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Identification of a serum-induced transcriptional signature associated with type 1 diabetes in the BioBreeding rat.

ABSTRACT: Inflammatory mediators associated with type 1 diabetes are dilute and difficult to measure in the periphery, necessitating development of more sensitive and informative biomarkers for studying diabetogenic mechanisms, assessing preonset risk, and monitoring therapeutic interventions.We previously utilized a novel bioassay in which human type 1 diabetes sera were used to induce a disease-specific transcriptional signature in unrelated, healthy peripheral blood mononuclear cells (PBMCs). Here, we apply this strategy to investigate the inflammatory state associated with type 1 diabetes in biobreeding (BB) rats.Consistent with their common susceptibility, sera of both spontaneously diabetic BB DRlyp/lyp and diabetes inducible BB DR+/+ rats induced transcription of cytokines, immune receptors, and signaling molecules in PBMCs of healthy donor rats compared with control sera. Like the human type 1 diabetes signature, the DRlyp/lyp signature, which is associated with progression to diabetes, was differentiated from that of the DR+/+ by induction of many interleukin (IL)-1-regulated genes. Supplementing cultures with an IL-1 receptor antagonist (IL-1Ra) modulated the DRlyp/lyp signature (P < 10(-6)), while administration of IL-1Ra to DRlyp/lyp rats delayed onset (P = 0.007), and sera of treated animals did not induce the characteristic signature. Consistent with the presence of immunoregulatory cells in DR+/+ rats was induction of a signature possessing negative regulators of transcription and inflammation.Paralleling our human studies, serum signatures in BB rats reflect processes associated with progression to type 1 diabetes. Furthermore, these studies support the potential utility of this approach to detect changes in the inflammatory state during therapeutic intervention.

SUBMITTER: Kaldunski M

PROVIDER: S-EPMC3279523 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Identification of a serum-induced transcriptional signature associated with type 1 diabetes in the BioBreeding rat.

Kaldunski Mary M Jia Shuang S Geoffrey Rhonda R Basken Joel J Prosser Simon S Kansra Sanjay S Mordes John P JP Lernmark Ake A Wang Xujing X Hessner Martin J MJ

Diabetes 20100803 10

<h4>Objective</h4>Inflammatory mediators associated with type 1 diabetes are dilute and difficult to measure in the periphery, necessitating development of more sensitive and informative biomarkers for studying diabetogenic mechanisms, assessing preonset risk, and monitoring therapeutic interventions.<h4>Research design and methods</h4>We previously utilized a novel bioassay in which human type 1 diabetes sera were used to induce a disease-specific transcriptional signature in unrelated, healthy ...[more]

PMID: 20682698

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Project description:Human type 1 diabetes (T1D) arises through autoimmunity towards the insulin-producing pancreatic β cells and is modeled by the BioBreeding (BB) rat. Factors associated with islet autoimmunity are dilute and difficult to directly measure in the periphery. Therefore, we previously utilized microarray-based bioassay where human T1D sera were used to induce a disease-specific gene expression signature in unrelated, healthy peripheral blood mononuclear cells (PBMC). Here we report that sera of both spontaneously diabetic BB DRlyp/lyp and diabetes inducible BB DR+/+ rats induce inflammatory signatures in healthy PBMC of non-diabetic Brown Norway (BN) rats, while allogeneic BN sera does not. Consistent with their common T1D susceptibility, transcriptional signatures of both BB sub-strains share identity, including cytokines, immune receptors and signaling molecules. However, like the human T1D signature, the DRlyp/lyp signature, which is associated with progression to diabetes, is differentiated from that of the DR+/+ by induction of many IL-1 regulated genes. Addition of IL-1RA to cultures significantly ablates the DRlyp/lyp signature. Daily treatment of DRlyp/lyp rats with human recombinant IL-1RA significantly delays onset and sera of treated animals do not induce the characteristic IL-1 signature. Consistent with the presence of immune regulation in DR+/+ rats is induction of a signature showing negative regulation of the NFκB pathway. This study supports prior human investigations of serum that reflect disease processes associated with progression to T1D and add to a growing body of evidence implicating the balance of IL-1 and IL-1RA as key factors influencing the severity and outcome of inflammatory responses. Experiment Overall Design: The induction of gene expression was accomplished by culturing the PBMCs of healthy day180 BN donor rats for 6 h at 37°C in 5% CO2 with a) 20% autologous BN plasma(10 replicates), b) allogeneic BN plasma (15 replicates), c) allogeneic DRlyp/lyp plasma (day 60, 4 replicates), or d) DR+/+ plasma (day 60, 4 replicates). Healthy BN PBMCs were also cultured with d60 DRlyp/lyp serum supplemented with IL-1RA (4 replicates) as well as autologous BN serum supplemented with IL-1B (4 replicates), to respectively block or induce IL-1 mediated gene expression. To determine if IL-1RA-treatment of DRlyp/lyp rats would result in modulation of the DRlyp/lyp signature, additional DRlyp/lyp rats were treated with hIL-1RA (n=6) or PBS (n=6). Rats were treated for 10 days, beginning at d30, then serum was collected at d40 and used to induce gene expression in PBMCs isolated from healthy d180 BN rats. Thus, there are a total of 53 chips being the addition of all the sample conditions mentioned above.

Project description:BackgroundCoronary artery disease (CAD) is the leading cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). The purpose of the present study was to discriminate the Indian CAD patients with or without T2DM by using multiple pathophysiological biomarkers.MethodsUsing sensitive multiplex protein assays, we assessed 46 protein markers including cytokines/chemokines, metabolic hormones, adipokines and apolipoproteins for evaluating different pathophysiological conditions of control, T2DM, CAD and T2DM with CAD patients (T2DM_CAD). Network analysis was performed to create protein-protein interaction networks by using significantly (p?<?0.05) altered protein markers in each disease using STRING 10.5 database. We used two supervised analysis methods i.e., between class analysis (BCA) and principal component analysis (PCA) to reveals distinct biomarkers profiles. Further, random forest classification (RF) was used to classify the diseases by the panel of markers.ResultsOur two supervised analysis methods BCA and PCA revealed a distinct biomarker profiles and high degree of variability in the marker profiles for T2DM_CAD and CAD. Thereafter, the present study identified multiple potential biomarkers to differentiate T2DM, CAD, and T2DM_CAD patients based on their relative abundance in serum. RF classified T2DM based on the abundance patterns of nine markers i.e., IL-1?, GM-CSF, glucagon, PAI-I, rantes, IP-10, resistin, GIP and Apo-B; CAD by 14 markers i.e., resistin, PDGF-BB, PAI-1, lipocalin-2, leptin, IL-13, eotaxin, GM-CSF, Apo-E, ghrelin, adipsin, GIP, Apo-CII and IP-10; and T2DM _CAD by 12 markers i.e., insulin, resistin, PAI-1, adiponectin, lipocalin-2, GM-CSF, adipsin, leptin, Apo-AII, rantes, IL-6 and ghrelin with respect to the control subjects. Using network analysis, we have identified several cellular network proteins like PTPN1, AKT1, INSR, LEPR, IRS1, IRS2, IL1R2, IL6R, PCSK9 and MYD88, which are responsible for regulating inflammation, insulin resistance, and atherosclerosis.ConclusionWe have identified three distinct sets of serum markers for diabetes, CAD and diabetes associated with CAD in Indian patients using nonparametric-based machine learning approach. These multiple marker classifiers may be useful for monitoring progression from a healthy person to T2DM and T2DM to T2DM_CAD. However, these findings need to be further confirmed in the future studies with large number of samples.

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Identification of a serum-induced transcriptional signature associated with type 1 diabetes in the BioBreeding rat.

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Identification of a serum-induced transcriptional signature associated with type 1 diabetes in the BioBreeding rat.

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