Exploring the functional, protective, and transcriptomic effects of GIP on cytokine-exposed human pancreatic islets and EndoC-βH5 cells
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ABSTRACT:
PROVIDER: PRJNA1124568 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29429253_1.fastq.gz | Fastqsanger.gz | |||
| SRR29429253_2.fastq.gz | Fastqsanger.gz | |||
| SRR29429254_1.fastq.gz | Fastqsanger.gz | |||
| SRR29429254_2.fastq.gz | Fastqsanger.gz | |||
| SRR29429255_1.fastq.gz | Fastqsanger.gz |
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Project description:Immune-mediated beta cell destruction and lack of alpha cell responsiveness to hypoglycaemia are hallmarks of type 1 diabetes pathology. The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) may hold therapeutic potential for type 1 diabetes due to its insulinotropic and glucagonotropic effects as well as its beta cell protective effects shown in rodent islets. Here, we examined the functional and transcriptomic effects of GIP treatment upon diabetogenic cytokine exposure to interleukin (IL)-1β ± interferon (IFN)-γ in human EndoC-βH5 beta cells and isolated human islets, respectively. GIP dose-dependently augmented glucose-stimulated insulin secretion from EndoC-βH5 cells and increased insulin and glucagon secretion from human islets during high and low glucose concentrations, respectively. The insulinotropic effect of GIP in EndoC-βH5 cells was abrogated by KN-93, an inhibitor of calcium/calmodulin-dependent protein kinase 2 (CaMK2). GIP did not prevent cytokine-induced apoptosis or cytokine-induced functional impairment of human EndoC-βH5 cells. GIP also did not prevent cytokine-induced apoptosis in human islets. GIP treatment of human islets with or without cytokines for 24 hours did not significantly impact the transcriptome. GIP potentiated cytokine-induced secretion of IL-10 and c-c motif chemokine ligand (CCL)-2 from human islets while decreasing the secretion of c-x-c motif chemokine ligand (CXCL)-8. In EndoC-βH5 cells, GIP reduced IFN-γ-induced secretion of tumor necrosis factor (TNF)-α, IL-2, IL-6, and IL-10, but increased the secretion of CXCL8, CCL2, CCL4, and CCL11. In conclusion, our results suggest that the insulinotropic effect of GIP is CaMK2-dependent. Furthermore, our results indicate that GIP does not provide substantial cytoprotective effects against diabetogenic cytokine challenge or significantly modulate the transcriptome of human islets when applied at a supraphysiological level. GIP may, however, still exert selective inflammation-modulatory effects upon diabetogenic cytokine exposure.
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Project description:Type 1 Diabetes (T1D) is characterized by autoimmune-mediated destruction of insulin-producing beta-cells. Recent research has focused on the role of the innate immune system in initiating this process. To investigate this further, we used m6A-profiling of human islets from non-diabetic individuals and the human beta-cell line EndoC-bH1 treated with PBS or interleukin 1 beta and interferon alpha, as well as established T1D patients. Our findings reveal that N6-Methyladenosine (m6A) is a mechanism that helps protect beta-cells by accelerating the decay of mRNA from the 2'-5'-oligoadenylate synthetase (OAS) genes, which controls the antiviral innate immune response at the onset of T1D. These results provide insight into the adaptive safeguarding mechanisms of beta-cells and the role of m6A in T1D development, highlighting potential targets for therapeutic interventions.
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Project description:Responsiveness of EndoC-BH5 cells to cytokines was examined by RNA-seq of cells treated with IFNγ and IL1β for 24 h. The treatment resulted in profound changes in their transcriptome and upregulation of genes involved in the inflammatory pathwayand antigen processing and presentation, similar to previous studies on EndoC-BH1 cells and adult human islets. EndoC-BH5 cells hence represent a powerful tool to investigate the dialogue between beta cells and the immune system.
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Project description:Abstract submitted to the Journal of clinical encodcrinology and metabolism: The molecular mechanisms responsible for the ectopic expression of the GIP receptor in the adrenal cortex of patients with GIP-dependent Cushing’s syndrome (CS) are unknown. Chronic adrenal stimulation by ACTH in Cushing’s disease (CD) or by GIP in GIP-dependent AIMAH both lead to induction of a set of genes which stimulate adrenal proliferation and steroidogenesis. The objective of this study was to compare the whole genome expression profile of adrenal glands of five cases of GIP-dependent bilateral macronodular adrenal hyperplasia with CS, one case of GIP-dependent adenoma, compared to five cases of ACTH-dependant hyperplasias (CD) and a pool of adrenals from 62 normal individuals. We used the genome-spanning Affymetrix U133 plus 2.0 microarray oligochips to identify genes differentially expressed specifically in GIP-dependent CS and which would be candidate genes implicated in the ectopic expression of the GIP receptor in the adrenal cortex. After data normalization and filtering, genes with differential expression were identified with a multi-step statistical analysis involving a student’s t-test, a filter on flags and a SAM analysis. A total of 721 probesets were thus isolated with intensity levels robustly related to the presence of a GIP-dependent hyperplasia. We performed a functional classification to further define potentially important biological processes and signaling mechanism for the formation of GIP-dependent AIMAH. Various probesets were related to metabolic processes, cell-surface and intracellular signaling, tumorigenesis, transport and transcription factors. The most relevant genes had their expression profile confirmed by real-time RT-PCR. This study reports an extensive series of potentially novel targets in the identification of the molecular mechanisms of ectopic expression of the GIP-receptor in this pathology. Keywords: Comparative genomic analysis
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Project description:Pancreatic islets are 3-dimensional micro-organs that maintain β-cell functionality via cell-cell and cell-matrix communication. Isolated primary islets are the gold standard for in vitro models. However, native islets present experimental challenges for long-term mechanistic studies owing to their short culture life (approximately 1 week). We developed a novel long-term protocol to study the function of primary islets. The protocol employed reformed islets following dispersion and a fine-tuned culture environment. Reformed islets are highly similar to their primary counterparts across various physiological characteristics. Long-term culture of reformed islets enables high-resolution imaging, repeated functional assessment, and the study of cell-cell communication. Unlike other platforms such as stem cell-derived organoids, reformed islets retain their resident immune populations, making them ideal for studying both resident and infiltrating immune cells and their interactions with hormone-producing islet cells. Qualitative and quantitative analyses revealed that the composition and cytoarchitecture of the reformed islets mimicked those found in primary islets, including the presence of macrophages and CD4+ and CD8+ T cells, which are the key resident immune cell types. Reformed islets secrete insulin and are glucose-responsive, and their β-cells can be stimulated to proliferate using GLP-1 receptor agonism. Furthermore, a comparison of the transcriptomic landscape of isolated human islets and reformed islets generated from the same donor demonstrated a high degree of similarity. Our reformed islets provide an ideal platform to study diabetes pathology. We recapitulated both the T1DM and T2DM disease milieu and validated our model for studying islet immune trafficking and invasion using activated macrophages and T cells. Our data illustrates that reformed islets are an anatomical and functional alternative to native human and mouse islets. Moreover, reformed islets have an advantage over mouse and human β-cell lines, including MIN6 and EndoC-βH1cells, that lack the signalling input of non-β-endocrine cells and immune cell crosstalk. In this study, we showed that reformed islets are a durable paradigm (cell-based model) for islet-based exploration and a means of target discovery/validation for diabetes research.
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