Canakinumab treatment for recent-onset type 1 diabeties mellitus: a multicenter randomized, placebo-controlled trial
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE68049 | GEO | 2015/10/01
SECONDARY ACCESSION(S): PRJNA281636
REPOSITORIES: GEO
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Project description:Background: Blocking the action of the pro-inflammatory cytokine interleukin-1 (IL-1) reduces beta-cell secretory dysfunction and apoptosis in vitro, diabetes incidence in animal models of Type 1 diabetes mellitus (T1D), and glycaemia via improved beta-cell function in patients with T2D. We hypothesised that anakinra, a recombinant human IL-1 receptor antagonist, improves beta-cell function in patients with new-onset T1D. Methods: In an individually randomised, two-group parallel trial involving 14 European tertiary referral centers, 69 patients aged 18-35 with T1D, < 12 weeks of symptoms, and standard mixed meal test (MMT) stimulated C-peptide ≥ 200 pM were enrolled between January, 2009 and July, 2011 and assigned by centralised computer-generated blocked randomisation with locked computer-file concealment to treatment with 100 mg anakinra (n=35) subcutaneously once daily or placebo (n=34) for 9 months as add-on to conventional therapy. Participants and care-givers, but not data monitoring unit, were masked to group assignment. The primary end-point was change in the two-hour area-under-the-curve C-peptide response to MMT, and secondary end-points changes in insulin requirements, glycaemia, and inflammatory markers at one, three, six, and nine months. Findings: The study was prematurely terminated due to slow accrual and is closed to follow-up. No interim analysis was performed. Ten patients withdrew in the anakinra and eight in the placebo arm, leaving 25 and 26 patients to be analysed, respectively. There was no statistical difference in adverse event category reporting between arms. Interpretation: Anakinra-treatment in T1D was safe, but the trial failed to meet primary and secondary outcome measures.
2015-10-01 | GSE37025 | GEO
Project description:Objective: We hypothesized that type 1 diabetes (T1D) is accompanied by changes in gene expression in peripheral blood mononuclear cells (PBMCs) due to dysregulation of adaptive and innate immunity, counterregulatory responses to immune dysregulation, insulin deficiency and hyperglycemia. Research Design and Methods: Microarray analysis was performed on PBMCs from 43 patients with newly diagnosed T1D, 12 patients with newly diagnosed type 2 diabetes (T2D) and 24 healthy controls. One and four month follow-up samples were obtained from 20 of the T1D patients. Results: Microarray analysis identified 282 genes differing in expression between newlydiagnosed T1D patients and controls at a false discovery rate of 0.05. Changes in expression of interleukin-1β (IL1B), early growth response gene 3 (EGR3), and prostaglandin-endoperoxide; synthase 2 (PTGS2) resolved within four months of insulin therapy and were also observed in T2D suggesting that they resulted from hyperglycemia. With use of a knowledge base, 81/282 genes could be placed within a network of interrelated genes with predicted functions including apoptosis and cell proliferation. IL1B and the MYC oncogene were the most highly-connected genes in the network. IL1B was highly overexpressed in both T1D and T2D, whereas MYC was dysregulated only in T1D. Conclusion: T1D and T2D likely share a final common pathway for beta cell dysfunction that includes secretion of interleukin-1β and prostaglandins by immune effector cells, exacerbating existing beta cell dysfunction, and causing further hyperglycemia. The results identify several targets for disease-modifying therapy of diabetes and potential biomarkers for monitoring treatment efficacy. Experiment Overall Design: We obtained blood samples from 24 healthy volunteers, 43 newly diagnosed T1D patients and 12 newly diagnosed T2D patients. All study participants were between the ages of 2 and 18 years. We collected samples one and four months after diagnosis from the last 20 of the T1D patients. For each time point one sample did not pass quality control and was dropped from the analysis. Patients with T2D were distinguished from T1D on the basis of age, body habitus, Experiment Overall Design: presence (11/12 patients) of acanthosis nigricans, family history of type 2 diabetes (11/12 patients), and absence of autoantibodies to insulin, IA-2, and GAD65. We allowed low titers of insulin antibodies in T2D patients (< 4 U/mL), which have been previously reported. All but two Experiment Overall Design: of the T1D patients with positive anti-insulin antibodies were also positive for at least one additional autoantibody.
2008-06-16 | E-GEOD-9006 | biostudies-arrayexpress
Project description:Islet β-cell dysfunction and aggressive macrophage activity are early features in the pathogenesis of type 1 diabetes (T1D). 12/15-lipoxygenase (12/15-LOX) is induced in β cells and macrophages during T1D and produces pro-inflammatory lipids and lipid peroxides that exacerbate β-cell dysfunction and macrophage activity. Inhibition of 12/15-LOX provides a potential therapeutic approach to prevent glycemic deterioration in T1D. Two inhibitors recently identified by our groups through screening efforts, ML127 and ML351, have been shown to selectively target 12/15-LOX with high potency. Only ML351 exhibited no apparent toxicity across a range of concentrations in mouse islets, and molecular modeling suggested reduced promiscuity of ML351 compared to ML127. In mouse islets, incubation with ML351 improved glucose-stimulated insulin secretion in the presence of pro-inflammatory cytokines and triggered gene expression pathways responsive to oxidative stress and cell death. Consistent with a role for 12/15-LOX in promoting oxidative stress, its chemical inhibition reduced production of reactive oxygen species in both mouse and human islets in vitro. In a streptozotocin-induced model of T1D in mice, ML351 prevented the development of diabetes, with coincident enhancement of nuclear Nrf2 in islet cells, reduced β-cell oxidative stress, and preservation of β-cell mass. In the non-obese diabetic mouse model of T1D, administration of ML351 during the prediabetic phase prevented dysglycemia, reduced β-cell oxidative stress, and increased the proportion of anti-inflammatory macrophages in the insulitis. Our data provide the first evidence to date that small molecules that target 12/15-LOX can prevent progression of β-cell dysfunction and glycemic deterioration in models of T1D.
2017-10-29 | GSE101722 | GEO
Project description:Objective: We hypothesized that type 1 diabetes (T1D) is accompanied by changes in gene expression in peripheral blood mononuclear cells (PBMCs) due to dysregulation of adaptive and innate immunity, counterregulatory responses to immune dysregulation, insulin deficiency and hyperglycemia. Research Design and Methods: Microarray analysis was performed on PBMCs from 43 patients with newly diagnosed T1D, 12 patients with newly diagnosed type 2 diabetes (T2D) and 24 healthy controls. One and four month follow-up samples were obtained from 20 of the T1D patients. Results: Microarray analysis identified 282 genes differing in expression between newlydiagnosed T1D patients and controls at a false discovery rate of 0.05. Changes in expression of interleukin-1β (IL1B), early growth response gene 3 (EGR3), and prostaglandin-endoperoxide synthase 2 (PTGS2) resolved within four months of insulin therapy and were also observed in T2D suggesting that they resulted from hyperglycemia. With use of a knowledge base, 81/282 genes could be placed within a network of interrelated genes with predicted functions including apoptosis and cell proliferation. IL1B and the MYC oncogene were the most highly-connected genes in the network. IL1B was highly overexpressed in both T1D and T2D, whereas MYC was dysregulated only in T1D. Conclusion: T1D and T2D likely share a final common pathway for beta cell dysfunction that includes secretion of interleukin-1β and prostaglandins by immune effector cells, exacerbating existing beta cell dysfunction, and causing further hyperglycemia. The results identify several targets for disease-modifying therapy of diabetes and potential biomarkers for monitoring treatment efficacy. Keywords: Diabetes, microarray analysis, peripheral blood mononuclear cells
2007-09-12 | GSE9006 | GEO
Project description:As early as one month of age, non-obese diabetic (NOD) mice feature pancreatic infiltration of autoreactive T lymphocytes, which destruct insulin-producing beta cells, leading to autoimmune diabetes mellitus (T1D) within eight months. Thus, we hypothesized that during the development of T1D, the transcriptional modulation of immune reactivity genes, as well as, modulation of microRNAs (miRNAs) may occur during thymocytes mature into peripheral CD3+ T lymphocytes. Our aim is to analyze the transcriptional modulation of mRNA and microRNAs during development of thymocytes into peripheral CD3+ T lymphocytes in the context of the emergence of T1D.
2011-07-01 | E-MEXP-3235 | biostudies-arrayexpress
Project description:Autologous nonmyeloablative hematopoietic stem cell transplantation (AHST) was the first therapeutic approaches that can improve beta cell function in type 1 diabetic (T1D) patients. This study was designed to investigate the potential mechanisms involved.We applied AHST to nine T1D patients diagnosed within six months and analyzed the acute response in peripheral blood genomic expression profiling at the six-month follow-up. Peripheral blood mononuclear of newly diagnosed type1 diabetes patients at diagnosis and at six months post-transplantation by autologous peripheral stem cell were purified by LymphoprepTm gradient purification according to the manufacturer's instructions (Axis-Shield PoC AS, Oslo, Norway) for futher microarray analysis.
2012-02-20 | E-GEOD-29908 | biostudies-arrayexpress
Project description:Type 1 diabetes (T1D) is an autoimmune disease caused by selective destruction of insulin producing pancreatic beta-cells in the islets of the Langerhans. The progression to clinical diabetes is characterized by the appearance of autoantibodies against islet cells (ICA) and beta-cell-specific antigens (IAA, IA-2 and GADA), which are considered the first markers signifying onset of autoimmunity. The mechanisms initiating or enhancing the autoimmune process remain poorly understood. Transcriptomic profiling on whole blood samples provides an approach for monitoring T1D disease process. In these investigations of pathways that are changed during the disease process, we have analyzed RNA from longitudinal peripheral blood samples of children who have developed T1D associated autoantibodies and eventually clinical type 1 diabetes . All study subjects were participants of the Type 1 Diabetes Prediction and Prevention (DIPP) study in Finland (38). Whole-blood RNA samples were collected during periodic clinic visits, typically at 3 to 12 month intervals. 2.5 ml venous blood was drawn into PAXgene Blood RNA tubes (Becton-Dickinson) and stored at -70°C. T1D-associated autoantibodies were measured from blood samples taken at each visit. Prospective samples from 3 children who developed T1D (subjects T1D_1 - T1D_3) and 2 children who developed ICA (subjects ICA_1 and ICA_2) during the DIPP follow-up were selected to the present study. Control children for the T1D cases (subjects T1D_C1 - T1D_C2) were matched for age, gender, birth place and HLA-genotype, from families who have no first-degree relatives with T1D. All samples (n=60) were processed and hybridized on Affymetrix Human Genome U133 Plus 2.0 arrays.
2010-03-31 | E-TABM-666 | 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: Activation of stress pathways intrinsic to the β cell are thought to both accelerate β cell death and increase β cell immunogenicity in type 1 diabetes (T1D). However, information on the timing and scope of these responses is lacking. Methods: To identify temporal and disease-related changes in islet β cell protein expression, SWATH-MS/MS proteomics analysis was performed on islets collected longitudinally from NOD mice and NOD-SCID mice rendered diabetic through T cell adoptive transfer. Findings: In islets collected from female NOD mice at 10, 12, and 14 weeks of age, we found a time-restricted upregulation of proteins involved in the maintenance of β cell function and stress mitigation, followed by loss of expression of protective proteins that heralded diabetes onset. Pathway analysis identified EIF2 signaling and the unfolded protein response, mTOR signaling, mitochondrial function, and oxidative phosphorylation as commonly modulated pathways in both diabetic NOD mice and NOD-SCID mice rendered acutely diabetic by adoptive transfer, highlighting this core set of pathways in T1D pathogenesis. In immunofluorescence validation studies, β cell expression of protein disulfide isomerase A1 (PDIA1) and 14-3-3b were found to be increased during disease progression in NOD islets, while PDIA1 plasma levels were increased in pre-diabetic NOD mice and in the serum of children with recent-onset T1D compared to age and sex-matched non-diabetic controls. Interpretation: We identified a common and core set of modulated pathways across distinct mouse models of T1D and identified PDIA1 as a potential human biomarker of β cell stress in T1D.
2023-03-11 | PXD035504 | Pride
Project description:Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing β cells and involves an interplay between β cells and cells of the innate and adaptive immune systems. We investigated the therapeutic potential of targeting 12-lipoxygenase (12-LOX), an enzyme implicated in inflammatory pathways in β cells and macrophages, using a mouse model in which the endogenous mouse Alox15 gene is replaced by the human ALOX12gene. Our findings demonstrate that VLX-1005, a potent 12-LOX inhibitor, effectively delays the onset of autoimmune diabetes in human gene replacement non-obese diabetic (NOD) mice. By spatial proteomics analysis, VLX-1005 treatment resulted in marked reductions in infiltrating T and B cells and macrophages with accompanying increases in immune checkpoint molecules PD-L1 and PD-1, suggesting a shift towards an immune-suppressive microenvironment. RNA sequencing analysis of isolated islets from inhibitor-treated mice revealed significant alteration of cytokine-responsive pathways. RNA sequencing of polarized proinflammatory macrophages showed that VLX-1005 significantly reduced the interferon response. This study highlights a functional equivalence of human ALOX12 and mouse Alox15 in T1D pathogenesis. Our studies provide a platform for the preclinical evaluation of LOX inhibitors and supports the development of 12-LOX inhibitors as a therapeutic strategy for T1D and other inflammatory diseases.
2024-08-23 | GSE272687 | GEO