by
logistic regression analysis
(– . – . – .),
with specificities based on the results for the control children
(n = 99).
|
|
View this table:
[in this window]
[in a new window]
|
Table 2. Sensitivity for different combinations of assays in 100
diabetic children at clinically relevant
specificities.
|
|
Among diabetic children, there were no effects of age (ICA,
rs = 0.11; IA2-ab, rs =
0.05; GADA, rs = 0.16) or gender (girls vs boys:
ICA, 96 ± 198 JDF vs 90 ± 220 JDF, P =
0.71; IA2-ab index, 70 ± 79 vs 56 ± 59, P =
0.31; GADA index, 31 ± 34 vs 23 ± 32, P =
0.25) on the antibody values. On the other hand, ICA values correlated
with IA2-ab and GADA results, although not too strongly
(rs = 0.40 and 0.38, respectively). Patients who
had both IA2-ab and GADA had higher ICA values than those who had only
IA2-ab or GADA (P <0.05) or neither (P =
0.001). Notably, there was no correlation between IA2-ab and GADA
values (rs=0.17) (Fig. 3
). Hence, although both IA2-ab and GADA correlated with ICA,
IA2-ab and GADA must reflect different aspects of ICA.
View larger version (21K):
[in this window]
[in a new window]
|
Figure 3. Scatter plot of IA2-ab and GADA in the diabetic children
(n = 100); cutoff limits indicated are the same as in Fig. 1
.
|
|
|
Discussion
|
|---|
This study demonstrates that, in newly diagnosed diabetic
children, combining the measurements of IA2-ab and GADA detects
autoimmunity to the same extent as determination of ICA by indirect
immunofluorescence. Therefore, the combination of the assays of IA2-ab
and GADA is a good alternative to the ICA assay in the definition of
autoimmune diabetes, as also can be inferred from other recent studies
(15)(16). Given the definite technical
advantages of the radioligand binding assays in comparison with
indirect immunofluorescence assays, the former two assays may be used
instead of the ICA assay, at least for screening large populations.
Nevertheless, our study also shows that there still is a place for the
ICA assay. In fact, 5% of the patients were ICA-positive but negative
for both IA2-ab and GADA, and combining ICA with IA2-ab and GADA gave
94% positivity for autoimmunity markers in our newly diagnosed
diabetic patients. Hence, ICA evidently reflect antibodies to other
antigens as well, possibly including the Glima 38 antigen
(17). The lack of correlation between IA2-ab and GADA
observed in this study is in accordance with previous studies
(18) that have shown these antibodies to contribute to the
ICA immunofluorescence assay independently of each other.
A crucial question is whether IA2-ab, GADA, or both reflect the primary
autoimmune process in IDDM. Previous studies have shown that GADA may
precede the clinical onset of diabetes by several years
(19), which suggests that GAD 65 may be the primary
antigen in the putative diabetogenic autoimmune destruction of
pancreatic ß-cells. Challenging this concept, however, is our
observation that, in contrast to ICA, GADA may persist for decades
after the onset of clinical diabetes (20) and also may
develop after the diagnosis of IDDM (21)(22).
In fact, some studies show ICA but not GADA associated with impairment
of ß-cell function (21). In our study, IA2-ab alone
occurred in only one control child, a boy who later developed diabetes.
Hence, IA2 and not just GAD 65 might be involved in the pathogenic
autoimmune process, as recently suggested by others (23).
Therefore, in studies aimed to clarify the pathogenesis of IDDM,
determinations of both IA2-ab and GADA seem necessary.
In conclusion, determination of both IA2-ab and GADA by radioligand
binding assays based on recombinant antigens gave a frequency (89%) of
islet autoimmunity in recently diagnosed diabetic children that
corresponded well to that found by the indirect immunofluorescence
assay for ICA (87%). Although the combination of IA2-ab, GADA, and ICA
assays together gave the highest frequency (94%), at least in the
clinical setting, IA2-ab and GADA determinations may be a valuable
alternative to the ICA assay.
|
Acknowledgments
|
|---|
We thank Michael R. Christie for providing IA2 cDNA; Ingegerd
Larsson, Ann Radelius, and Christina Rosborn for valuable technical
assistance; and Jan-Åke Nilsson for help with ROC curve constructions.
This study was supported by grants from the Child Diabetes Fund,
Lundström Foundation, Malmö Diabetes Association,
Novo-Nordic Foundation, Research Funds Malmö University Hospital,
Swedish Diabetes Association, Swedish Medical Research Council (7507
and 5913), and University Funds Lund University.
|
Footnotes
|
|---|
1 Nonstandard abbreviations: IDDM, insulin-dependent diabetes mellitus; ICA, islet cell antibodies; GAD 65, 65-kDa glutamic acid decarboxylase; GADA, glutamic acid decarboxylase antibodies; IA2, protein tyrosine phosphatase-like protein; IA2-ab, antibodies against IA2; JDF, Juvenile Diabetes Foundation (units). 
|
References
|
|---|
-
Landin-Olsson M, Palmer JP, Lernmark Å, Blom L, Sundkvist G, Nyström L, Dahlquist G. Predictive value of islet cell and insulin autoantibodies for type 1 (insulin-dependent) diabetes mellitus in a population-based study of newly-diagnosed diabetic and matched control children. Diabetologia 1992;35:1068-1073.
[Web of Science][Medline]
[Order article via Infotrieve]
-
Bækkeskov S, Jan-Aanstoot H, Christgau S, Reetz A, Solimena M, Cascalho M, et al. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA synthesizing enzyme glutamate decarboxylase. Nature 1990;347:151-156.
[Medline]
[Order article via Infotrieve]
-
Verge CF, Howard NJ, Rowley MJ, Mackay IR, Zimmer PZ, Egan M, et al. Anti-glutamate decarboxylase and other antibodies at the onset of childhood IDDM, a population-based study. Diabetologia 1994;37:1113-1120.
[Web of Science][Medline]
[Order article via Infotrieve]
-
Borg H, Fernlund P, Sundkvist G. Measurements of antibodies to glutamic acid decarboxylase 65 (GADA): two new 125I assays compared with [35S]GAD 65-ligand binding assay. Clin Chem 1997;43:779-785.
[Abstract/Free Full Text]
-
Payton MA, Hawkes CJ, Christie MR. Relationship of the 37,000- and 40,000-Mr tryptic fragments of the islet antigens in insulin-dependent diabetes to the protein tyrosine phosphatase-like molecule IA2 (ICA512). J Clin Invest 1995;:1506-1511.
[Abstract]
-
Bonifacio E, Lampasona V, Genovese S, Ferrari M, Bosi E. Identification of protein tyrosine phosphatase-like insulin dependent-related 37/40K autoantigen and a target for islet-cell antibodies. J Immunol 1995;155:5419-5426.
-
Lan MS, Wasserfall C, Maclaren NK, Notkins AL. IA-2, a transmembrane protein of the protein tyrosine phosphatase family, is a major autoantigen in insulin-dependent diabetes mellitus. Med Sci 1996;93:6367-6370.
-
Hawkes CJ, Wasmeier C, Christie MR, Hutton JC. Identification of the 37-kDa antigen in IDDM as a tyrosine phosphatase-like protein (phogrin) related to IA-2. Diabetes 1996;45:1187-1192.
[Abstract]
-
Notkins AL, Lu J, Li Q, Van derVegt FP, Wasserfall C, Maclaren NK, Lan MS. IA-2, IA-2b are major autoantigens in IDDM and the precursors of the 40 kDa and 37 kDa tryptic fragments. J Autoimmun 1996;9:677-682.
[Medline]
[Order article via Infotrieve]
-
Kawasaki E, Eisenbart GS, Wasmeier C, Hutton JC. Autoantibodies to protein tyrosine phosphatase-like proteins in type 1 diabetes. Overlapping specificities to phogrin and ICA512/IA-2. Diabetes 1996;45:1344-1349.
[Abstract]
-
Samuelsson U, Ludvigsson J, Sundkvist G. Islet cell antibodies (ICA), insulin autoantibodies (IAA), islet cell surface antibodies (ICSA) and C-peptide in 1031 school children in a population with a high background incidence of IDDM. Diabetes Res Clin Pract 1994;26:155-162.
[Web of Science][Medline]
[Order article via Infotrieve]
-
Sambrook J, Fritsch EF, Maniatis T. Molecular cloning, a
laboratory manual. Cold Spring Harbor, NY: Cold Spring Harbor
Laboratory Press, 1989:I.21–31, I82–4..
-
Lan MS, Lu J, Goto Y, Notkins AL. Molecular cloning and identification of a receptor-type protein tyrosine phosphatase, IA-2, from human insulinoma. DNA Cell Biol 1994;13:505-514.
[Web of Science][Medline]
[Order article via Infotrieve]
-
Landin-Olsson M, Sundkvist G, Lernmark Å. Prolonged incubation in the two-color immunofluorescence test increases the prevalence of titres of islet cell antibodies in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1987;30:327-332.
[Web of Science][Medline]
[Order article via Infotrieve]
-
Seissler J, Morgenthaler NG, Achenbach P, Lampeter EF, Glawe D, Payton M, et al. Combined screening for autoantibodies to IA-2 and antibodies to glutamic acid decarboxylase in first-degree relatives of patients with IDDM. Diabetologia 1996;39:1351-1356.
[Web of Science][Medline]
[Order article via Infotrieve]
-
Gorus FK, Goubert P, Semakula C, Vandewalle CL, De Schepper J, Scheen A, et al. IA-2-autoantibodies complement GAD65-autoantibodies in new-onset IDDM patients and help predict impending diabetes in their siblings. Diabetologia 1997;40:95-99.
[Medline]
[Order article via Infotrieve]
-
Aanstoot HJ, Kang SM, Kim J, Lindsay L, Roll U, Knip M, et al. Identification and characterisation of Glima 38, a glycosylated islet cell membrane antigen, which together with GAD65 and IA2 marks the early phases of autoimmune response in type 1 diabetes. J Clin Invest 1996;97:2772-2783.
[Web of Science][Medline]
[Order article via Infotrieve]
-
Myers AM, Rabin DU, Rowley MJ. Pancreatic islet cell cytoplasmic antibody in diabetes is represented by antibodies to islet cell antigen 512 and glutamic acid decarboxylase. Diabetes 1995;44:1290-1295.
[Abstract]
-
Bækkeskov S, Landin M, Kvist Kristensen J, Srikanta S, Bruining J, Mandrup-Poulsen T, et al. Antibodies to a 64,000 Mr human islet cell antigen precede the clinical onset of insulin-dependent diabetes. J Clin Invest 1987;79:926-934.
-
Sundkvist G, Velloso LA, Kämpe O, Rabinowe SL, Ivarsson SA, Lilja B, Karlsson FA. Glutamic acid decarboxylase antibodies, autonomic nerve antibodies and autonomic neuropathy in diabetic patients. Diabetologia 1994;37:293-299.
[Web of Science][Medline]
[Order article via Infotrieve]
-
Sundkvist G, Hagopian WA, Landin-Olsson M, Lernmark Å, Ohlsson L, Ericsson C, Ahlmen J. Islet cell antibodies, but not glutamic acid decarboxylase antibodies, are decreased by plasmapheresis in patients with newly diagnosed insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1994;78:1159-1165.
[Abstract]
-
Batstra MR, Pina M, Quan J, Mulder P, de Beaufort CE, Bruining GJ, Aanstoot HJ. Fluctuations in GAD65 antibodies after clinical diagnosis of IDDM in young children. Diabetes Care 1997;20:642-644.
[Abstract]
-
McEvoy RC, Thomas NM, Greig F, Larson S, Vargas-Rodrigues I, Felix I, et al. Anti-islet autoantibodies detected by monoclonal antibody 1A2: further studies suggesting a role in the pathogenesis of IDDM. Diabetologia 1996;39:1365-1371.
[Medline]
[Order article via Infotrieve]
The following articles in journals at HighWire Press have cited this article:
|
|
|
|
 
M. Henricsson, L. Nystrom, G. Blohme, J. Ostman, C. Kullberg, M. Svensson, A. Scholin, H. J. Arnqvist, E. Bjork, J. Bolinder, et al.
The Incidence of Retinopathy 10 Years After Diagnosis in Young Adult People With Diabetes: Results from the nationwide population-based Diabetes Incidence Study in Sweden (DISS)
Diabetes Care,
February 1, 2003;
26(2):
349 - 354.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. E. Winter, N. Harris, and D. Schatz
Immunological Markers in the Diagnosis and Prediction of Autoimmune Type 1a Diabetes
Clin. Diabetes,
October 1, 2002;
20(4):
183 - 191.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Borg, A. Gottsater, P. Fernlund, and G. Sundkvist
A 12-Year Prospective Study of the Relationship Between Islet Antibodies and {beta}-Cell Function At and After the Diagnosis in Patients With Adult-Onset Diabetes
Diabetes,
June 1, 2002;
51(6):
1754 - 1762.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Borg, A. Gottsater, M. Landin-Olsson, P. Fernlund, and G. Sundkvist
High Levels of Antigen-Specific Islet Antibodies Predict Future {beta}-Cell Failure in Patients with Onset of Diabetes in Adult Age
J. Clin. Endocrinol. Metab.,
July 1, 2001;
86(7):
3032 - 3038.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. R. Batstra, A. van Driel, J. S. Petersen, C. A. van Donselaar, M. J. van Tol, G. J. Bruining, D. E. Grobbee, T. Dyrberg, and H.-J. Aanstoot
Glutamic Acid Decarboxylase Antibodies in Screening for Autoimmune Diabetes: Influence of Comorbidity, Age, and Sex on Specificity and Threshold Values
Clin. Chem.,
December 1, 1999;
45(12):
2269 - 2272.
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction
