Only Multiple Autoantibodies to Islet Cells (ICA), Insulin, GAD65, IA-2 and IA-2β Predict Immune-Mediated (Type 1) Diabetes in Relatives

Maclaren, Noel K.; Lan, Michael S.; Coutant, Régis; Schatz, Desmond; Silverstein, Janet H.; Muir, Andrew; Clare-Salzer, M; She, Jin‐Xiong; Malone, John I.; Crockett, Samual; Schwartz, Sherwyn; Quattrin, Teresa; Desilva, Mark G.; Vegt, Pierre Vander; Notkins, Abner Louis; Krischer, Jeffrey P.

doi:10.1006/jaut.1999.0281

Cited by 101 publications

(76 citation statements)

References 46 publications

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“…In the absence of IA-2A, other antibodies are also predictive of diabetes but to a much lower degree. Although the number of relatives included and their follow-up time may be smaller than in some other reports [6,9], the present study has analysed a large unselected group of first-degree relatives with a substantial follow-up, unbiased towards certain antibody positivities in the absence of prescreening for ICA or enrichment in prediabetic relatives, as may be the case in some studies [4,7], and with a wider age range than in other studies [6]. Our confirmation [13] of the primacy of IA-2A positivity over the number of autoantibodies-at variance with other claims [9]-should not be ascribed to differences in study size but rather to differences in study protocol and/ or the way the data were analysed; indeed, when expressed in the same way as in other studies [4] our results also indicate an increasing risk of type 1 diabetes with the number of (molecular) antibodies present.…”

Section: Discussionmentioning

confidence: 85%

“…A recent study in siblings of type 1 diabetic patients [13] confirmed the generally held view that the risk of diabetes increases with the number of islet autoantibody specificities [4][5][6][7][8][9], but in addition indicated that the presence of autoantibodies against the intracellular domain of insulinomaassociated protein-2 (IA-2 autoantibodies, IA-2A), which is often associated with multiple antibody positivity [13][14][15][16], confers a higher risk of rapid progression towards clinical onset than multiple antibody positivity per se [13]. In persistently IA-2A-negative siblings the risk of diabetes increased significantly with the number of other autoantibodies present (GADA, IAA and/or ICA), but the progression rate remained less than 10% within 5 years [13].…”

Section: Introductionmentioning

confidence: 72%

“…The appearance of circulating islet autoantibodies before the clinical onset of immune-mediated type 1 diabetes makes it possible to select subjects at increased risk of becoming hyperglycaemic among first-degree relatives of known pa-tients [1][2][3][4][5][6][7][8][9]. However, prevention studies testing the potential of pharmacological interventions to arrest or slow down the subclinical disease process in antibody-positive relatives are still hampered by large differences in disease progression rate in marker-positive subjects [1][2][3][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

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Combined positivity for HLA DQ2/DQ8 and IA-2 antibodies defines population at high risk of developing type 1 diabetes

Decochez

Truyen²,

Auwera

et al. 2005

Diabetologia

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Aims/hypothesis: Prevention trials in first-degree relatives of type 1 diabetic patients are hampered by large interindividual differences in progression rate to diabetes. We investigated whether specific combinations of immune and genetic markers can identify subgroups with more homogeneous progression to clinical onset. Methods: Antibodies against islet cell cytoplasm (ICA), insulin (IAA), glutamate decarboxylase (GADA) and IA-2 protein (IA-2A) were measured in 790 non-diabetic control subjects and 4,589 first-degree relatives under age 40. Results: On first sampling, 11.1% of the siblings presented at least one antibody type (p<0.001 vs other relatives). During follow-up (median 52 months) 43 subjects developed type 1 diabetes (31 siblings, ten offspring of a diabetic father, two offspring of a diabetic mother). Using Kaplan-Meier survival analysis and Cox regression, IA-2A conferred the highest 5-year diabetes risk (>50%) irrespective of the number of antibodies present. In initially IA-2A-positive relatives (n=58) progression to hyperglycaemia depended more on HLA DQ status than on type of kinship (84% progression in the presence of DQ2/DQ8 vs 32% in its absence; p<0.003). In IA-2A-negative relatives (n=4,531) 5-year progression to diabetes increased with the number of other antibodies (ICA, GADA and/or IAA) (p<0.001) but overall did not exceed 10% even for two or more antibodies. Among relatives initially positive for one or more antibody type other than IA-2A (n=315), there was significantly more progression to diabetes (overall still <10%) in carriers of DQ2 (p<0.001 vs no DQ2), regardless of DQ8 status. Conclusions/interpretation: These observations suggest that the HLA-DQ-inferred risk of diabetes can proceed through two distinct pathways distinguished by IA-2A status. Combined positivity for DQ2/DQ8 and IA-2A defines a more homogeneous high-risk population for prevention trials than those used so far.

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Section: Discussionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Combined positivity for HLA DQ2/DQ8 and IA-2 antibodies defines population at high risk of developing type 1 diabetes

Decochez

Truyen²,

Auwera

et al. 2005

Diabetologia

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show abstract

“…Type 1 diabetic patients with detectable islet autoantibodies lose beta cell function faster than those who do not [57]. Similarly, the number and titre of islet autoantibodies predicts the rate of progression to diabetes in individuals at risk of type 1 diabetes [58]. Therefore exercise may not provide any clinically meaningful preservation of beta cell function in patients with new-onset type 1 diabetes, particularly those with elevated levels of islet autoantibodies.…”

Section: Beta Cell Preservation In Healthy Individualsmentioning

confidence: 99%

The time has come to test the beta cell preserving effects of exercise in patients with new onset type 1 diabetes

et al. 2014

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Type 1 diabetes is characterised by immunemediated destruction of insulin-producing beta cells. Significant beta cell function is usually present at the time of diagnosis with type 1 diabetes, and preservation of this function has important clinical benefits. The last 30 years have seen a number of largely unsuccessful trials for beta cell preservation, some of which have been of therapies that have potential for significant harm. There is a need to explore new, more tolerable approaches to preserving beta cell function that can be implemented on a large clinical scale. Here we review the evidence for physical exercise as a therapy for the preservation of beta cell function in patients with newly diagnosed type 1 diabetes. We highlight possible mechanisms by which exercise could preserve beta cell function and then present evidence from other models of diabetes that demonstrate that exercise preserves beta cell function. We conclude by proposing that there is now a need for studies to explore whether exercise can preserve beta cell in patients newly diagnosed with type 1 diabetes.

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“…In particular, IAA are an important predictor in the diagnosis of T1D (3). IAA are frequently found and are among the first detectable autoantibodies in young children developing the disease (12)(13)(14)(15)(16). They precede T1D with reported appearance between 8 and 20 wk of age in the NOD mouse and they correlate with diabetes incidence (3).…”

Section: Iaa As An Early Phenotypic Marker For T1dmentioning

confidence: 99%

Early and Quantal (by Litter) Expression of Insulin Autoantibodies in the Nonobese Diabetic Mice Predict Early Diabetes Onset

Melanitou

Devendra

Liu

et al. 2004

The Journal of Immunology

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International audienceAiming to study the early stages of type 1 diabetes phenotype, before insulitis appears, we measured insulin autoantibodies (IAA) between 3 and 5 wk of age in the NOD mouse (early-IAA (E-IAA)). We report that IAA are found as early as at 3 wk of age, at weaning, and their expression is a quantal phenotype. Maternal autoantibody status influences this early phenotype, because animals of litters issued from IAA-positive ante partum mothers develop E-IAA with a significantly higher incidence than animals issued from IAA-negative mothers. These E-IAA represent synthesized rather than transplacental autoantibodies, as evidenced by higher levels in many offspring compared with maternal IAA, and negative as well as positive offspring in the same litters and it correlates with early diabetes onset, defining the first autoimmune window in diabetes pathogenesis. Therefore, autoimmune processes leading to type 1 diabetes initiate early in life, are influenced by maternal autoantibody status, and can be revealed by the presence of IAA. Our data suggest that the mechanisms responsible for the breakdown of self-tolerance are subjected not only to genetic predisposition, but also to the physiological status of the mother. Pathological progression to autoimmunity is marked by the presence of immunological windows relating early steps with final disease onset

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Only Multiple Autoantibodies to Islet Cells (ICA), Insulin, GAD65, IA-2 and IA-2β Predict Immune-Mediated (Type 1) Diabetes in Relatives

Cited by 101 publications

References 46 publications

Combined positivity for HLA DQ2/DQ8 and IA-2 antibodies defines population at high risk of developing type 1 diabetes

Combined positivity for HLA DQ2/DQ8 and IA-2 antibodies defines population at high risk of developing type 1 diabetes

The time has come to test the beta cell preserving effects of exercise in patients with new onset type 1 diabetes

Early and Quantal (by Litter) Expression of Insulin Autoantibodies in the Nonobese Diabetic Mice Predict Early Diabetes Onset

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