Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies

Verge, C. F.; Gianani, R.; Kawasaki, Eiji; Yu, L.; Pietropaolo, M.; Jackson, R. A.; Chase, H. Peter; Eisenbarth, George S.

doi:10.2337/diabetes.45.7.926

Cited by 311 publications

(224 citation statements)

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“…No single aAb specificity alone performs well at predicting disease, and the positive predictive value increases with the number of positive aAbs, but not with their titers (32,33,34). No unique pattern stems out in the order of appearance of these aAbs, although IAAs often appear first (but are frequently absent in adults), whereas GAD, IA-2, and ZnT8 aAbs appear around the same time.…”

Section: Aab Responses To Insulinmentioning

confidence: 99%

“…This shift also applied to different epitopes derived from PI. Indeed, new-onset T1D patients preferentially displayed T-cell reactivities against the leader sequence epitope PPI [6][7][8][9][10][11][12][13][14] , whereas the B-chain epitope PI [33][34][35][36][37][38][39][40][41][42] was predominantly recognized in long-standing patients (63).…”

Section: T-cell Responses To Insulinmentioning

confidence: 99%

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MECHANISMS IN ENDOCRINOLOGY: Insulin and type 1 diabetes: immune connections

Čulina

Brezar

Mallone

2013

European Journal of Endocrinology

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Insulin is the hormone produced by pancreatic b-cells, with a central role in carbohydrate and fat metabolism. Together with its precursors preproinsulin and proinsulin, insulin is also a key target antigen (Ag) of the autoimmune islet destruction leading to type 1 diabetes. Being recognized by both autoantibodies (aAbs) and autoreactive T cells, insulin plays a triggering role, at least in rodent models, in diabetes pathogenesis. It is expressed not only by b-cells but also in the thymus, where it plays a major role in central tolerance mechanisms. We will summarize current knowledge concerning insulin, its role in b-cell autoimmunity as initial target Ag, its recognition by aAbs and autoreactive T cells, and the detection of these immune responses to provide biomarkers for clinical trials employing insulin as an immune modulatory agent.European Journal of Endocrinology 168 R19-R31

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Section: Aab Responses To Insulinmentioning

confidence: 99%

Section: T-cell Responses To Insulinmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Insulin and type 1 diabetes: immune connections

Čulina

Brezar

Mallone

2013

European Journal of Endocrinology

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“…In contrast, expression of multiple autoantibodies was associated with a very high risk of progression. The ‘combinatorial’ analysis allowing more than two autoantibodies to be defined, independent of which two autoantibodies are expressed, gives approximately an 80% sensitivity for progression to diabetes with a very high specificity [20, 21]. The progression to overt diabetes resulting in a significant beta cell destruction is triggered by the development of a more aggressive T cell phenotype and a change in the Th1-to-Th2 balance towards a more proinflammatory milieu (Th1 dominant).…”

Section: Immune Mechanisms Responsible For Islet Cell Lossmentioning

confidence: 99%

Recent Advancement of Understanding Pathogenesis of Type 1 Diabetes and Potential Relevance to Diabetic Nephropathy

Ichinose

Kawasaki²,

Eguchi³

2007

Am J Nephrol

101

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Type 1 diabetes mellitus is an autoimmune disease characterized by progressive destruction of pancreatic beta cells by genetic and environmental factors which leads to an absolute dependence of insulin for survival and maintenance of health. Although the majority of mechanisms of beta cell destruction remain unclear, many molecules, including proinflammatory cytokines and chemokines such as tumor necrosis factor alpha and monocyte chemoattractant protein-1, are implicated in the development of beta cell damage. Furthermore, beta cell destruction is enhanced by the Th1 and Th17 subsets of CD4+ T cells. In contrast, there are mechanisms involved in the maintenance of peripheral tolerance by regulatory T cells, the function of which depends on the pleiotropic cytokine transforming growth factor beta. Development and progression of renal injuries in patients with diabetic nephropathy are also associated with several growth factors and proinflammatory cytokines, including tumor necrosis factor alpha, insulin-like growth factor-1, monocyte chemoattractant protein-1, vascular endothelial growth factor, and transforming growth factor beta. Although the pathogenic mechanisms underlying type 1 diabetes and diabetic nephropathy are principally different, i.e., autoimmunity and inflammation, some common factors, including susceptibility genes and proinflammatory cytokines, are involved in both mechanisms, including infiltrating cell recruitment, upregulation of other cytokines and chemokines, or apoptosis.

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“…Clinical manifestations of T1D occur once a substantial proportion of the insulin-producing β cells are destroyed [6]. The development of autoantibodies against multiple islet cell antigens is a well-established feature of T1D [7,8]. Although not an active component of the disease process itself, the presence of circulating autoantibodies to two or more islet antigens, namely insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen 2 (IA-2A), and zinc transporter-8 (ZnT8A), is highly predictive when combined with a family history of the disease or genetic risk [7-13].…”

Section: Introductionmentioning

confidence: 99%

“…The development of autoantibodies against multiple islet cell antigens is a well-established feature of T1D [7,8]. Although not an active component of the disease process itself, the presence of circulating autoantibodies to two or more islet antigens, namely insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen 2 (IA-2A), and zinc transporter-8 (ZnT8A), is highly predictive when combined with a family history of the disease or genetic risk [7-13]. IAA are usually the first islet autoantibodies to appear in prediabetic children [14-16], making it one of the earliest measurable signs of the autoimmune process.…”

Section: Introductionmentioning

confidence: 99%

Antibodies against insulin measured by electrochemiluminescence predicts insulitis severity and disease onset in non-obese diabetic mice and can distinguish human type 1 diabetes status

Swafford

Shafer‐Weaver

et al. 2011

J Transl Med

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BackgroundThe detection of insulin autoantibodies (IAA) aids in the prediction of autoimmune diabetes development. However, the long-standing, gold standard 125I-insulin radiobinding assay (RBA) has low reproducibility between laboratories, long sample processing times and requires the use of newly synthesized radiolabeled insulin for each set of assays. Therefore, a rapid, non-radioactive, and reproducible assay is highly desirable.MethodsWe have developed electrochemiluminescence (ECL)-based assays that fulfill these criteria in the measurement of IAA and anti-insulin antibodies (IA) in non-obese diabetic (NOD) mice and in type 1 diabetic individuals, respectively. Using the murine IAA ECL assay, we examined the correlation between IAA, histopathological insulitis, and blood glucose in a cohort of female NOD mice from 4 up to 36 weeks of age. We developed a human IA ECL assay that we compared to conventional RBA and validated using samples from 34 diabetic and 59 non-diabetic individuals in three independent laboratories.ResultsOur ECL assays were rapid and sensitive with a broad dynamic range and low background. In the NOD mouse model, IAA levels measured by ECL were positively correlated with insulitis severity, and the values measured at 8-10 weeks of age were predictive of diabetes onset. Using human serum and plasma samples, our IA ECL assay yielded reproducible and accurate results with an average sensitivity of 84% at 95% specificity with no statistically significant difference between laboratories.ConclusionsThese novel, non-radioactive ECL-based assays should facilitate reliable and fast detection of antibodies to insulin and its precursors sera and plasma in a standardized manner between laboratories in both research and clinical settings. Our next step is to evaluate the human IA assay in the detection of IAA in prediabetic subjects or those at risk of type 1 diabetes and to develop similar assays for other autoantibodies that together are predictive for the diagnosis of this common disorder, in order to improve prediction and facilitate future therapeutic trials.

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Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies

Cited by 311 publications

References 0 publications

MECHANISMS IN ENDOCRINOLOGY: Insulin and type 1 diabetes: immune connections

MECHANISMS IN ENDOCRINOLOGY: Insulin and type 1 diabetes: immune connections

Recent Advancement of Understanding Pathogenesis of Type 1 Diabetes and Potential Relevance to Diabetic Nephropathy

Antibodies against insulin measured by electrochemiluminescence predicts insulitis severity and disease onset in non-obese diabetic mice and can distinguish human type 1 diabetes status

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