Pancreatic Differentiation of stem cells reveals pathogenesis of a syndrome of Ketosis-Prone Diabetes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA694301 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13514234.fastq.gz | Fastqsanger.gz | |||
| SRR13514235.fastq.gz | Fastqsanger.gz | |||
| SRR13514236.fastq.gz | Fastqsanger.gz | |||
| SRR13514237.fastq.gz | Fastqsanger.gz | |||
| SRR13514238.fastq.gz | Fastqsanger.gz |
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Project description: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.
2021-06-01 | GSE165385 | GEO
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
Project description:Diabetic ketoacidosis (DKA) has been considered a key clinical feature of Type 1 diabetes mellitus; however, increasing evidence indicates that DKA is also a common feature of Type 2 diabetes (T2DM). Many cases of DKA develop under stressful conditions such as trauma or infection but an increasing number of cases without precipitating cause have been reported in children and adults with T2DM. Such patients present with severe hyperglycemia and ketosis as in Type 1 diabetes mellitus but can discontinue insulin after a few months and maintain acceptable glycemic control on diet or oral agents. This subtype of diabetes has been referred to as ketosis-prone T2DM. In this article, we reviewed the literature on ketosis-prone T2DM and summarized the epidemiology, putative pathophysiology and approaches to management.
| S-EPMC3351851 | biostudies-literature
Project description:Ketosis-prone diabetes (KPD) is a widespread, emerging, heterogeneous syndrome characterized by patients who present with diabetic ketoacidosis or unprovoked ketosis but do not necessarily have the typical phenotype of autoimmune type 1 diabetes. Multiple, severe forms of beta-cell dysfunction appear to underlie the pathophysiology of KPD. Until recently, the syndrome has lacked an accurate, clinically relevant and etiologically useful classification scheme. We have utilized a large, longitudinally followed, heterogeneous, multiethnic cohort of KPD patients to identify four clinically and pathophysiologically distinct subgroups that are separable by the presence or absence of beta-cell autoimmunity and the presence or absence of beta-cell functional reserve. The resulting "Abeta" classification system of KPD has proven to be highly accurate and predictive of such clinically important outcomes as glycemic control and insulin dependence, as well as an aid to biochemical and molecular investigations into novel causes of beta-cell dysfunction. In this review, we describe the current state of knowledge in regard to the natural history, pathophysiology, and treatment of the subgroups of KPD, with an emphasis on recent advances in understanding their immunological and genetic bases.
| S-EPMC2528854 | biostudies-literature
Project description:Maternal ketosis during pregnancy can impact fetal development, yet its effects on kidney development are not well understood. This study investigates the impact of maternal ketosis on offspring nephrogenesis using two mouse models: a ketogenic diet and β-hydroxybutyrate supplementation. Pregnant mice were subjected to either intervention from conception until birth. Offspring kidneys were analyzed at birth and in adulthood for nephron number, glomerular density, and renal function. Nephron progenitor cells (NPCs) were isolated from embryonic kidneys and analyzed using RNA sequencing, immunostaining, and quantitative PCR. Both ketosis models resulted in significantly reduced glomerular density at birth and a 25% decrease in nephron number in adult offspring, accompanied by impaired renal function. RNA sequencing revealed over 1,000 differentially expressed genes in the ketogenic diet group and 164 in the β-hydroxybutyrate group, with 67 overlapping genes. Pathway analysis showed downregulation of cell cycle and Myc target pathways, and upregulation of inflammatory pathways in both models. Immunostaining confirmed a 40% reduction in NPC proliferation and decreased c-Myc expression under ketotic conditions. Additionally, ketosis increased TNFα expression and activated the NFκB pathway in NPCs. These findings provide the first evidence linking maternal ketosis to impaired nephrogenesis, demonstrating a negative impact on offspring kidney development by altering NPC proliferation, Myc signaling, and inflammatory responses. This study highlights potential risks associated with ketogenic diets or other ketosis-inducing conditions during pregnancy.
2024-11-10 | GSE274301 | GEO
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
Project description:ObjectiveKetosis-prone diabetes (KPD) is an emerging syndrome that encompasses several distinct phenotypic subgroups that share a predisposition to diabetic ketoacidosis. We investigated whether the A-beta- subgroup of KPD, characterized by complete insulin dependence, absent beta-cell functional reserve, lack of islet cell autoantibodies, and strong family history of type 2 diabetes, represents a monogenic form of diabetes.Research design and methodsOver 8 years, 37 patients with an A-beta- phenotype were identified in our longitudinally followed cohort of KPD patients. Seven genes, including hepatocyte nuclear factor 4A (HNF4A), glucokinase (GCK), HNF1A, pancreas duodenal homeobox 1 (PDX1), HNF1B, neurogenic differentiation 1 (NEUROD1), and PAX4, were directly sequenced in all patients. Selected gene regions were also sequenced in healthy, unrelated ethnically matched control subjects, consisting of 84 African American, 96 Caucasian, and 95 Hispanic subjects.ResultsThe majority (70%) of the A-beta- KPD patients had no significant causal polymorphisms in either the proximal promoter or coding regions of the seven genes. The combination of six potentially significant low-frequency, heterozygous sequence variants in HNF-1 alpha (A174V or G574S), PDX1 (putative 5'-untranslated region CCAAT box, P33T, or P239Q), or PAX4 (R133W) were found in 27% (10/37) of patients, with one additional patient revealing two variants, PDX1 P33T and PAX4 R133W. The A174V variant has not been previously reported.ConclusionsDespite its well-circumscribed, robust, and distinctive phenotype of severe, nonautoimmune-mediated beta-cell dysfunction, A-beta- KPD is most likely not a predominantly monogenic diabetic syndrome. Several A-beta- KPD patients have low-frequency variants in HNF1A, PDX1, or PAX4 genes, which may be of functional significance in their pathophysiology.
| S-EPMC2671096 | biostudies-literature
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
Project description:Gene expression changes during Type 1 diabetes pathogenesis
| PRJNA143979 | ENA
Project description:Ketosis-prone type 2 diabetes is recognized as atypical diabetes. These patients are often male, characterized by obesity, sudden onset of ketosis and a transient decrease in insulin secretion capacity that can be recovered with temporal insulin therapy. Here, we report a male patient with ketosis-prone type 2 diabetes who was followed up for 8 years. During the follow-up period, his bodyweight fluctuated and he experienced four episodes of critical ketosis recurrence in association with bodyweight gain. He discontinued insulin therapy after each ketosis episode within the first 4 years, but thereafter, he had to continue insulin therapy because of decreased insulin secretion capacity. Interestingly, his peak bodyweight just before the repeated ketosis episode gradually decreased, and the insulin secretion capacity after the recovery from repeated ketosis decreased in parallel with his peak bodyweight. This long-term clinical course might be a clue to understand the pathophysiology of ketosis-prone type 2 diabetes.
| S-EPMC7078091 | biostudies-literature