Distinct immune features in the partial remission phase of type 1 diabetes identified through Single-Cell RNA Sequencing and Functional Analysis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE221297 | GEO | 2024/01/18
REPOSITORIES: GEO
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Project description:Partial remission (PR) occurs in only half of patients with new-onset type 1 diabetes (T1D) and correspond to a transient period characterized by low daily insulin needs, low glycemic fluctuations and increased endogenous insulin secretion. While identification of newly-onset T1D patients with significant residual beta-cell function may foster patient-specific interventions, reliable predictive biomarkers of PR occurrence currently lack. We analyzed the plasma of children with new-onset T1D to identify biomarkers present at diagnosis that predicted PR at 3 months post-diagnosis. We first performed an extensive shotgun proteomic analysis using Liquid Chromatography-Tandem-Mass-Spectrometry (LCMS/MS) on the plasma of 16 children with new-onset T1D and quantified nearly 1500 unique proteins with 98 significantly correlating with Insulin-Dose Adjusted glycated hemoglobin A1c score (IDAA1C). We next applied a series of both qualitative and statistical filters that yielded to the selection of 26 protein candidates that were associated to pathophysiological mechanisms related to T1D. Finally, we translationally validated several of the candidates using single-shot targeted proteomic (PRM method) on raw plasma. Taken together, we identified plasmatic biomarkers present at diagnosis that may predict the occurrence of PR in a single mass-spectrometry run. We believe that the identification of new predictive biomarkers of PR and β-cell function is key to stratify patients with new-onset T1D for β-cell preservation therapies
2024-04-05 | PXD049795 | Pride
Project description:New measures are needed to predict type 1 diabetes disease trajectory. We have developed a sensitive array-based bioassay whereby patient plasma is used to induce transcription in healthy “reporter” leukocytes. Here we report a refined gene ontology-based inflammatory index (I.I.359) that is based upon expression levels of 359 transcripts identified in cross-sectional studies of new onset Type 1 diabetes patients and controls, where higher scores reflect greater inflammatory bias. We examined the relationship between I.I.359 measured at onset and the post-onset disease course in local patients as well as participants of the TrialNet CTLA4-Ig trial. In untreated patients, I.I.359 at baseline was highly variable and exhibited a significant inverse relationship with stimulated C-peptide AUC at 3, 6, 12, 18 and 24 months post-onset. Further, duration of the post-onset partial remission was negatively related to baseline I.I.359 and positively associated with the peripheral abundance of activated regulatory T cells (CD4+/CD45RA-/FoxP3high).
2018-07-19 | GSE102234 | GEO
Project description:Gastric bypass surgery (GBP) emerging as a powerful tool for treatment of obesity has been applied for remission of diabetes. However, the GBP global molecular effects on diabetes remission independent of weight loss remain largely unknown. We profiled plasma metabolites and proteins of 10 normoglycemic obese (NO) and 9 diabetic obese (DO) patients at 1-week, 3-months and 1-year stages after Roux-en-Y gastric bypass (RYGB) as well pre-RYGB stage, by which 146 proteins and 128 metabolites were detected from both NO and DO groups at all four stages. By analyzing a set of bi-molecular associations among the corresponding network of the subjects with our newly developed computational method, we defined the representing physiological states (called the edge-states, in contrast to the traditional node-states) and the related molecular networks of NO and DO patients, respectively. The PCA results and hubnetworks of NO subjects were significantly different from those of DO patients; particularly, the hub-network rearrangement of both groups differentially went through after RYGB. In conclusion, by developing network-based systems signatures rather than relying on individual molecules, we for the first time reveal that RYGB generates a unique recovering-path for diabetes remission independent of weight loss.
2017-12-13 | PXD008071 | Pride
Project description:Targeted pharmacological therapy restores β-cell function for diabetes remission
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Project description:Collapsing focal segmental glomerulosclerosis (FSGS), also known as collapsing glomerulopathy (CG), is the most aggressive variant of FSGS and is characterized by rapid progression to end-stage kidney disease (ESKD). Understanding CG pathogenesis represents a key step for the development of targeted therapies. Previous work implicated the telomerase protein component TERT in CG pathogenesis, as transgenic TERT expression in adult mice resulted in a CG resembling that seen in human primary CG and HIV-associated nephropathy (HIVAN). We used the telomerase-induced mouse model of CG (i-TERTci mice) to identify mechanisms to inhibit CG pathogenesis. We found that inactivation of WIP1 phosphatase, a p53 target acting in a negative feedback loop, blocks disease initiation in i-TERTci mice. Repression of disease initiation upon WIP1 deficiency is associated with senescence enhancement and requires TGF-b functions. We further assessed efficacy of a pharmacologic treatment to reduce disease severity in both i-TERTci mice and in a mouse model of HIVAN (Tg26 mice). We found that pharmacologic inhibition of WIP1 enzymatic activity in either telomerase mice with CG or in Tg26 mice promotes partial remission of proteinuria and ameliorates renal histopathologic features. Histological as well as high throughput sequencing methods further showed that selective inhibition of WIP1 does not promote kidney fibrosis or inflammation. Our findings suggest that targeting WIP1 may be an effective therapeutic strategy for patients with CG.
2024-02-09 | GSE249878 | GEO
Project description:Type 1 Diabetes (T1D) is considered to be a Th1 autoimmune disease characterised by an absolute lack of insulin caused by an autoimmune destruction of the insulin producing pancreatic beta cells. Th1 lymphocytes are responsible for the infiltration of the islets of Langerhans and for the cytokine release that supports cytotoxic (Tc) lymphocytes to mediate destruction of the beta cells. The preclinical disease stage is characterized by the generation of the self-reactive lymphocytes that infiltrate the pancreas and selectively destroy the insulin-producing beta cells present in the islets. Other cellular immune mechanisms regarding immunoregulation and antigen presentation and processing are involved in T1D pathogenesis as well. Our aim was to identify genes involved in the corresponding signalling cascades, especially those which may serve as promising diagnostic tools for the identification of persons in the prediabetic phase of the disease. We addressed the question by analysing gene expression profiles of freshly isolated peripheral blood mononuclear cells in type 1 diabetes patients, their first degree relatives divided according to their autoantibody status, and healthy controls. 9 T1D-patients versus 10 first degree relatives versus 10 healthy controls
2011-05-09 | E-GEOD-29142 | biostudies-arrayexpress
Project description:Diabetes mellitus results from an inadequately functioning beta-cell mass. In the adult pancreas, beta-cell mass is dynamic, increasing to meet metabolic demands and decreasing with metabolic or injury insults. Exendin-4 (Ex-4) is a glucagon-like peptide-1 receptor agonist that augments beta-cell mass by increasing beta-cell neogenesis and proliferation and by reducing apoptosis. We utilized a cDNA microarray approach to identify genes that are differentially regulated during islet growth after Ex-4 treatment or a partial pancreatectomy (Ppx). Mice underwent 50% Ppx or sham operation and received Ex-4 or vehicle every 24 hours. cDNA prepared from total pancreatic RNA isolated at 12, 24 and 48 hrs after surgery was hybridized to the PancChip 4.0 microarray.
2005-12-01 | E-CBIL-5 | biostudies-arrayexpress
Project description:Type 1 and type 2 diabetes (T1D and T2D) share pathophysiological characteristics, yet mechanistic links have remained elusive. T1D results from autoimmune destruction of pancreatic beta cells, while 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 alter 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 for beta cell fragility in genetic predisposition to diabetes.
2016-02-24 | PXD000859 | Pride
Project description:Background: This study addresses whether existing specific transcriptional profiles can improve and support the current status of the definition of ulcerative colitis (UC) remission apart from the existing endoscopic, histologic, and laboratory scoring systems. For that purpose, a well-stratified UC patient population in remission was compared to active UC and control patients and was investigated by applying the next-generation technology RNA-Seq. Methods: Mucosal biopsies from patients in remission (n = 14), patients with active UC (n = 14), and healthy control patients (n = 16) underwent whole-transcriptome RNA-Seq. Principal component analysis, cell deconvolution methods, gene profile enrichment, and pathway enrichment methods were applied to define a specific transcriptional signature of UC in remission. Results: Analyses revealed specific transcriptional signatures for UC in remission with increased expression of genes involved in O-glycosylation (MUC17, MUC3A, MUC5AC, MUC12, SPON1, B3GNT3), ephrin-mediated repulsion of cells (EFNB2E, EFNA3, EPHA10, EPHA1), GAP junction trafficking (TUBA1C, TUBA4A, TUBB4B, GJB3, CLTB), and decreased expression of several toll-like receptors (TLR1, TLR3, TLR5, TLR6). Conclusions: This study reveals specific transcriptional signatures for remission. Partial restoration and improvement of homeostasis in the epithelial mucus layer and revival of immunological functions were observed. A clear role for bacterial gut flora composition can be implied. The results can be useful for the development of treatment strategies for UC in remission and may be useful targets for further investigations aiming to predict the outcome of UC in the future.
2020-01-18 | GSE128682 | GEO
Project description:Type 1 Diabetes (T1D) is considered to be a Th1 autoimmune disease characterised by an absolute lack of insulin caused by an autoimmune destruction of the insulin producing pancreatic beta cells. Th1 lymphocytes are responsible for the infiltration of the islets of Langerhans and for the cytokine release that supports cytotoxic (Tc) lymphocytes to mediate destruction of the beta cells. The preclinical disease stage is characterized by the generation of the self-reactive lymphocytes that infiltrate the pancreas and selectively destroy the insulin-producing beta cells present in the islets. Other cellular immune mechanisms regarding immunoregulation and antigen presentation and processing are involved in T1D pathogenesis as well. Our aim was to identify genes involved in the corresponding signalling cascades, especially those which may serve as promising diagnostic tools for the identification of persons in the prediabetic phase of the disease. We addressed the question by analysing gene expression profiles of freshly isolated peripheral blood mononuclear cells in type 1 diabetes patients, their first degree relatives divided according to their autoantibody status, and healthy controls.
2011-05-09 | GSE29142 | GEO