Global gene expression changes in type 1 diabetes: Insights into autoimmune response in the target organ and in the periphery

Planas, Raquel; Pujol-Borrell, Ricardo; Vives-Pi, Marta

doi:10.1016/j.imlet.2010.08.001

Cited by 32 publications

(24 citation statements)

References 60 publications

(70 reference statements)

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“…Macrophages, dendritic cells and lymphocytes are involved in this pathogenic process through a complex interplay of mechanisms implicated in the loss of immune tolerance to autoantigens, including i) the hypoexpression of insulin in the thymus during promiscuous antigen expression [5,6]; ii) autoantigen presentation mediated by molecules coded by the HLA-DRB1*04–DQB1:03:02 and HLA-DR31*03–DQB1*02:01 haplotypes resulting in the development of insulin autoantibodies (IAA) and autoantibodies against the 65 kDa isoform of glutamic acid decarboxylase (GADA), respectively [7]; iii) a deregulation of the immune response mediated by either an impaired expression of surface regulatory molecules ( IL2RA , IL2RB , and CTLA-4 ) or a deregulation of intracellular signals ( PTPN2 and PTPN22 ) [8]; iv) a decreased number of suppressive or T regulatory cells [9]; v) a decreased number of iNKT cells [10]; and vi) a loss of function of molecules involved in the innate immune response [11,12]. In addition, several other genes have been implicated in the development of T1D by human genome wide association studies (GWAS) [13-15], including genes identified by transcriptome analyses in human or animal models [16,17] that evaluated peripheral blood mononuclear cells [18,19], pancreatic beta cells [20] and whole blood cells [21]. …”

Section: Introductionmentioning

confidence: 99%

Integrative analysis of the transcriptome profiles observed in type 1, type 2 and gestational diabetes mellitus reveals the role of inflammation

et al. 2014

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BackgroundType 1 diabetes (T1D) is an autoimmune disease, while type 2 (T2D) and gestational diabetes (GDM) are considered metabolic disturbances. In a previous study evaluating the transcript profiling of peripheral mononuclear blood cells obtained from T1D, T2D and GDM patients we showed that the gene profile of T1D patients was closer to GDM than to T2D. To understand the influence of demographical, clinical, laboratory, pathogenetic and treatment features on the diabetes transcript profiling, we performed an analysis integrating these features with the gene expression profiles of the annotated genes included in databases containing information regarding GWAS and immune cell expression signatures.MethodsSamples from 56 (19 T1D, 20 T2D, and 17 GDM) patients were hybridized to whole genome one-color Agilent 4x44k microarrays. Non-informative genes were filtered by partitioning, and differentially expressed genes were obtained by rank product analysis. Functional analyses were carried out using the DAVID database, and module maps were constructed using the Genomica tool.ResultsThe functional analyses were able to discriminate between T1D and GDM patients based on genes involved in inflammation. Module maps of differentially expressed genes revealed that modulated genes: i) exhibited transcription profiles typical of macrophage and dendritic cells; ii) had been previously associated with diabetic complications by association and by meta-analysis studies, and iii) were influenced by disease duration, obesity, number of gestations, glucose serum levels and the use of medications, such as metformin.ConclusionThis is the first module map study to show the influence of epidemiological, clinical, laboratory, immunopathogenic and treatment features on the transcription profiles of T1D, T2D and GDM patients.

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Section: Introductionmentioning

confidence: 99%

Integrative analysis of the transcriptome profiles observed in type 1, type 2 and gestational diabetes mellitus reveals the role of inflammation

et al. 2014

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“…Complex longitudinal changes in beta cells during T1D progression are well established 13 ; however, separating potential genetic beta cell defects from induced secondary changes has not been possible in human samples. The genetics of T1D susceptibility in NOD mice have been well characterized and show striking parallels with human data, making these mice an ideal testing ground for the hypothesis that genetic abnormalities in beta cells contribute to pathogenic outcome 1 .…”

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confidence: 99%

Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes

et al. 2016

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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 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.

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“…In other studies, overexpression of inflammatory, innate, and autoimmune response genes have been found in affected islets from individuals with T1D (34). Upon exposure to cytokines, the islet responded by increasing expression of apoptosis and inflammation related genes and T1D candidate gene expression was altered specifically in the β cell (27).…”

Section: Text Of Reviewmentioning

confidence: 71%

The pancreatic β-cell transcriptome and integrated-omics

Blodgett

Cura

Harlan

2014

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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Purpose of Review β cells represent one of many cell types in heterogeneous pancreatic islets and play the central role in maintaining glucose homeostasis, such that disrupting β cell function leads to diabetes. This review summarizes methods for isolating and characterizing β cells, and describes integrated “omics” approaches used to define the β cell by its transcriptome and proteome. Recent Findings RNA Sequencing and mass spectrometry-based protein identification have now identified RNA and protein profiles for mouse and human pancreatic islets and β cells, and for β cell lines. Recent publications have outlined these profiles and, more importantly, have begun to assign the presence or absence of specific genes and regulatory molecules to β cell function and dysfunction. Overall, researchers have focused on understanding the pathophysiology of diabetes by connecting genome, transcriptome, proteome, and regulatory RNA profiles with findings from genome wide association studies (GWAS). Summary Studies employing these relatively new techniques promise to identify specific genes or regulatory RNAs with altered expression as β cell function begins to deteriorate in the spiral toward the development of diabetes. The ultimate goal is to identify potential therapeutic targets to prevent β cell dysfunction and thereby better treat the individual with diabetes.

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Global gene expression changes in type 1 diabetes: Insights into autoimmune response in the target organ and in the periphery

Cited by 32 publications

References 60 publications

Integrative analysis of the transcriptome profiles observed in type 1, type 2 and gestational diabetes mellitus reveals the role of inflammation

Integrative analysis of the transcriptome profiles observed in type 1, type 2 and gestational diabetes mellitus reveals the role of inflammation

Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes

The pancreatic β-cell transcriptome and integrated-omics

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