The pancreatic β cell and type 1 diabetes: innocent bystander or active participant? (original) (raw)
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Genes Affecting β-Cell Function in Type 1 Diabetes
Current Diabetes Reports, 2015
Type 1 diabetes (T1D) is a multifactorial disease resulting from an immune-mediated destruction of the insulin-producing pancreatic β cells. Several environmental and genetic risk factors predispose to the disease. Genomewide association studies (GWAS) have identified around 50 genetic regions that affect the risk of developing T1D, but the disease-causing variants and genes are still largely unknown. In this review, we discuss the current status of T1D susceptibility loci and candidate genes with focus on the β cell. At least 40 % of the genes in the T1D susceptibility loci are expressed in human islets and β cells, where they according to recent studies modulate the β-cell response to the immune system. As most of the risk variants map to noncoding regions of the genome, i.e., promoters, enhancers, intergenic regions, and noncoding genes, their possible involvement in T1D pathogenesis as gene regulators will also be addressed. Keywords T1D. GWAS. Candidate genes. Pancreatic islets. Noncoding RNA. CTSH This article is part of the Topical Collection on Pathogenesis of Type 1 Diabetes
From Pancreatic β-Cell Gene Networks to Novel Therapies for Type 1 Diabetes
Diabetes, 2021
Completion of the Human Genome Project enabled a novel systems- and network-level understanding of biology, but this remains to be applied for understanding the pathogenesis of type 1 diabetes (T1D). We propose that defining the key gene regulatory networks that drive β-cell dysfunction and death in T1D might enable the design of therapies that target the core disease mechanism, namely, the progressive loss of pancreatic β-cells. Indeed, many successful drugs do not directly target individual disease genes but, rather, modulate the consequences of defective steps, targeting proteins located one or two steps downstream. If we transpose this to the T1D situation, it makes sense to target the pathways that modulate the β-cell responses to the immune assault—in relation to signals that may stimulate the immune response (e.g., HLA class I and chemokine overexpression and/or neoantigen expression) or inhibit the invading immune cells (e.g., PDL1 and HLA-E expression)—instead of targeting ...
Molecular Footprints of the Immune Assault on Pancreatic Beta Cells in Type 1 Diabetes
Frontiers in Endocrinology, 2020
Type 1 diabetes (T1D) is a chronic disease caused by the selective destruction of the insulin-producing pancreatic beta cells by infiltrating immune cells. We presently evaluated the transcriptomic signature observed in beta cells in early T1D and compared it with the signatures observed following in vitro exposure of human islets to inflammatory or metabolic stresses, with the aim of identifying "footprints" of the immune assault in the target beta cells. We detected similarities between the beta cell signatures induced by cytokines present at different moments of the disease, i.e., interferon-α (early disease) and interleukin-1β plus interferon-γ (later stages) and the beta cells from T1D patients, identifying biological process and signaling pathways activated during early and late stages of the disease. Among the first responses triggered on beta cells was an enrichment in antiviral responses, pattern recognition receptors activation, protein modification and MHC class I antigen presentation. During putative later stages of insulitis the processes were dominated by T-cell recruitment and activation and attempts of beta cells to defend themselves through the activation of anti-inflammatory pathways (i.e., IL10, IL4/13) and immune check-point proteins (i.e., PDL1 and HLA-E). Finally, we mined the beta cell signature in islets from T1D patients using the Connectivity Map, a large database of chemical compounds/drugs, and identified interesting candidates to potentially revert the effects of insulitis on beta cells.
Identification of Key β Cell Gene Signaling Pathways Involved in Type 1 Diabetes
Annals of the New York Academy of Sciences, 2004
In type 1 diabetes,  cells die through a process of immunemediated apoptosis. To better understand this process, it has been accepted practice to study  cell or islet apoptosis in vitro in response to a range of immune stimuli, such as interferon gamma, interleukin-1, nitric oxide or free radicals. In particular, much use has been made of immortalized  cell lines for such studies, although it is not clear to what extent the behavior of these cell lines might mimic the behavior of normal  cells in vivo, or freshly isolated  cells ex vivo. To address this question we compared the gene expression of freshly isolated NOD islets in the presence or absence of insulitis, with previously published data examining either islet or  cell gene or protein expression in a range of different species and contexts. There was a high correlation between  cell genes found be to be expressed by mouse and rat islets, by either gene expression or proteomic analysis. There was also a surprisingly high correlation between  cell genes found be to be expressed by islets exposed to insulitis in vivo and islets stimulated with IFN-␥ and IL-1 in vitro, suggesting that these two cytokines as produced by the islet infiltrate are important for priming  cells in vivo. There was a much lower correlation when gene expression was compared between fresh  cells and  cell lines, consistent with the view that  cell lines are very poorly representative of real  cells. Hence, any results obtained using  cell lines should be interpreted with great caution when extrapolating to the behavior of real  cells.
Islet‐Immune Interactions in Type 1 Diabetes: The Nexus of Beta Cell Destruction
Clinical & Experimental Immunology
Recent studies in Type 1 Diabetes (T1D) support an emerging model of disease pathogenesis that involves intrinsic β-cell fragility combined with defects in both innate and adaptive immune cell regulation. This combination of defects induces systematic changes leading to organ-level atrophy and dysfunction of both the endocrine and exocrine portions of the pancreas, ultimately culminating in insulin deficiency and β-cell destruction. In this review, we discuss the animal model data and human tissue studies that have informed our current understanding of the crosstalk that occurs between β-cells, the resident stroma, and immune cells that potentiate T1D. Specifically, we will review the cellular and molecular signatures emerging from studies on tissues derived from organ procurement programs, focusing on in situ defects occurring within the T1D islet microenvironment, many of which are not yet detectable by standard peripheral blood biomarkers. In addition to improved access to organ donor tissues, various methodological advances, including immune receptor repertoire sequencing and single-cell molecular profiling, are poised to improve our understanding of antigen-specific autoimmunity during disease development. Collectively, the knowledge gains from these studies at the isletimmune interface are enhancing our understanding of T1D heterogeneity, likely to be Accepted Article This article is protected by copyright. All rights reserved. an essential component for instructing future efforts to develop targeted interventions to restore immune tolerance and preserve β-cell mass and function.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, 2016
Type 1 (T1D) and type 2 (T2D) diabetes share pathophysiological characteristics, yet mechanistic links have remained elusive. T1D results from autoimmune destruction of pancreatic beta cells, whereas beta cell failure inT2D is delayed and progressive. Here we find a new genetic component of diabetes susceptibility in T1D non-obese diabetic (NOD) mice, identifying immuneindependent beta cell fragility. Genetic variation in Xrcc4 and Glis3 alters the response of NOD beta cells to unfolded protein stress, enhancing the apoptotic and senescent fates. The same transcriptional relationships were observed in human islets, demonstrating the role of beta cell fragility in genetic predisposition to diabetes. Dooley et al.
Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes
Nature genetics, 2016
Type 1 (T1D) and type 2 (T2D) diabetes share pathophysiological characteristics, yet mechanistic links have remained elusive. T1D results from autoimmune destruction of pancreatic beta cells, whereas beta cell failure in T2D is delayed and progressive. Here we find a new genetic component of diabetes susceptibility in T1D non-obese diabetic (NOD) mice, identifying immune-independent beta cell fragility. Genetic variation in Xrcc4 and Glis3 alters the response of NOD beta cells to unfolded protein stress, enhancing the apoptotic and senescent fates. The same transcriptional relationships were observed in human islets, demonstrating the role of beta cell fragility in genetic predisposition to diabetes.
Use of a systems biology approach to understand pancreatic β-cell death in Type 1 diabetes
Biochemical Society Transactions, 2008
Accumulating evidence indicates that β-cells die by apoptosis in T1DM (Type 1 diabetes mellitus). Apoptosis is an active gene-directed process, and recent observations suggest that β-cell apoptosis depends on the parallel and/or sequential up- and down-regulation of hundreds of genes controlled by key transcription factors such as NF-κB (nuclear factor κB) and STAT-1 (signal transducer and activator of transcription 1). Understanding the regulation of these gene networks, and how they modulate β-cell death and the ‘dialogue’ between β-cells and the immune system, will require a systems biology approach to the problem. This will hopefully allow the search for a cure for T1DM to move from a ‘trial-and-error’ approach to one that is really mechanistically driven.