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Pancreatic Differentiation of stem cells reveals pathogenesis of a syndrome of Ketosis-Prone Diabetes

ABSTRACT: We describe an unusual course of Ketosis Prone Diabetes and investigate potential mechanisms using induced pluripotent stem cell technology with high throughput mRNA sequencing and validation of a lecuine sensitive mTOR pathway.

ORGANISM(S): Homo sapiens

PROVIDER: GSE165385 | GEO | 2021/06/01

REPOSITORIES: GEO

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Pancreatic Differentiation of stem cells reveals pathogenesis of a syndrome of Ketosis-Prone Diabetes

Project description:Pancreatic Differentiation of stem cells reveals pathogenesis of a syndrome of Ketosis-Prone Diabetes

| PRJNA694301 | ENA

Pancreatic Differentiation of Stem Cells Reveals Pathogenesis of a Syndrome of Ketosis-Prone Diabetes.

Project description:Genetic analysis of an adult patient with an unusual course of ketosis-prone diabetes (KPD) and lacking islet autoantibodies demonstrated a nucleotide variant in the 5'-untranslated region (UTR) of PDX1, a β-cell development gene. When differentiated to the pancreatic lineage, his induced pluripotent stem cells stalled at the definitive endoderm (DE) stage. Metabolomics analysis of the cells revealed that this was associated with leucine hypersensitivity during transition from the DE to the pancreatic progenitor (PP) stage, and RNA sequencing showed that defects in leucine-sensitive mTOR pathways contribute to the differentiation deficiency. CRISPR/Cas9 manipulation of the PDX1 variant demonstrated that it is necessary and sufficient to confer leucine sensitivity and the differentiation block, likely due to disruption of binding of the transcriptional regulator NFY to the PDX1 5'-UTR, leading to decreased PDX1 expression at the early PP stage. Thus, the combination of an underlying defect in leucine catabolism characteristic of KPD with a functionally relevant heterozygous variant in a critical β-cell gene that confers increased leucine sensitivity and inhibits endocrine cell differentiation resulted in the phenotype of late-onset β-cell failure in this patient. We define the molecular pathogenesis of a diabetes syndrome and demonstrate the power of multiomics analysis of patient-specific stem cells for clinical discovery.

| S-EPMC8576504 | biostudies-literature

Gene expression Fulminant type 1 diabetes vs classical type 1A diabetes

Project description:We determined the genes that were differentially expressed between fulminant type 1 diabetes and classical type 1A diabetes using gene expression microarray in peripheral blood cells. Ten patients with type 1 diabetes (5 fulminant and 5 classical type 1A) were enrolled in this study. All patients had recovered from ketosis or ketoacidosis at disease onset and had been receiving intensive insulin injection therapy for at least 1 month, which means that all patients and healthy controls were free of metabolic derangements at the time of blood sampling. To determine the genes that were differentially expressed between classical type 1A and fulminant type 1 diabetes, a volcano plot analysis (fold change >1.5 and p-value <0.05) was performed.

2014-01-01 | E-GEOD-44313 | biostudies-arrayexpress

gene expression Fulminant type 1 diabetes vs classical type 1A diabetes vs healthy controls

Project description:We determined the genes that were differentially expressed between fulminant type 1 diabetes and classical type 1A diabetes or healthy control using gene expression microarray in peripheral blood cells. Ten patients with type 1 diabetes (5 fulminant and 5 classical type 1A) and 6 healthy controls were enrolled in this study. All patients had recovered from ketosis or ketoacidosis at disease onset and had been receiving intensive insulin injection therapy for at least 1 month, which means that all patients and healthy controls were free of metabolic derangements at the time of blood sampling. To determine the genes that were differentially expressed among fulminant type 1 diabetes, classical type 1A and healthy controls, a volcano plot analysis (fold change >1.5 and p-value <0.05) was performed.

2014-01-01 | E-GEOD-44314 | biostudies-arrayexpress

The impact of aging on beta-cell functionality and structural integrity under metabolic stress conditions in diabetes-prone and diabetes-resistant mice [ob].

Project description:Young and aged, diabetes-prone (NZO/HIBomDife) as well as diabetes-resistant (B6.V-Lep ob/ob) mice exhibited different islet functions and phenotypes in response to a carbohydrate-rich diet (CRD) subsequent to a high-fat, carbohydrate-free diet (HFD). To unravel the molecular basis underlying these alterations, a microarray-based transcriptome analysis of isolated pancreatic islets before and after 2 days of CRD feeding was performed. A high number of differentially expressed genes associated with redox homeostasis, in particular Thioredoxin-interacting protein (Txnip), as well as genes involved in cell cycle entry and cell proliferation, such as cyclins, cyclin-dependent kinases and Mki67 were identified and associated with these changes. In addition, aged NZO/HIBomDife and age-matched, B6.V-Lep ob/ob mice revealed a high overlap of regulated genes, also linked to cell cycle progression under the same dietary regimen.

2023-11-03 | GSE160694 | GEO

The impact of aging on beta-cell functionality and structural integrity under metabolic stress conditions in diabetes-prone and diabetes-resistant mice.

Project description:Overnutrition contributes to insulin resistance, obesity and metabolic stress, initiating a loss of functional beta-cells and diabetes development. Whether these damaging effects are amplified in advanced age is barely investigated. Therefore, New Zealand Obese (NZO) mice, a well-established model for the investigation of human obesity-associated type 2 diabetes, were fed a metabolically challenging diet with a high-fat, carbohydrate restricted period followed by a carbohydrate intervention in young as well as advanced age. Interestingly, while young NZO mice developed massive hyperglycemia in response to carbohydrate feeding, leading to beta-cell dysfunction and cell death, aged counterparts compensated the increased insulin demand by persistent beta-cell function and beta-cell mass expansion. Beta-cell loss in young NZO islets was linked to increased expression of thioredoxin-interacting protein (TXNIP), presumably initiating an apoptosis-signaling cascade via caspase-3 activation. In contrast, islets of aged NZOs exhibited a sustained redox balance without changes in TXNIP expression, associated with higher proliferative potential by cell cycle activation. These findings support the relevance of a maintained proliferative potential and redox homeostasis for preserving islet functionality under metabolic stress, with the peculiarity that this adaptive response emerged with advanced age in diabetes-prone NZO mice.

2020-11-02 | GSE150281 | GEO

Pancreatic islet expression profiling in diabetes prone C57BLKS/J mice vs C57BL6/J mice.

Project description:C57BLKS/J mice are susceptible to diabetes, because of islet dysfunction, whereas C57BL6/J mice are not. Differences in gene expression between the two strains may account for this sensitivity. Furthermore these differences may only be evident in the hyperstimulated (diabetic or hyperglycemic) state. To this end profiling islets from these two strains cultured in both low and high glucose may reveal the underlying mechanism. Keywords: Mouse strain comparison under different culture conditions In the study presented here, pancreatic islets from 20 mice grown in low and high glucose conditions were assayed for differences in gene expression. (five C57BLKS/J low glucose, four C57BLKS/J high glucose, six C57BL6/J low glucose, five C57BL6/J high glucose). Technical replicates are achieved by labeling each sample with both Cy3 and Cy5, and combining the values for each hybridization.

2008-12-30 | E-GEOD-11257 | biostudies-arrayexpress

Pancreatic islet expression profiling in diabetes prone C57BLKS/J mice vs C57BL6/J mice.

2008-12-31 | GSE11257 | GEO

The repertoire of newly developing regulatory T cells in the type I diabetes-prone NOD mouse is very diverse

Project description:Regulatory T lymphocytes expressing the forkhead/winged helix transcription factor Foxp3 (Treg) play a vital role in the protection of the organism from autoimmune disease and other immunopathologies. The antigen-specificity of Treg plays an important role in their in vivo activity. We therefore assessed the diversity of the T cell receptors for antigen (TCR) expressed by Treg newly developed in the thymus of autoimmune type I diabetes-prone NOD mice and compared it to the control mouse strain C57BL/6. Our results demonstrate that usage of the TCRα and TCRβ variable (V) and joining (J) segments, length of the complementarity determining region (CDR) 3, and the diversity of the TCRα and TCRβ chains are comparable between NOD and C57BL/6 mice. Genetic defects affecting the diversity of the TCR expressed by newly developed Treg therefore do not appear to be involved in the etiology of type I diabetes in the NOD mouse.

2021-05-31 | GSE159001 | GEO

The impact of aging on beta-cell functionality and structural integrity under metabolic stress conditions in diabetes-prone and diabetes-resistant mice.

Project description:The impact of aging on beta-cell functionality and structural integrity under metabolic stress conditions in diabetes-prone and diabetes-resistant mice.

| PRJNA631714 | ENA

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