Original Article
A Prospective Study of the Development of Diabetes in Relatives of Patients with Insulin-Dependent Diabetes
N Engl J Med 1990; 323:1167-1172October 25, 1990
- Abstract
- Abstract
Background.
The presence of cytoplasmic islet-cell autoantibodies has been recognized as a risk factor for the development of diabetes mellitus in relatives of patients with insulin-dependent diabetes mellitus (IDDM), but the magnitude of the risk is unknown, as is the influence of other factors, such as age, sex, and race.
Methods.
From 1979 through 1989, we studied 4015 initially nondiabetic relatives of 1590 probands with IDDM to determine the risk of IDDM according to the presence and titer of autoantibodies, as well as other factors.
Results.
Of the 4015 nondiabetic relatives, 125 (3.1 percent) had islet-cell antibodies in their initial serum samples, and 40 contracted IDDM. Islet-cell antibodies were most frequent (4.3 percent) in relatives who were under 20 years of age (P = 0.001) and in those (4.8 percent) from families with more than one affected member (a multiplex pedigree) (P = 0.003). Independent risk factors for the development of diabetes in the relatives included age of less than 10 years at the time of the initial study (P = 0.001), membership in a multiplex pedigree (P = 0.02), and a positive test for islet-cell antibodies in the initial serum sample (P = 0.0001). Twenty-seven of the relatives in whom diabetes developed (67.5 percent) had positive tests for islet-cell antibodies before the diagnosis of IDDM, giving a relative risk of IDDM of 68 (95 percent confidence interval, 34 to 134) for antibody-positive relatives. Islet-cell—antibody titers of 20 Juvenile Diabetes Foundation units or higher were associated with an increasing risk of diabetes.
Conclusions.
Nondiabetic relatives of probands with IDDM who are in the first two decades of life, are members of multiplex pedigrees, and have increased titers of islet-cell antibodies are the most likely to contract IDDM themselves. (N Engl J Med 1990; 323:1167–72.)
Article Activity
- Article
THAT insulin-dependent diabetes mellitus (IDDM) is an autoimmune disorder is now generally accepted. Autoantibodies to cytoplasmic antigens in the pancreatic islet cells were originally described nearly 15 years ago in patients with the autoimmune polyglandular syndrome.1 These islet-cell antibodies were subsequently found in 60 to 80 percent of patients in whom IDDM had recently developed,2 , 3 as well as in some persons who were tested before IDDM developed.4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 However, the qualitative nature of the tests for islet-cell antibodies made it difficult to compare the results, not only between laboratories but also within laboratories. With the support of the Juvenile Diabetes Foundation (JDF) International, an international standard for use in assays for cytoplasmic islet-cell antibodies was developed by the Immunology of Diabetes Workshops20 , 21 so that the titer of islet-cell antibodies could be expressed quantitatively in standardized, defined units. Recently, the titer of islet-cell antibodies was reported to predict the development of IDDM in a closely followed cohort of first-degree relatives of patients with IDDM.19 We report here that quantitation of islet-cell antibodies is of value in predicting the subsequent risk of IDDM in a large group of unaffected relatives followed for as long as 10 years. We have also identified additional factors as important determinants of the risk of IDDM, such as age at the time of first testing and membership in a family with two or more members affected by the disease (a multiplex pedigree).
Methods
Patients
From 1979 through 1989, we obtained serum samples from 3413 first-degree and 602 second- and third-degree nondiabetic relatives of 1590 probands with IDDM. The probands had been identified at the diabetes clinics at the University of Florida, Gainesville; the University of South Florida, Tampa; Cedars—Sinai Hospital, Los Angeles; and the Humana Diabetes Center, San Antonio, Texas. Serum was also obtained from families in cooperation with the Florida Camp for Children and Youth with Diabetes and through the meetings of local chapters of the Juvenile Diabetes Foundation and the youth groups of the American Diabetes Association in Florida. Informed consent was obtained from the subjects or their parents (in the case of subjects under 19), and the study design was approved by the University of Florida institutional review board. Subjects who were referred for evaluation of glucose intolerance have been described elsewhere.22 To avoid any referral bias, they were not included in this study, regardless of whether their level of glucose tolerance proved to be normal or abnormal.
Our study group contained 747 nondiabetic members (18 percent of the sample) of 234 families (14.7 percent) in which more than one relative had IDDM at the time of the initial testing. In such families with multiplex pedigrees, the proband was identified as the first family member in whom IDDM developed before the age of 21 years. The age of each relative was defined as that person's age at the time of initial testing. The nondiabetic relatives were subsequently contacted annually to determine whether they had acquired IDDM, and whenever possible, additional serum samples were obtained every two years. The median duration of follow-up was 3 1/2 years, and only subjects for whom follow-up data were available were included in the analyses. Any relative negative for islet-cell antibody in whom IDDM developed had serum drawn as soon as possible after the diagnosis, for an additional determination of the presence of islet-cell antibodies.
Diabetes was defined according to the criteria of the World Health Organization,23 as the presence of a fasting blood glucose level of 7.8 mmol per liter (140 mg per deciliter) or more in a person with typical symptoms of hyperglycemia, or in some patients, as the presence of typical symptoms that were reversed by the administration of insulin.
Laboratory Analysis
Islet-cell antibodies were detected by indirect immunofluorescence with the use of unfixed, snap-frozen human pancreas tissue as described elsewhere.3 For the purpose of these analyses, subjects were considered to have islet-cell antibodies only if their first sample was positive. A test was considered to be positive for islet-cell antibodies if the intensity of the fluorescence and pattern of staining of the undiluted serum were the same as or higher than that of a standard laboratory serum that had been calibrated to contain 10 JDF units.20 , 21 All positive serum samples of sufficient quantity were then measured for their titer, expressed in JDF units after comparison of the end-point dilution of each positive sample with a standard dilution curve using the international JDF reference serum accepted by the Immunology of Diabetes Workshops.20 , 21 The endpoint titer of the JDF standard was defined at the initial workshop as 80 JDF units.20 , 21 In the Fourth International Islet Cell Antibody Workshop, our laboratory was 100 percent accurate and had the highest possible sensitivity and specificity in blinded analyses of test serum samples.
The presence of insulin autoantibodies was also determined in the initial serum sample of 3042 relatives by a modification of a radiobinding assay.24 Insufficient serum was available to perform the assay for the remaining 973 relatives, including 22 in whom IDDM subsequently developed. The insulin-antibody assay used human insulin monoiodinated at amino acid 14 of the A chain (generously provided by Eli Lilly, Indianapolis). Any serum found to have a binding level more than 3 SD above the mean of 83 normal subjects analyzed for the Third International Insulin Antibody Workshop was defined as being positive for insulin antibodies. In an independent analysis of the results obtained by the participants of this workshop, our assay was found to be highly specific for IDDM and among the most sensitive of the laboratories submitting results achieved with radiobinding assays.
Statistical Analysis
Life-table methods were used to estimate the likelihood of IDDM,25 and the log-rank statistic was used to compare estimates.26 The standard error of these estimates after seven years was also calculated. The length of follow-up and the time of islet-cell—antibody positivity were calculated from the time the initial test was performed. The Cox proportional-hazards general linear model,27 which included age, sex, race, proband's age at diagnosis, type of pedigree (simplex or multiplex), and type of relationship to the proband, was used for multivariate analyses. If the frequencies were sufficiently large, the chi-square statistic was calculated. Otherwise, an exact test of proportions was used. A two-tailed P value of 0.05 was considered to indicate statistical significance.
Results
Islet-cell antibodies were detected in serum samples from relatives (3.1 percent) at the time of their first test (Table 1Table 1
Prevalence of Islet-Cell Antibodies in Relatives of Patients with IDDM at Initial Testing.). Positive tests were significantly more frequent in sibling relatives, relatives less than 20 years old at the time of their first test, and relatives from multiplex pedigrees, as compared with non-sibling relatives, relatives 20 or older at the time of their first test, and relatives from simplex pedigrees (P = 0.01, 0.001, and 0.003, respectively). The frequency of detection of islet-cell antibodies did not differ significantly according to race, sex, or the proband's age at onset of IDDM.An additional 21 relatives who had no islet-cell antibodies at the time of their first test had positive tests after a median follow-up of 2.2 years (data not shown). There were no significant differences with respect to age, sex, race, family relationship, or type of pedigree between these subjects who converted from negative to positive islet-cell—antibody status and those who were antibody-positive at the time of their first test. Although all 21 of these persons were relatives of probands who had had IDDM before the age of 21 (P = 0.05), none had IDDM as yet, perhaps because they had been followed for a median period of only 17 months (range, 1 to 108) since the test was first found to be positive.
Forty relatives (27 positive for islet-cell antibody and 13 negative) have acquired IDDM after periods of follow-up of less than one year to as much as seven years after their initial testing (Table 2Table 2
Seven-Year Life-Table Estimates of the Risk of Developing IDDM in Relatives of Patients with IDDM, According to the Results of Islet-Cell—Antibody Testing.*). Thirty-six of these 40 (90 percent) were first-degree relatives of probands in whom IDDM developed before the age of 21. The remaining four were a nephew, a niece, a first cousin, and a grandparent. Of the 40 relatives, 10 (25 percent) acquired IDDM before the age of 10. Another seven who were tested initially before the age of 10 acquired the disease after the age of 10. Sixteen relatives (40 percent) acquired IDDM from 10 through 20 years of age, whereas in the remaining 14 (35 percent) the disease developed after the age of 20.The risk of IDDM as estimated by univariate analysis (Table 2) was significantly higher among the relatives with islet-cell antibodies (P = 0.0001), those from multiplex pedigrees (P = 0.0002), and those tested initially before the age of 10 (P = 0.0004). A multivariate analysis confirmed the independent contributions of islet-cell antibodies (P = 0.0001), age under 10 years at the time of the first test (P = 0.001), and membership in a multiplex family as significant risk factors for the development of IDDM (P = 0.02). Black race was also a risk factor in this analysis (P = 0.02). The adjusted relative risk of IDDM for all islet-cell-antibody—positive relatives was 68 (95 percent confidence interval, 34 to 134). For relatives under 10 years of age it was 2.9 (95 percent confidence interval, 1.5 to 5.6), for blacks 3.4 (95 percent confidence interval, 1.2 to 9.9), and for relatives from multiplex pedigrees 2.1 (95 percent confidence interval, 1.1 to 3.9).
Among the relatives who were negative for islet-cell antibody (Table 2), there was a significant additional likelihood of acquiring IDDM among men (P = 0.04) and among relatives from multiplex pedigrees (P = 0.0002), as determined by univariate analyses. Type of family relationship, proband's age at onset of IDDM, relative's age at initial testing, and race were not significant predictors in the relatives who were negative for islet-cell antibody.
The identification of islet-cell antibodies indicated a significantly higher likelihood of IDDM in every subgroup of relatives. If the subject was found to be positive for islet-cell antibody before the age of 10 (Fig. 1Figure 1
Probability of Remaining Free of IDDM in Three Groups of Relatives of Probands with IDDM, According to Islet-Cell—Antibody Status and Age at Initial Testing., Table 3Table 3
Development of IDDM over Seven Years of Follow-up in Relatives of Probands with IDDM, According to Islet-Cell—Antibody Status and Age at Initial Testing.), the likelihood of acquiring IDDM was increased (P = 0.03). However, no additional demographic factors were found to enhance the likelihood of IDDM in this young group of subjects positive for islet-cell antibody.The titer of islet-cell antibodies as expressed in JDF units also conveyed a differential risk for the development of IDDM (P = 0.0001) (Fig. 2Figure 2
Probability of Remaining Free of IDDM in Four Groups of Relatives of Probands with IDDM, According to Islet-Cell—Antibody Status Expressed as JDF Units., Table 4Table 4
Development of IDDM over Seven Years of Follow-up in Relatives of Probands with IDDM, According to Islet-Cell—Antibody Status Expressed in Juvenile Diabetes Foundation (JDF) Units.). Although one third of the relatives in whom IDDM developed had negative tests for islet-cell antibodies on first testing, 5 of these 13 antibody-negative relatives (38 percent) had positive tests in serum samples obtained at the time of onset of IDDM, suggesting that they must have become seropositive in the interim. It is important to note that IDDM developed subsequently in 47 percent (15 of 32) of the relatives who had initial antibody titers of 40 JDF units or more. As noted in Methods, we did not have enough serum from all patients with islet-cell antibodies to determine the titer. Thus, the numbers of antibody-positive patients who contracted IDDM shown in Figure 2 and Table 4 are lower than those in Table 2 and Figure 1.In the subgroup of 3042 relatives in whom insulin antibodies were measured in the initial serum sample, 5 of the 18 who contracted IDDM (27.8 percent) were found to have such antibodies. This frequency was significantly higher than that in the relatives who did not contract IDDM (P = 0.001) (Table 5Table 5
Prevalence of Insulin Antibodies in Relatives of Patients with IDDM.*). The presence of insulin antibodies was also associated significantly with that of islet-cell antibodies (P = 0.001), but it did not contribute further to the increased risk of IDDM in the relatives positive for islet-cell antibodies. No multivariate analyses of demographic characteristics were performed for insulin antibodies, since the data were incomplete.Discussion
The presence of islet-cell antibodies in the relatives of probands with IDDM in our study was highly prognostic for the development of IDDM, as has been reported by others.6 7 8 9 10 11 12 13 14 15 16 17 18 19
Our study differs from others in that we also identified several independent factors affecting the risk of IDDM, such as age at initial testing, membership in a multiplex pedigree, and titer of islet-cell antibodies.
The relatives studied in the first two decades of life had not only the highest frequency of positive tests for islet-cell antibodies, but also the highest risk of progression to IDDM if they were antibody-positive. The increased risk for the development of IDDM in these young persons is not unexpected. IDDM is known to be a disease of childhood and adolescence, with a large peak in incidence during puberty.28 In 75 percent of all patients it develops before the age of 21. In fact, seven islet-cell-antibody—positive relatives identified before the age of 10 as well as four antibody-positive relatives who were initially tested after the age of 10 had IDDM during pubertal development. The rise in insulin resistance during puberty could account for the development of IDDM at this time.29
In the adult relatives, progression to IDDM was often slow. Of the 14 relatives in whom IDDM developed after the age of 20, 3 who were positive for islet-cell antibody progressed from a state of normal glucose tolerance to diabetes mellitus that could be controlled with oral hypoglycemic agents, diet, or both. Two of these three persons later required insulin therapy. This transient non-insulin-dependent stage was not seen in any of the children who contracted IDDM.
For the majority of the islet-cell-antibody—positive relatives in whom IDDM developed, the disease had appeared in the probands before the age of 21 — a finding that may have genetic explanations if found to be significant in a larger population sample than ours. Similarly, the increases in frequency of islet-cell antibodies and in risk of IDDM among members of multiplex pedigrees might reflect an increased load of genes for susceptibility to IDDM in those families. The fact that 18.1 percent of the relatives we studied belonged to multiplex pedigrees may represent a slight ascertainment bias beyond that expected from other population studies.27
We had previously reported a variant of IDDM in black patients in whom the occurrence of islet-cell antibodies was relatively infrequent and the expected HLA-DR alleles were absent.30 However, the identification of islet-cell antibodies in the small number of relatives of black probands we studied was associated with the same increased risk of IDDM as was found in the relatives of white probands.
It is difficult to compare our results with those of the several other studies of nondiabetic relatives of persons with IDDM,10 , 11 , 14 , 16 , 19 because of the differing definitions in those studies of a positive result on an islet-cell—antibody test. Some investigators consider the test for islet-cell antibodies to be positive only when the titers are high, perhaps accounting for the relatively high rates of progression to IDDM7 , 10 found in their studies. Other workers consider weakly reactive tests using undiluted serum to be positive — a policy that may lead to many false positive results. To overcome such specificity-related problems, one study defined an antibody-positive subject as one in whom three separate samples were positive for cmplement-fixing islet antibodies.6 , 11 We showed, however, that complement-fixing islet antibodies indicate the presence of high titers of antibodies detectable on standard immunofluorescence testing, rather than a novel species of antibody.31 The importance of the antibody titer was clearly evident in our study, as well as in another recent report.19 Any titer of islet-cell antibodies of 20 JDF units or more was associated with an increased risk of IDDM; however, the higher the titer, the more likely the progression to IDDM over the following decade.
Thirteen of the relatives negative for islet-cell antibodies also contracted IDDM. Five of these 13 persons had positive titers at the onset of diabetes and might have been identified as positive earlier if more frequent antibody determinations had been performed. Were this so, then 80 percent of these relatives (32 of 40) would have been antibody-positive before the onset of IDDM. The use of insulin antibodies as an additional screening test has been proposed.24 In our study, only one (14.3 percent) of the seven relatives negative for islet-cell antibodies had insulin antibodies in his initial serum sample and so would have been identified if tests for both antibodies had been used to screen the relatives. Another islet-cell-antibody—negative relative in whom IDDM developed became positive for insulin antibodies after the initial study. A finding that may have greater potential for future screening programs was that six of the persons negative for islet-cell antibodies who later had diabetes and for whom we had sufficient serum to perform the assay retrospectively had antibodies to a 64-kd protein specific to pancreatic islet cells in their initial serum samples.32 Thus, the use of this latter test may preclude the need for more frequent blood screening or the use of additional screening assays; however, the current method of detecting antibodies to the 64-kd protein is far too cumbersome and expensive to be used in screening programs at present.13 , 33
We conclude that the determination of islet-cell antibodies in relatives of probands with IDDM can identify those at increased risk for IDDM. The risk depends on the titer of islet-cell antibodies, the age at first testing, and membership in a multiplex pedigree. Such information can be used in counseling families, developing strategies for future screening programs, and most important, developing intervention trials aimed at preventing the clinical onset of disease.13
Supported in part by grants (HD19469 and PO1 DK39079) from the National Institutes of Health, a Clinical Research Center grant (GCRC-RR082), and a grant from the Stuart Foundations. Dr. Riley is the recipient of a Research Career Development Award (AM01421) from the National Institutes of Health. Dr. Schatz is supported by a Juvenile Diabetes Foundation fellowship.
We are indebted to Linda Brown, Linda Allen, and Margaret Dukes for their assistance in the laboratory analyses and data management for these studies; and to Stephanie Cogeos for assistance in the preparation of the manuscript.
Source Information
From the Departments of Pathology and Laboratory Medicine (W.J.R., N.K.M., J.K., R.P.S., D.A.S.) and Pediatrics (W.J.R., N.K.M., J.K., R.P.S., J.H.S., D.A.S.), University of Florida, Gainesville; the Humana Diabetes Center for Excellence, San Antonio, Tex. (S. Schwartz); the Department of Pediatrics, University of South Florida, Tampa (J.M., S. Shah); and the Departments of Medicine and Pediatrics, Cedars—Sinai Hospital, Los Angeles (C.V., J.I.R.). Address reprint requests to Dr. Riley at the Department of Pathology, Box J-275, JHMHC, University of Florida College of Medicine, Gainesville, FL 32610.
- References
References
1
Bottazzo
CrossRef | Web of Science | Medline2
Lendrum
CrossRef | Web of Science | Medline3
Neufeld
CrossRef | Web of Science | Medline4
Irvine
CrossRef | Web of Science | Medline5
Irvine
CrossRef | Web of Science | Medline6
Gorsuch
CrossRef | Web of Science | Medline7
Srikanta
Full Text | Web of Science | Medline8
Srikanta
Web of Science | Medline9
Srikanta
CrossRef | Web of Science | Medline10
Srikanta
Full Text | Web of Science | Medline11
Dean
CrossRef | Web of Science | Medline12
Betterle
CrossRef | Web of Science | Medline13
Maclaren
CrossRef | Web of Science | Medline14
Tarn
CrossRef | Web of Science | Medline15
Riley
CrossRef | Web of Science | Medline16
Hitchcock
Medline17
Bruining
CrossRef | Web of Science | Medline18
Kuglin
CrossRef | Medline19
Bonifacio
CrossRef | Web of Science | Medline20
Bonifacio
CrossRef | Web of Science | Medline21
Gleichmann
CrossRef | Web of Science | Medline22
Schatz
CrossRef | Web of Science | Medline23
Michaelis
CrossRef | Medline24
Vardi
CrossRef | Web of Science | Medline25
Kaplan
CrossRef | Web of Science26
Mantel
Medline27
Cox 28
Wagener
CrossRef | Web of Science | Medline29
Amiel
Full Text | Web of Science | Medline30
Winter
Full Text | Web of Science | Medline31
Riley
CrossRef | Web of Science | Medline32
Atkinson
CrossRef | Web of Science | Medline33
Riley
CrossRef | Medline
- Citing Articles (91)
Citing Articles
1
N. Bouhours-Nouet, R. Coutant. (2011) Aspectos clínicos y diagnósticos de la diabetes infantil. EMC - Pediatría 46:4, 1-20
CrossRef2
Sabine Pankuweit, Anette Richter, Volker Ruppert, Bernhard Maisch. (2009) Familiäre Prädisposition und mikrobielle Ätiologie bei dilatativer Kardiomyopathie. Herz Kardiovaskuläre Erkrankungen 34:2, 110-116
CrossRef3
Jon D Piganelli, Clayton E Mathews. (2007) Autoreactive T-cell responses: new technology in pursuit of an old nemesis. Pediatric Diabetes 8:5, 249-251
CrossRef4
J S Skyler. (2007) Prediction and Prevention of Type 1 Diabetes: Progress, Problems, and Prospects. Clinical Pharmacology & Therapeutics 81:5, 768-771
CrossRef5
Jung Hyun Oh, Ji Sung Yoon, Kyu Chang Won, Hyoung Woo Lee. (2007) Antibodies to GAD and ICA in Type 2 DM with Secondary Failure of Oral Hypoglycemic Therapy. The Journal of Korean Diabetes Association 31:5, 402
CrossRef6
Clive H. Wasserfall, Mark A. Atkinson. (2006) Autoantibody markers for the diagnosis and prediction of type 1 diabetes. Autoimmunity Reviews 5:6, 424-428
CrossRef7
JESSICA RENEE EDWARDS, DANIEL Y.C. FUNG. (2006) PREVENTION AND DECONTAMINATION OF ESCHERICHIA COLI O157:H7 ON RAW BEEF CARCASSES IN COMMERCIAL BEEF ABATTOIRS. Journal of Rapid Methods and Automation in Microbiology 14:1, 1-95
CrossRef8
Pablo R. Olmos, María I. Hodgson, Alberto Maiz, Mónica Manrique, Marcelo Díaz De Valdés, Rocío Foncea, Ana M. Acosta, Matías V. Emmerich, Soledad Velasco, Osvaldo P. Muñiz, Cristóbal A. Oyarzún, Juan C. Claro, María J. Bastías, Luis A. Toro. (2006) Nicotinamide protected first-phase insulin response (FPIR) and prevented clinical disease in first-degree relatives of type-1 diabetics. Diabetes Research and Clinical Practice 71:3, 320-333
CrossRef9
Simona Cernea, Kevan C Herold. (2006) Drug Insight: new immunomodulatory therapies in type 1 diabetes. Nature Clinical Practice Endocrinology & Metabolism 2:2, 89-98
CrossRef10
G. Dahlquist. (2006) Can we slow the rising incidence of childhood-onset autoimmune diabetes? The overload hypothesis. Diabetologia 49:1, 20-24
CrossRef11
Christoph D. Dieterle, Franz-Xaver Hierl, Bodo Gutt, Helmut Arbogast, Georg R. Meier, Martin Veitenhansl, Johannes N. Hoffmann, Rudiger Landgraf. (2005) Insulin and islet autoantibodies after pancreas transplantation. Transplant International 18:12, 1361-1365
CrossRef12
Bernd Franke, Tamara S. Galloway, Terry J. Wilkin. (2005) Developments in the prediction of type 1 diabetes mellitus, with special reference to insulin autoantibodies. Diabetes/Metabolism Research and Reviews 21:5, 395-415
CrossRef13
M. Schlosser, J. P. Banga, A. M. Madec, K. A. Binder, M. Strebelow, I. Rjasanowski, R. Wassmuth, L. K. Gilliam, D. Luo, C. S. Hampe. (2005) Dynamic changes of GAD65 autoantibody epitope specificities in individuals at risk of developing type 1 diabetes. Diabetologia 48:5, 922-930
CrossRef14
Wei Chen, Jeffrey A. Bluestone, Kevan C. Herold. (2005) Achieving Antigen-Specific Tolerance in Diabetes: Regulating Specifically. International Reviews of Immunology 24:5-6, 287-305
CrossRef15
BERRIN ERGUN-LONGMIRE, JOHN MARKER, ADINA ZEIDLER, ROBERT RAPAPORT, PHILIP RASKIN, BRUCE BODE, DESMOND SCHATZ, ALFONSO VARGAS, DOUGLAS ROGERS, SHERWYN SCHWARTZ, JOHN MALONE, JEFFREY KRISCHER, NOEL K. MACLAREN. (2004) Oral Insulin Therapy to Prevent Progression of Immune-Mediated (Type 1) Diabetes. Annals of the New York Academy of Sciences 1029:1, 260-277
CrossRef16
Desmond Schatz, David Cuthbertson, Mark Atkinson, Michael Clare Salzler, William Winter, Andrew Muir, Janet Silverstein, Roberta Cook, Noel Maclaren, Jin-Xiong She, Carla Greenbaum, Jeffrey Krischer. (2004) Preservation of C-peptide secretion in subjects at high risk of developing type 1 diabetes mellitus - a new surrogate measure of non-progression?. Pediatric Diabetes 5:2, 72-79
CrossRef17
Edwin AM Gale. (2004) European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes. The Lancet 363:9413, 925-931
CrossRef18
THOMAS MANDRUP-POULSEN. (2003) Beta Cell Death and Protection. Annals of the New York Academy of Sciences 1005:1, 32-42
CrossRef19
Andrea K. Steck, Marian J. Rewers. 2003. Epidemiology and Geography of Type 1 Diabetes Mellitus. .
CrossRef20
Joel N. Hirschhorn. (2003) Genetic epidemiology of type 1 diabetes. Pediatric Diabetes 4:2, 87-100
CrossRef21
B.D. Tait, P.G. Colman, G. Morahan, L. Marchinovska, E. Dore, S. Gellert, M.C. Honeyman, K. Stephen, A. Loth. (2003) HLA genes associated with autoimmunity and progression to disease in type 1 diabetes. Tissue Antigens 61:2, 146-153
CrossRef22
William E. Winter, Neil Harris, Desmond Schatz. (2002) Type 1 Diabetes Islet Autoantibody Markers. Diabetes Technology & Therapeutics 4:6, 817-839
CrossRef23
Peter G. Colman, Peter D. McNair, Shane Gellert, Kim Kewming, Robert S. Schmidli, Cheryl E. Steele, Leonard C. Harrison. (2002) Development of autoantibodies to islet antigens during childhood: implications for preclinical type 1 diabetes screening. Pediatric Diabetes 3:3, 144-148
CrossRef24
Sari Korhonen, Maria M. Knip, Petri Kulmala, Kaisa Savola, Hans K.
kerblom, Mikael Knip, . (2002) Autoantibodies to GAD, IA-2 and insulin in ICA-positive first-degree relatives of children with type 1 diabetes: a comparison between parents and siblings. Diabetes/Metabolism Research and Reviews 18:1, 43-48
CrossRef25
Frans K. Gorus, Daniel G. Pipeleers, Belgian Diabetes Registry. (2001) Prospects for predicting and stopping the development of type 1 of diabetes. Best Practice & Research Clinical Endocrinology & Metabolism 15:3, 371-389
CrossRef26
Karen Lin-Su, Anjli Kukreja, Noel K. MacLaren. (2001) Diabetes Vaccines: A Future to be Realized. Diabetes Technology & Therapeutics 3:3, 451-461
CrossRef27
A.M.James Shapiro, Edmond A. Ryan, Jonathan R.T. Lakey. (2001) Pancreatic islet transplantation in the treatment of diabetes mellitus. Best Practice & Research Clinical Endocrinology & Metabolism 15:2, 241-264
CrossRef28
Massimo Pietropaolo, Dorothy J Becker. (2001) Type 1 diabetes intervention trials. Pediatric Diabetes 2:1, 2-11
CrossRef29
Alba E. Morales, Jing Xiong She, Desmond A. Schatz. (2001) Prediction and prevention of type 1 diabetes. Current Diabetes Reports 1:1, 28-32
CrossRef30
U Samuelsson, G Sundkvist, H Borg, P Fernlund, J Ludvigsson. (2001) Islet autoantibodies in the prediction of diabetes in school children. Diabetes Research and Clinical Practice 51:1, 51-57
CrossRef31
Peter G Colman, Peter McNair, Jenny King, Jan Caudwell, Connie Jankulovski, Brian D Tait, Margo C Honeyman, Leonard C Harrison, . (2000) Screening for preclinical type 1 diabetes in a discrete population with an apparent increased disease incidence. Pediatric Diabetes 1:4, 193-198
CrossRef32
Shinya Nakamoto, Akira Kasuga, Taro Maruyama, Yukako Ozawa, Shin Amemiya, Takao Saruta. (2000) Age of onset, not type of onset, affects the positivity and evanescence of IA-2 antibody. Diabetes Research and Clinical Practice 50:2, 147-152
CrossRef33
G Dahlquist. (1999) Potentials and pitfalls in neonatal screening for type 1 diabetes. Acta Paediatrica 88, 80-82
CrossRef34
Noel Maclaren, Michael Lan, Regis Coutant, Desmond Schatz, Janet Silverstein, Andrew Muir, Michael Clare-Salzer, Jin-Xiong She, John Malone, Samual Crockett, Sherwyn Schwartz, Teresa Quattrin, Mark DeSilva, Pierre Vander Vegt, Abner Notkins, Jeffrey Krischer. (1999) Only Multiple Autoantibodies to Islet Cells (ICA), Insulin, GAD65, IA-2 and IA-2β Predict Immune-Mediated (Type 1) Diabetes in Relatives. Journal of Autoimmunity 12:4, 279-287
CrossRef35
E. Anastasi, F. Dotta, C. Tiberti, E. Vecci, E. Ponte, U. Di Mario. (1999) Insulin Prophylaxis Down-regulates Islet Antigen Expression and Islet Autoimmunity in the Low-dose Stz Mouse Model of Diabetes. Autoimmunity 29:4, 249-256
CrossRef36
Mona Landin-Olsson, Hans J. Arnqvist, Göran Blohmé, Bengt Littorin, Folke Lithner, Lennarth Nyström, Bengt Scherstéan, Göran Sundkvist, Lars Wibell, Jan Östman, Åke Lernmark. (1999) Appearance of Islet Cell Autoantibodies after Clinical Diagnosis of Diabetes Mellitus. Autoimmunity 29:1, 57-63
CrossRef37
H. E. Wasmuth, W. A. Scherbaum. (1999) Autoantikörper beim Diabetes mellitus: Diagnostischer Stellenwert. Autoantibodies in Diabetes Mellitus: Diagnostic Value. LaboratoriumsMedizin 23:10, 535-542
CrossRef38
Bengt Lindberg, Anneli Carlsson, Ulla-Britt Ericsson, Ingrid Kockum, Ake Lernmark, Mona Landin-Olsson, GÖRan Sundkvist, Sten-Anders Ivarsson. (1999) Prevalence of β-cell and Thyroid Autoantibody Positivity in Schoolchildren during Three-Year Follow-up. Autoimmunity 31:3, 175-185
CrossRef39
Ana M. Yamamoto, Ingebold Deschamps, Henri-Jean Garchon, Hughette Roussely, Nathalie Moreau, Geneviève Beaurain, Jean-Jacques Robert, Jean-François Bach. (1998) Young Age and HLA Markers Enhance the Risk of Progression to Type 1 Diabetes in Antibody-Positive Siblings of Diabetic Children. Journal of Autoimmunity 11:6, 643-650
CrossRef40
M Knip. (1998) Prediction and prevention of type 1 diabetes. Acta Paediatrica 87, 54-62
CrossRef41
G Dahlquist. (1998) The aetiology of type 1 diabetes: an epidemiological perspective. Acta Paediatrica 87, 5-10
CrossRef42
Kenneth P Tercyak, Suzanne Bennett Johnson, Desmond A Schatz. (1998) Patient and Family Reflections on the Use of Subcutaneous Insulin to Prevent Diabetes. Journal of Diabetes and its Complications 12:5, 279-286
CrossRef43
Juan C. Vitoria, Luis Castaño, Rica Itxaso, J. Ramón Bilbao, Arantza Arrieta, María D. García-Masdevall. (1998) Association of Insulin-Dependent Diabetes Mellitus and Celiac Disease: A Study Based on Serologic Markers. Journal of Pediatric Gastroenterology & Nutrition 27:1, 47-52
CrossRef44
A. El-Nawawy, T. Soliman, O. El-Azzouni, A. A. Abbassy, M. N. Massoud, Salah Marzouk, F. Ibrahim, L. Helal. (1998) Interleukin-1-β, tumor necrosis factor-α, insulin secretion and oral glucose tolerance in non-diabetic siblings of children with IDDM. The Indian Journal of Pediatrics 65:3, 455-460
CrossRef45
Robert Turner, Irene Stratton, Virginia Horton, Sue Manley, Paul Zimmet, Ian R Mackay, Marion Shattock, Gian Franco Bottazzo, Rury Holman. (1997) UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. The Lancet 350:9087, 1288-1293
CrossRef46
GISELA DAHLQUIST, BENGT K??LL??N. (1997) Early Neonatal Events and the Disease Incidence in Nonobese Diabetic Mice. Pediatric Research 42:4, 489-491
CrossRef47
Lawrence S Gazda, Brett Charlton, Kevin J Lafferty. (1997) Diabetes Results from a Late Change in the Autoimmune Response of NOD Mice. Journal of Autoimmunity 10:3, 261-270
CrossRef48
Gisela G. Dahlquist. (1997) Viruses and Other Perinatal Exposures as Initiating Events for β-cell Destruction. Annals of Medicine 29:5, 413-417
CrossRef49
Manou R. Batstra, G. Jan Bruining, Henk-Jan Aanstoot. (1997) Antibody Screening in a Population of Children. Annals of Medicine 29:5, 453-460
CrossRef50
Nils G. Morgenthaler, Jochen Seissler, Peter Achenbach, Daniela Glawe, Mark Payton, Hans-Michael Meinck, Michael R. Christie, Werner A. Scherbaum. (1997) Antibodies to the Tyrosine Phosphatase-like Protein IA-2 are highly associated with IDDM, but not with Autoimmune Endocrine Diseases or Stiff Man Syndrome. Autoimmunity 25:4, 203-211
CrossRef51
Eduardo Cabrera-Rode. (1997) Prevalence of Islet Cell Antibodies (ICA) in Diabetes Mellitus and Other Diseases in Cubans. Autoimmunity 26:1, 7-9
CrossRef52
Dídac Mauricio, Montse Balsells, Josefa Morales, Rosa Corcoy, Manel Puig-Domingo, Alberto de Leiva. (1996) Islet Cell Autoimmunity in Women with Gestational Diabetes and Risk of Progression to Insulin-dependent Diabetes Mellitus. Diabetes/Metabolism Reviews 12:4, 275-285
CrossRef53
J. KARJALAINEN, P. VÁHŚLO, M. KNIP, E. TUOMILEHTO-WOLF, E. VIRTALA, H. K. ÅKERBLOM, . (1996) Islet cell autoimmunity and progression to insulin-dependent diabetes mellitus in genetically high- and low-risk siblings of diabetic children. European Journal of Clinical Investigation 26:8, 640-649
CrossRef54
C. Rodríguez-Villar, I. Conget, J.M. González-Clemente, J. Vidal, P. Navarro, R. Casamitjana, R. Gomis. (1996) Effects of insulin administration on β-cell function in subjects at high risk for type I diabetes mellitus. Metabolism 45:7, 873-875
CrossRef55
Eiji Kawasaki, Mayumi Yano, Norio Abiru, Shoichi Akazawa, Shigenobu Nagataki. (1996) Detection of recombinant GAD65 and GAD67 antibodies using a simple radioimmunoassay. Diabetes Research and Clinical Practice 32:1-2, 61-69
CrossRef56
Lucy Chaillous, Vincent Rohmer, Didier Maugendre, Pierre Lecomte, Richard Maréchaud, Michel Marre, Isabelle Guilhem, Bernard Charbonnel, Pierre Saï. (1996) Differential β-cell response to glucose, glucagon, and arginine during progression to type I (insulin-dependent) diabetes mellitus. Metabolism 45:3, 306-314
CrossRef57
Hiroshi Kajio, Tetsuro Kobayashi, Koji Nakanishi, Minoru Okubo, Toshihiko Tsukada, Toshimasa Nakayama, Nobuhiro Yamada, Toshio Murase, Yoshio Yazaki, Kinori Kosaka. (1995) Relationship between insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus: β-cell function, islet cell antibody, and haptoglobin in parents of IDDM patients. Metabolism 44:7, 869-875
CrossRef58
E. Bonifacio, S. Genovese, S. Braghi, E. Bazzigaluppi, Y. Lampasona, P. J. Bingley, L. Rogge, M. R. Pastore, E. Bognetti, G. F. Bottazzo, E. A. M. Gale, E. Bosi. (1995) Islet autoantibody markers in IDDM: risk assessment strategies yielding high sensitivity. Diabetologia 38:7, 816-822
CrossRef59
Gisela Dahlquist. (1995) Environmental risk factors in human type 1 diabetes-An epidemiological perspective. Diabetes / Metabolism Reviews 11:1, 37-46
CrossRef60
A. Gottsäter, M. Landin-Olsson, Å. Lernmark, P. Fernlund, G. Sundkvist, W.A. Hagopian. (1995) Glutamate decarboxylase antibody levels predict rate of β-cell decline in adult-onset diabetes. Diabetes Research and Clinical Practice 27:2, 133-140
CrossRef61
A Cantor. (1995) A test of the association of a time-dependent state variable to survival. Computer Methods and Programs in Biomedicine 46:2, 101-105
CrossRef62
V. Lampasona, M. Ferrari, E. Bonifacio, M. R. Pastore, P. Carrera, A. Sergi, S. Genovese, M. Trucco, J. Dorman, E. Bosi. (1995) HLA-DQ screening for risk assessment of insulin dependent diabetes in northern Italy. Acta Diabetologica 32:3, 137-142
CrossRef63
Alberto Falorni, Ingrid Kockum, Carani B. Sanjeevi, ke Lernmark. (1995) Pathogenesis of insulin-dependent diabetes mellitus. Baillière's Clinical Endocrinology and Metabolism 9:1, 25-46
CrossRef64
Epstein, Franklin H., , Atkinson, Mark A.Maclaren, Noel K.. (1994) The Pathogenesis of Insulin-Dependent Diabetes Mellitus. New England Journal of Medicine 331:21, 1428-1436
Full Text65
F. Lühder, M. Schlosser, D. Michaelis, B. Ziegler, K.-D. Kohnert, M. Ziegler. (1994) No association between anti-bovine serum albumin antibodies and islet cell reactive antibodies in newly diagnosed type 1 diabetic patients. Diabetes Research and Clinical Practice 26:1, 35-41
CrossRef66
L. Chaillous, A. Elmansour, B. Charbonnel, P. Saí, M. Delamaire, D. Maugendre, H. Allannic, V. Rohmer, M. G. Joseph, J. M. Limal, P. Lecomte. (1994) Combined analysis of islet cell antibodies which cross-react with mouse pancreas, antibodies to the Mr 64,000 islet protein, and antibodies to glutamate decarboxylase in subjects at risk for IDDM. Diabetologia 37:5, 491-499
CrossRef67
Kaichi Kida, Goro Mimura, Tetsuro Kobayashi, Nobuo Matsuura, Takayoshi Toyota, Teruo Kitagawa, Itsuro Hibi, Yoshio Ikeda, Isamu Tuchida, Hideshi Kuzuya, Shigeo Aono, Kunihiro Doi, Hiroaki Nishimukai, Yukikazu Kaino, Tomio Jinnouchi, Keiji Murakami. (1994) ICA and organ-specific autoantibodies among Japanese patients with early-onset insulin-dependent diabetes mellitus — the JDS study. Diabetes Research and Clinical Practice 23:3, 187-193
CrossRef68
Alicia Schiffrin, Antonio Ciampi, Lisa Hendricks, Rima Rozen, Gabriel Weitzner. (1994) Evidence for different clinical subtypes of Type 1 diabetes mellitus: a prospective study. Diabetes Research and Clinical Practice 23:2, 95-102
CrossRef69
Jochen Seissler, Sabine Bieg, Nadja Yassin, Ludwig Mauch, Wolfgang Northemann, Bernhard O. Boehm, Werner A. Scherbaum. (1994) Association between Antibodies to the MR 67,000 Isoform of Glutamate Decarboxylase (GAD) and Type 1 (Insulin-Dependent) Diabetes Mellitus with Coexisting Autoimmune Polyendocrine Syndrome Type II. Autoimmunity 19:4, 231-238
CrossRef70
W. A. Scherbaum. (1994) Cytoplasmic islet cell antibodies (ICA): towards a molecular understanding of the autoantigens. Clinical Endocrinology 40:1, 15-18
CrossRef71
Atkinson, Mark A.Bowman, Mark A.Kao, Kuo-JangCampbell, LalitaDush, Paula J.Shah, Shirish C.Simell, OlliMaclaren, Noel K.. (1993) Lack of Immune Responsiveness to Bovine Serum Albumin in Insulin-Dependent Diabetes. New England Journal of Medicine 329:25, 1853-1858
Full Text72
Marian Rewers. (1993) Can assessment of IDDM risk in siblings be improved?. Diabetes Research and Clinical Practice 21:1, 1-3
CrossRef73
Alicia Schiffrin, Eleanor Colle, Antonio Ciampi, Lisa Hendricks, Philippe Poussier. (1993) Different rates of conversion to IDDM in siblings of type 1 diabetic children: The Montreal family study. Diabetes Research and Clinical Practice 21:1, 75-84
CrossRef74
B. Vialettes, D. Maraninchi, M. P. San Marco, F. Birg, A. M. Stoppa, C. Mattei-Zevaco, C. Thivolet, L. Hermitte, P. Vague, P. Mercier. (1993) Autoimmune polyendocrine failure — Type 1 (insulin-dependent) diabetes mellitus and hypothyroidism — after allogenic bone marrow transplantation in a patient with lymphoblastic leukaemia. Diabetologia 36:6, 541-546
CrossRef75
Noel K. Maclaren. (1993) Diabetes intervention therapy. Journal of Diabetes and its Complications 7:2, 151-156
CrossRef76
Andrew Muir, Desmond A. Schatz, Paolo Pozzilli, Noel K. Maclaren. (1993) Intervention Therapies for Insulin-Dependent Diabetes. Autoimmunity 16:4, 301-310
CrossRef77
Irving Lieberman, Brian V. Heil, W.Kim Seow, Y.H. Thong. (1993) Synergy between tetrandrine and FK 506 in prevention of diabetes in BB rats. Life Sciences 53:26, PL453-PL458
CrossRef78
M. Landin-Olsson, J. P. Palmer, Å. Lernmarks, L. Blom, G. Sundkvist, L. Nyström, G. Dahlquist. (1992) 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 35:11, 1068-1073
CrossRef79
S.C. Bain, J.A. Todd, Robert Matz. (1992) Prophylactic insulin. The Lancet 340:8815, 376-377
CrossRef80
(1992) Insulin for prophylaxis of insulin-dependent diabetes. The Lancet 339:8808, 1512-1513
CrossRef81
R. B. Lipton, J. Atchison, J. S. Dorman, R. J. Duquesnoy, K. Eckenrode, T. J. Orchard, R. E. LaPorte, W. J. Riley, L. H. Kuller, A. L. Drash, D. J. Becker. (1992) Genetic, Immunological, and Metabolic Determinants of Risk for Type 1 Diabetes Mellitus in Families. Diabetic Medicine 9:3, 224-232
CrossRef82
M.A Atkinson, L Campbell, K.A Gibbs, N.K Maclaren, D.L Kaufman, D-F Bu, M.G Erlander, A.J Tobin, S Shah. (1992) Response of peripheral-blood mononuclear cells to glutamate decarboxylase in insulin-dependent diabetes. The Lancet 339:8791, 458-459
CrossRef83
Francois P. Lang, Desmond A. Schatz, Brad H. Pollock, William J. Riley, Noel K. Maclaren, Marilyn Dumont-Driscoll, Douglas J. Barrett. (1991) Increased T lymphocytes bearing the gamma-delta T cell receptor in subjects at high risk for insulin dependent diabetes. Journal of Autoimmunity 4:6, 925-933
CrossRef84
P. Vardi, R. Brik, D. Barzilai. (1991) Insulin autoantibodies: Reflection of disturbed self-identification and their use in the prediction of type I diabetes. Diabetes / Metabolism Reviews 7:4, 209-222
CrossRef85
S. S. S. Lo, R. Y. M. Tun, M. Hawa, R. D. G. Leslie. (1991) Studies of diabetic twins. Diabetes / Metabolism Reviews 7:4, 223-238
CrossRef86
S.S.S. Lo, R.Y.M. Tun, R.D.G. Leslie. (1991) Non-genetic Factors Causing Type 1 Diabetes. Diabetic Medicine 8:7, 609-618
CrossRef87
Terence J. Wilkin. (1991) Autoantibodies as mechanisms, markers, and mediators of B-cell disease. Diabetes / Metabolism Reviews 7:2, 105-120
CrossRef88
D. Andreani, U. Di Mario, P. Pozzilli. (1991) Prediction, prevention, and early intervention in insulin-dependent diabetes. Diabetes / Metabolism Reviews 7:1, 61-77
CrossRef89
Desmond A. Schatz, William J. Riley, Noel K. Maclaren, Douglas J. Barrett. (1991) Defective inducer T-cell function before the onset of insulin-dependent diabetes mellitus. Journal of Autoimmunity 4:1, 125-136
CrossRef90
Gian Franco Bottazzo, Stefano Genovese, Emanuele Bosi, Betty M. Dean, Michael R. Christie, Ezio Bonifacio. (1991) Novel Considerations on the Antibody/Autoantigen System in Type I (insulin-dependent) Diabetes Mellitus. Annals of Medicine 23:4, 453-461
CrossRef91
Allan L. Drash, Rebecca B. Upton, Janice S. Dorman, Dorothy J. Becker, Ronald E. Laporte, Trevor J. Orchard, William J. Riley, Massimo Trucco, Lewis H. Kuller. (1991) The Interface between Epidemiology and Molecular Biology in the Search for the Causes of Insulin-Dependent Diabetes Mellitus. Annals of Medicine 23:4, 463-471
CrossRef
