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Spatiotemporal Dynamics of Insulitis in Human Type 1 Diabetes.

ABSTRACT: Type 1 diabetes (T1D) is an auto-immune disease characterized by the selective destruction of the insulin secreting beta cells in the pancreas during an inflammatory phase known as insulitis. Patients with T1D are typically dependent on the administration of externally provided insulin in order to manage blood glucose levels. Whilst technological developments have significantly improved both the life expectancy and quality of life of these patients, an understanding of the mechanisms of the disease remains elusive. Animal models, such as the NOD mouse model, have been widely used to probe the process of insulitis, but there exist very few data from humans studied at disease onset. In this manuscript, we employ data from human pancreases collected close to the onset of T1D and propose a spatio-temporal computational model for the progression of insulitis in human T1D, with particular focus on the mechanisms underlying the development of insulitis in pancreatic islets. This framework allows us to investigate how the time-course of insulitis progression is affected by altering key parameters, such as the number of the CD20+ B cells present in the inflammatory infiltrate, which has recently been proposed to influence the aggressiveness of the disease. Through the analysis of repeated simulations of our stochastic model, which track the number of beta cells within an islet, we find that increased numbers of B cells in the peri-islet space lead to faster destruction of the beta cells. We also find that the balance between the degradation and repair of the basement membrane surrounding the islet is a critical component in governing the overall destruction rate of the beta cells and their remaining number. Our model provides a framework for continued and improved spatio-temporal modeling of human T1D.

SUBMITTER: Wedgwood KC

PROVIDER: S-EPMC5186767 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Spatiotemporal Dynamics of Insulitis in Human Type 1 Diabetes.

Wedgwood Kyle C A KC Richardson Sarah J SJ Morgan Noel G NG Tsaneva-Atanasova Krasimira K

Frontiers in physiology 20161227

Type 1 diabetes (T1D) is an auto-immune disease characterized by the selective destruction of the insulin secreting beta cells in the pancreas during an inflammatory phase known as insulitis. Patients with T1D are typically dependent on the administration of externally provided insulin in order to manage blood glucose levels. Whilst technological developments have significantly improved both the life expectancy and quality of life of these patients, an understanding of the mechanisms of the dise ...[more]

PMID: 28082906

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Project description:Aims/hypothesisAccording to the consensus criteria developed for type 1 diabetes, an individual can be diagnosed with insulitis when ≥ 15 CD45+ cells are found within the parenchyma or in the islet-exocrine interface in ≥ 3 islets. The aim of this study was to determine the frequency of individuals with type 2 diabetes fulfilling these criteria with reference to non-diabetic and type 1 diabetic individuals.MethodsInsulitis was determined by examining CD45+ cells in the pancreases of 50, 13 and 44 organ donors with type 2 diabetes, type 1 diabetes and no diabetes, respectively. CD3+ cells (T cells) infiltrating the islets were evaluated in insulitic donors. In insulitic donors with type 2 diabetes, the pancreases were characterised according to the presence of CD68 (macrophages), myeloperoxidase (MPO; neutrophils), CD3, CD20 (B cells) and HLA class I hyperstained islets. In all type 2 diabetic donors, potential correlations of insulitis with dynamic glucose-stimulated insulin secretion in vitro or age, BMI, HbA1c or autoantibody positivity were examined.ResultsOverall, 28% of the type 2 diabetic donors fulfilled the consensus criteria for insulitis developed for type 1 diabetes. Of the type 1 diabetic donors, 31% fulfilled the criteria. None of the non-diabetic donors met the criteria. Only type 1 diabetic donors had ≥ 15 CD3+ cells in ≥ 3 islets. Type 2 diabetic donors with insulitis also had a substantial number of CD45+ cells in the exocrine parenchyma. Macrophages constituted the largest fraction of CD45+ cells, followed by neutrophils and T cells. Of type 2 diabetic pancreases with insulitis, 36% contained islets that hyperstained for HLA class I. Isolated islets from type 2 diabetic donors secreted less insulin than controls, although with preserved dynamics. Insulitis in the type 2 diabetic donors did not correlate with glucose-stimulated insulin secretion, the presence of autoantibodies, BMI or HbA1c.Conclusions/interpretationThe current definition of insulitis cannot be used to distinguish pancreases retrieved from individuals with type 1 diabetes from those with type 2 diabetes. On the basis of our findings, we propose a revised definition of insulitis, with a positive diagnosis when ≥ 15 CD3+ cells, not CD45+ cells, are found in ≥ 3 islets.

Dataset Information

Spatiotemporal Dynamics of Insulitis in Human Type 1 Diabetes.

Publications

Spatiotemporal Dynamics of Insulitis in Human Type 1 Diabetes.

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