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Functional Genomics Analysis of Islets from Recent and Longstanding T1D Reveals the Need for Distinct Approaches to Therapy

ABSTRACT: Our current understanding of the pathogenesis of T1D arose in large part from studies using the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D). Of concern, therapeutic interventions shown to significantly dampen or even reverse disease in mouse models have not successfully translated into interventions in human T1D. The present study addresses this disconnect in research translation by directly analyzing human donor islets from individuals with T1D, aiming to provide insight into disease mechanisms and identify potential target pathways for therapeutic intervention. We obtained human islets from a young individual with short-duration T1D, an older individual with long-duration T1D and three non-diabetic donors, and performed unbiased functional genomic analysis by high depth RNA sequencing on these unique cases. This analysis identified several inflammatory pathways upregulated in short-duration disease, which surprisingly included many components of innate immunity. Subsequent manipulation of one of these pathways/factors in NOD mice resulted in a significant reduction in diabetes progression when inhibition occurred early in disease progression. Taken together our data demonstrates that the direct analysis of human islets is essential for identifying relevant and promising novel targets for translation into effective therapeutic interventions for human T1D.

ORGANISM(S): Homo sapiens

PROVIDER: GSE102371 | GEO | 2018/07/30

REPOSITORIES: GEO

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A discovery-based proteomics approach identifies protein disulfide isomerase (PDIA1) as a biomarker of β cell stress in type 1 diabetes

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

Transcriptional analysis of type 1 diabetes reveals an interferon signature that precedes T cell activation

Project description:Type 1 diabetes (T1D) is an autoimmune disease triggered by T cell reactivity to protein antigens produced by the β-cells. Here we present a chronological compendium of transcriptional profiles from islets of Langerhans isolated from non-obese diabetic (NOD) mice ranging from 2 wks up to diabetes and compared to controls. Parallel analysis was made of cellular components of the islets. Myeloid cells populated the islets early during development in all mouse strains. This was followed by a type I interferon signature detectable at 4-6 wks of age only in diabetes susceptible mice. Concurrently, CD4 T cells were found within islets, many in contact with intra-islet antigen presenting cells. Early cellular signs of islet reactivity were detected by six wks. By 8 wks, NOD islets contained all major leukocytes populations and an inflammatory gene signature. This work establishes the natural transcriptional signature of T1D and provides a resource for future research. 57 RNA samples isolated from the pancreatic islets of langerhans of experimental mice: 2-18 wk old non-obese diabetic (NOD) and newly diabetic NOD were compared to controls: NOD.RAG-/-, B6.g7 and C57BL/6. There were 3 or 6 biological replicates per condition. All mice were female. All data was normalized using RMA in Arraystar. Data table includes normalized probe intensity for every probe.

2013-01-28 | E-GEOD-41203 | biostudies-arrayexpress

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

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.

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2023-11-16 | PXD032664 | Pride

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2023-01-04 | GSE218336 | GEO

Proteome and (ox)PTP profile analysis of diabetic NOD mouse under single (anti-CD3) or combined (anti-CD3 + IL1RA) treatment

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2022-11-10 | PXD025394 | Pride

Single cell RNA-sequencing analysis of islets from WT NOD mice on different diets

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2023-11-16 | PXD041616 | Pride

Transcriptional analysis of type 1 diabetes reveals an interferon signature that precedes T cell activation

2013-01-28 | GSE41203 | GEO

Single cell RNA-sequencing analysis of islets from NOD.SCID mice on chow and hydrolyzed casein diets

Project description:Protein source in diet greatly influences the incidence of type-1 diabetes (T1D) in non-obese diabetic (NOD) mouse colonies. NOD mice fed a diet containing hydrolyzed casein (HC) as the sole protein source are protected from T1D. Exposure to HC also reduced beta-cell insulin secretion during glucose challenge suggesting that beneficial changes to beta-cell physiology might protect NOD mice from T1D. We used single cell RNA sequencing (scRNAseq) to contrast the transcriptional profiles of beta-cells and from the pancreatic islets of Langerhans of NOD mice with the scid mutation (scid mice were used to avoid confouding influence of infiltrating leukocytes) fed a 20% HC diet or a standard chow diet.

2023-01-04 | GSE217495 | GEO

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