Type I diabetes mellitus: A predictable autoimmune disease with interindividual variation in the rate of β cell destruction

Dotta, Francesco; Eisenbarth, George S.

doi:10.1016/0090-1229(89)90115-3

Cited by 24 publications

(7 citation statements)

References 29 publications

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“…Childhood-onset diabetes can result from multiple disease processes, but for the majority of children, diabetes results from immune-mediated beta cell destruction (type 1A) [1,2]. Type 1A diabetes is characterised by the presence of antiislet autoantibodies at onset [3] and extensive beta cell destruction as seen in pancreases of patients who died at onset.…”

Section: Introductionmentioning

confidence: 99%

Dimorphic histopathology of long-standing childhood-onset diabetes

et al. 2010

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Aims/hypothesis Childhood diabetes is thought to usually result from autoimmune beta cell destruction (type 1A) with eventual total loss of beta cells. Analysis of C-peptide in children characterised at diabetes onset for autoantibodies shows heterogeneous preservation of insulin secretion in long-standing diabetes. The aim of this study was to characterise the pancreases of childhood-onset diabetes in order to define the pathological basis of this heterogeneity. Methods We evaluated 20 cadaveric organ donor pancreases of childhood-onset long-term patients for disease heterogeneity and obtained corresponding C-peptide measurements.Results Pancreases from the majority of cadaveric donors contained only insulin-deficient islets (14 of 20). The remaining six patients (30%) had numerous insulinpositive cells within at least some islets, with two different histological patterns. Pattern A (which we would associate with type 1A diabetes) had lobular retention of areas with 'abnormal' beta cells producing the apoptosis inhibitor survivin and HLA class I. In pattern B, 100% of all islets contained normal-appearing but quantitatively reduced beta cells without survivin or HLA class I. Conclusions/interpretation Our data demonstrate that C-peptide secretion in long-standing diabetic patients can be explained by two different patterns of beta cell survival, possibly reflecting different subsets of type 1 diabetes.

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Section: Introductionmentioning

confidence: 99%

Dimorphic histopathology of long-standing childhood-onset diabetes

et al. 2010

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“…Although we do not yet know if autoreactivity against endogenous β-cell protein antigens actually triggers onset of disease—this remains a leading hypothesis. The acknowledgment of autoantigens in pancreatic islet cells in patients with T1D (who may also have additional endocrinopathies) has been recognized for nearly 40 years—initially by immunofluorescence of human pancreas (Bottazzo et al 1974)—and occasionally by cross-reaction in pancreatic β-cell lines in culture (in some cases even including β cells of other species [Dotta and Eisenbarth 1989; Karounos and Thomas 1990]). The islet autoantigens identified to date tend to be largely (but not exclusively) proteinaceous.…”

mentioning

confidence: 99%

Islet Autoantigens: Structure, Function, Localization, and Regulation

Arvan¹,

Pietropaolo²,

Ostrov³

et al. 2012

Cold Spring Harbor Perspectives in Medicine

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Islet autoantigens associated with autoimmune type 1 diabetes (T1D) are expressed in pancreatic β cells, although many show wider patterns of expression in the neuroendocrine system. Within pancreatic β cells, every T1D autoantigen is in one way or another linked to the secretory pathway. Together, these autoantigens play diverse roles in glucose regulation, metabolism of biogenic amines, as well as the regulation, formation, and packaging of secretory granules. The mechanism(s) by which immune tolerance to islet-cell antigens is lost during the development of T1D, remains unclear. Antigenic peptide creation for immune presentation may potentially link to the secretory biology of β cells in a number of ways, including proteasomal digestion of misfolded products, exocytosis, and endocytosis of cell-surface products, or antigen release from dying β cells during normal or pathological turnover. In this context, we evaluate the biochemical nature and immunogenicity of the major autoantigens in T1D including (pro)insulin, GAD65, ZnT8, IA2, and ICA69.

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“…A reduced first‐phase insulin response (FPIR) (progressively lost during the prodromal phase) is indicative of β‐cell damage and has been shown to be predictive of progression to T1DM in aAb positive first‐degree relatives 71, 72. The combination of reduced FPIR and positive aAb facilitates estimation of the T1DM risk in unaffected siblings and accounts for more than 75% of the variation in time to diabetes over a 6‐year interval 73, 74.…”

Section: Clinical Trials For Prevention Of T1dmmentioning

confidence: 99%

Challenges in developing endpoints for type 1 diabetes intervention studies

Herold

Hirshberg

Roep

et al. 2009

Diabetes Metabolism Res

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Development of efficient and safe intervention strategies for preserving and/or restoring endogenous insulin production in type 1 diabetes has encountered a wide range of challenges, including lack of standardized trial protocols and of consensus on appropriate efficacy endpoints. For the greatest part, difficulties resided in choosing the most suitable assay(s) and parameter(s) to assess the beta-cell function. It is now an accepted approach to evaluate endogenous insulin secretion by measuring C-peptide levels (with highly sensitive and normalized measurement methods) in response to a physiologic stimulus (liquid mixed-meal) under standardized conditions. Preventive interventions mandate the identification of well-defined, reliable and validated mechanistic or immunological markers of efficacy that would correlate with (and predict) the clinical outcome. This has not been consistently achieved to date. However, it has been generally agreed that for preventive studies performed very early in the disease course (in subjects without signs of autoimmunity against beta-cells) development of two or more islet related autoantibodies could be employed as biomarkers of disease and thereafter, diagnostic criteria of diabetes serve as suitable endpoints.This report summarizes the conclusions of the D-Cure workshop of international experts held in Barcelona in April 2007 and the current recommendations and updates in the field.

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Type I diabetes mellitus: A predictable autoimmune disease with interindividual variation in the rate of β cell destruction

Cited by 24 publications

References 29 publications

Dimorphic histopathology of long-standing childhood-onset diabetes

Dimorphic histopathology of long-standing childhood-onset diabetes

Islet Autoantigens: Structure, Function, Localization, and Regulation

Challenges in developing endpoints for type 1 diabetes intervention studies

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