Project Abstracts - CBDS

Carmella Evans-Molina, MD, PhD, Investigator, Indiana University
Decio Eizirik, MD, PhD, Investigator, University of Brussels
Thomas Metz, PhD, Investigator, Pacific Northwest National Laboratory
Jerry Nadler, MD, Investigator, Eastern Virginia Medical School
Margaret Morris, PhD, Co-Investigator, Eastern Virginia Medical School
Julius Nyalwidhe, PhD, Co-Investigator, Eastern Virginia Medical School
Bobbie-Jo Webb-Robertson, PhD, Co-Investigator, Pacific Northwest National Laboratory
Ernesto Nakayasu, PhD, Co-Investigator, Pacific Northwest National Laboratory

Start Date: September 23, 2014

End Date:  August 31, 2018

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Abstract

The pathogenesis of type 1 diabetes (T1D) involves islet beta cell loss mediated at a very late stage by cytotoxic T-cells and macrophages. Clinical studies have focused on the administration of immune modulatory drugs at the time of diagnosis, however, in none of these studies has the recovery or durable preservation of beta cell function been achieved. These disappointing outcomes have questioned both our understanding of the pathogenesis of the disease and whether timing of treatment (i.e. earlier in the disease) may yield better outcomes. An unmet need in the field has been the development of simple and reliable biomarkers that can identify those who have a virtually certain or very high likelihood of developing T1D, thereby allowing for earlier treatment interventions. Recent studies from our research Team (Drs. Mirmira, Evans-Molina, Nadler, Metz, and Eizirik) and others suggest the provocative concept that stress pathways triggered within the beta cell very early in T1D evolution may initiate and/or accelerate autoimmune-mediated beta cell destruction. This overdue emphasis on the beta cell offers a unique opportunity to improve current T1D prediction strategies. This application is based on the hypothesis that stressed beta cells of pre-diabetic individuals liberate specific protein and DNA species into plasma, and that measurement of multiple such species can define the beta cell “stress signature” that confers risk for developing T1D. To test this hypothesis, we have assembled an interactive Team of scientists that will collectively engage its proteomics, functional genomics, islet biology, and bioinformatics/statistics expertise to identify protein and nucleic acid-derived biomarkers emanating from stressed beta cells that can stratify better the risk of developing T1D. This project, called “BetaMarker” will take a two-pronged approach: in the first, candidate beta cell-specific protein and nucleic acid biomarkers will be tested in human samples from the DPT-1 and TrialNet PTP cohorts, and in the second, a comprehensive proteomics and functional genomics approach will be undertaken to discover new beta cell-specific biomarkers that will be funneled back into testing in human populations. Three aims will be achieved: 1. Aim 1: Test candidate beta cell-derived protein biomarkers as predictors of T1D risk. 2. Aim 2: Validate differentially methylated DNA species as biomarkers of beta cell stress in T1D. 3. Aim 3: Identify novel protein and nucleic acid biomarkers of beta cell stress and T1D risk. The impact of the BetaMarker project will be the development of a group of biomarkers that reflect the beta cell “stress signature” and that will serve collectively or as components in a risk score for the development of T1D.

Publications

• Emerging concepts and success stories in type 1 diabetes research: a roadmap for a bright future
• Sodium butyrate prevents cytokine-induced β-cell dysfunction through restoration of stromal interaction molecule 1 expression and activation of store-operated calcium entry
• Diabetes mellitus-Progress and opportunities in the evolving epidemic
• Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice
• A Golden Hour and Golden Opportunity for β-Cell Preservation
• Islet autoantibodies as precision diagnostic tools to characterize heterogeneity in type 1 diabetes: a systematic review
• miR-146a-5p mediates inflammation-induced β cell mitochondrial dysfunction and apoptosis
• Regulation of β-cell death by ADP-ribosylhydrolase ARH3 via lipid signaling in insulitis
• Mapping the daily rhythmic transcriptome in the diabetic retina
• Histone Deacetylase Inhibitors Prevent Cytokine-Induced β Cell Dysfunction Through Restoration of Stromal Interaction Molecule 1 Expression and Activation of Store-Operated Calcium Entry
• SERCA2 regulates proinsulin processing and processing enzyme maturation in pancreatic beta cells
• Stromal Interaction Molecule 1 Maintains β Cell Identity and Function in Female Mice through Preservation of G Protein-Coupled Estrogen Receptor 1 Signaling
• Title: β Cell microRNAs Function as Molecular Hubs of Type 1 Diabetes Pathogenesis and as Biomarkers of Diabetes Risk
• A discovery-based proteomics approach identifies protein disulphide isomerase (PDIA1) as a biomarker of β cell stress in type 1 diabetes
• Precision medicine in type 1 diabetes
• Does the Gut Microbiome Play a Role in Obesity in Type 1 Diabetes? Unanswered Questions and Review of the Literature
• HOMA2-B enhances assessment of type 1 diabetes risk among TrialNet Pathway to Prevention participants
• The Impact of Pro-Inflammatory Cytokines on Alternative Splicing Patterns in Human Islets
• Tutorial: best practices and considerations for mass-spectrometry-based protein biomarker discovery and validation
• Proinsulin:C-peptide ratio trajectories over time in relatives at increased risk of progression to type 1 diabetes
• A Computational Approach for Defining a Signature of beta-Cell Golgi Stress in Diabetes
• Expression of SARS-CoV-2 Entry Factors in the Pancreas of Normal Organ Donors and Individuals with COVID-19
• Circulating unmethylated CHTOP and INS DNA fragments provide evidence of possible islet cell death in youth with obesity and diabetes
• An integrated multi-omics approach identifies the landscape of interferon-α-mediated responses of human pancreatic beta cells
• Cigarette smoke exposure impairs β-cell function through activation of oxidative stress and ceramide accumulation
• Proteomic and Transcriptional Profiles of Human Stem Cell-Derived β Cells Following Enteroviral Challenge
• Comprehensive Proteomics Analysis of Stressed Human Islets Identifies GDF15 as a Target for Type 1 Diabetes Intervention
• Profiling of RNAs from Human Islet-Derived Exosomes in a Model of Type 1 Diabetes
• The impact of proinflammatory cytokines on the β-cell regulatory landscape provides insights into the genetics of type 1 diabetes
• Serum miR-204 is an early biomarker of type 1 diabetes-associated pancreatic beta-cell loss
• Abnormalities in proinsulin processing in islets from individuals with longstanding T1D
• The microRNAs miR-211-5p and miR-204-5p modulate ER stress in human beta cells
• The role of proteomics in assessing beta-cell dysfunction and death in type 1 diabetes
• Response to Comment on Sims et al Proinsulin Secretion Is a Persistent Feature of Type 1 Diabetes Diabetes Care 2019;42:258-264
• Beta cells in type 1 diabetes: mass and function; sleeping or dead?
• Analysis of serum Hsp90 as a potential biomarker of β cell autoimmunity in type 1 diabetes
• Proinsulin Secretion Is a Persistent Feature of Type 1 Diabetes
• DEXI, a candidate gene for type 1 diabetes, modulates rat and human pancreatic beta cell inflammation via regulation of the type I IFN/STAT signalling pathway
• Endoplasmic reticulum stress alters ryanodine receptor function in the murine pancreatic β cell
• PDL1 is expressed in the islets of people with type 1 diabetes and is up-regulated by interferons-α and-γ via IRF1 induction
• The Effect of Age on the Progression and Severity of Type 1 Diabetes: Potential Effects on Disease Mechanisms
• When one becomes many-Alternative splicing in β-cell function and failure
• Combined Analysis of GAD65, miR-375, and Unmethylated Insulin DNA Following Islet Transplantation in Patients With T1D
• Impaired Store-Operated Calcium Entry and STIM1 Loss Lead to Reduced Insulin Secretion and Increased Endoplasmic Reticulum Stress in the Diabetic β-cell
• Biomarkers of islet beta cell stress and death in type 1 diabetes
• β Cell dysfunction exists more than 5 years before type 1 diabetes diagnosis
• Persistent Elevations in Circulating INS DNA Among Subjects with Longstanding Type 1 Diabetes
• Conventional and Neo-Antigenic Peptides Presented by β Cells Are Targeted by Circulating Naïve CD8+ T Cells in Type 1 Diabetic and Healthy Donors
• Type 1 diabetes
• Episodic β-cell death and dedifferentiation during diet-induced obesity and dysglycemia in male mice
• Immune reconstitution in ART treated, but not untreated HIV infection, is associated with abnormal beta cell function
• Interleukin-6 Reduces β-Cell Oxidative Stress by Linking Autophagy With the Antioxidant Response
• Pancreas regeneration
• The influence of body mass index and age on C-peptide at the diagnosis of type 1 diabetes in children who participated in the diabetes prevention trial-type 1
• Restructuring of the Gut Microbiome by Intermittent Fasting Prevents Retinopathy and Prolongs Survival in db/db Mice
• Distinct Gene Expression Pathways in Islets from Individuals with Short- and Long-Duration Type 1 Diabetes
• IFN-α induces a preferential long-lasting expression of MHC class I in human pancreatic beta cells
• Hypoglycemia in a Patient With a Polyhormonal Pancreatic Neuroendocrine Tumor With Evidence of Endocrine Progenitors
• SRp55 Regulates a Splicing Network that Controls Human Pancreatic β-Cell Function and Survival
• Elevated unmethylated and methylated insulin DNA are unique markers of A+β+ ketosis prone diabetes
• Coxsackievirus-Induced Proteomic Alterations in Primary Human Islets Provide Insights for the Etiology of Diabetes
• Molecular mechanisms of nonalcoholic fatty liver disease: Potential role for 12-lipoxygenase
• Comparative quantitative proteomic analysis of disease stratified laser captured microdissected human islets identifies proteins and pathways potentially related to type 1 diabetes
• Combination Immunotherapy for Type 1 Diabetes
• Chronic high fat feeding restricts islet mRNA translation initiation independently of ER stress via DNA damage and p53 activation.
• Protective role of complement C3 against cytokine-mediated β-cell apoptosis
• Inflammatory Stress of Pancreatic Beta Cells Drives Release of Extracellular Heat-shock Protein 90α
• Smoking and the risk of type 2 diabetes
• Checks and Balances-The Limits of β-Cell Endurance to ER Stress
• Mechanisms in endocrinology: Alternative splicing: the new frontier in diabetes research
• Neuron-enriched RNA-binding Proteins Regulate Pancreatic Beta Cell Function and Survival
• Interferon-α mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes
• Measurement of Differentially Methylated INS DNA Species in Human Serum Samples as a Biomarker of Islet β Cell Death
• A case of extragastrointestinal stromal tumor complicated by severe hypoglycemia: a unique presentation of a rare tumor.
• Long-Term GABA Administration Induces Alpha Cell-Mediated Beta-like Cell Neogenesis
• MicroRNAs miR-23a-3p, miR-23b-3p, and miR-149-5p Regulate the Expression of Proapoptotic BH3-Only Proteins DP5 and PUMA in Human Pancreatic β-Cells
• SERCA2 Deficiency Impairs Pancreatic β-Cell Function in Response to Diet-Induced Obesity
• Biomarkers of β-Cell Stress and Death in Type 1 Diabetes
• Peroxisome Proliferator-Activated Receptor-γ Activation Augments the β-Cell Unfolded Protein Response and Rescues Early Glycemic Deterioration and β Cell Death in Non-Obese Diabetic Mice
• Elevations in the Fasting Serum Proinsulin-to-C-Peptide Ratio Precede the Onset of Type 1 Diabetes
• Nucleic acid biomarkers of β cell stress and death in type 1 diabetes
• Loss of Free Fatty Acid Receptor 2 leads to impaired islet mass and beta cell survival
• Ubiquitin D Regulates IRE1α/c-Jun N-terminal Kinase (JNK) Protein-dependent Apoptosis in Pancreatic Beta Cells
• The relationship between BMI and insulin resistance and progression from single to multiple autoantibody positivity and type 1 diabetes among TrialNet Pathway to Prevention participants
• ER stress and the decline and fall of pancreatic beta cells in type 1 diabetes
• Viral infections in type 1 diabetes mellitus–why the β cells?
• Relative sensitivity of immunohistochemistry, multiple reaction monitoring mass spectrometry, in situ hybridization and PCR to detect Coxsackievirus B1 in A549 cells
• Metabolic dysfunction and adipose tissue macrophages: is there more to glean from studying the lean?: Comment on “Adipose tissue infiltration in normal-weight subjects and its impact on metabolic function” by Moreno-Indias et al.
• Proinsulin and heat shock protein 90 as biomarkers of beta-cell stress in the early period after onset of type 1 diabetes
• Elevations in Circulating Methylated and Unmethylated Preproinsulin DNA in New-Onset Type 1 Diabetes
• Editorial: Lessons From the Classic Scientific Literature
• Proteomic Analysis of Disease Stratified Human Pancreas Tissue Indicates Unique Signature of Type 1 Diabetes
• An Acetate-Specific GPCR, FFAR2, Regulates Insulin Secretion
• Expression pattern of 12-lipoxygenase in human islets with type 1 diabetes and type 2 diabetes