The role of BAF60C in type 2 diabetes ——ATAC-seq
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE317708 | GEO | 2026/02/06
REPOSITORIES: GEO
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Project description:This research identify reduced expression of BAF60C in diabetic islets and demonstrate that altered β-cell BAF60C levels strongly influence metabolic homeostasis. Genetic loss of BAF60C in β-cells exacerbates hyperglycemia and islet dysfunction under metabolic stress, whereas β-cell–specific restoration of BAF60C produces protective effects. These findings establish BAF60C as an important regulator of β-cell integrity and disease progression in T2D.
2026-02-06 | GSE317978 | GEO
Project description:This research identify reduced expression of BAF60C in diabetic islets and demonstrate that altered β-cell BAF60C levels strongly influence metabolic homeostasis. Genetic loss of BAF60C in β-cells exacerbates hyperglycemia and islet dysfunction under metabolic stress, whereas β-cell–specific restoration of BAF60C produces protective effects. These findings establish BAF60C as an important regulator of β-cell integrity and disease progression in T2D.
2026-02-06 | GSE318318 | GEO
Project description:This research identify reduced expression of BAF60C in diabetic islets and demonstrate that altered β-cell BAF60C levels strongly influence metabolic homeostasis. Genetic loss of BAF60C in β-cells exacerbates hyperglycemia and islet dysfunction under metabolic stress, whereas β-cell–specific restoration of BAF60C produces protective effects. These findings establish BAF60C as an important regulator of β-cell integrity and disease progression in T2D.
2026-01-29 | PXD073272 |
Project description:Genetic and environmental factors together cause islet beta-cell failure, leading to Type 2 diabetes (T2D). Here, we study how two members of the Myelin transcription factor family (MYT1, MYT1L, and ST18) prevent human beta-cell failure under obesity-related stress. We have reported that these factors are induced by high levels of obesity-related nutrients. They prevent beta-cell failure in mouse islets and human beta-cell lines. Their variants are all associated with human T2D, and their downregulation accompanies beta-cell dysfunction during T2D development. By knocking down MYT1 or ST18 separately in primary human donor islets, we show here that they have overlapping but distinct functions. Under normal culture conditions, MYT1-knockdown (KD) causes beta-cell death, while ST18-KD compromises glucose-stimulated insulin secretion. Under obesity-induced metabolic stress in vivo, ST18-KD also causes beta-cell death. These findings led us to explore the molecular mechanisms by which MUYT1/ST18 regulate beta cells. The data presented here are the RNAseq of human islet beta cells with knockdown of these factors.
2025-10-10 | GSE307815 | GEO
Project description:The transition from β-cell compensation to β-cell failure is not well understood. Previous works by our group and others have demonstrated a role for Prostaglandin EP3 receptor (EP3), encoded by the Ptger3 gene, in the loss of functional β-cell mass in T2D. The primary endogenous EP3 ligand is the arachidonic acid metabolite, prostaglandin E2 (PGE2). Pancreatic islet EP3 expression, expression of PGE2 synthetic enzymes, and/or PGE2 excretion itself have all been shown as up-regulated in primary mouse and human islets isolated from animals or human organ donors with established T2D as compared to non-diabetic controls. In this study, we took advantage of a rare and fleeting phenotype in which a subset of Black and Tan BRachyury (BTBR) mice homozygous for the Leptinob/ob mutation—a strong genetic model of T2D—were entirely protected from fasting hyperglycemia even with equal obesity and insulin resistance as their hyperglycemic littermates. Utilizing this model, we found numerous alterations in full-body metabolic parameters in T2D-protected mice (e.g., gut microbiome composition, circulating pancreatic and incretin hormones, and markers of systemic inflammation) that correlate with improvements in EP3-mediated β-cell dysfunction.
2021-09-09 | PXD022624 | Pride
Project description:Protein misfolding is a contributor to the development of type 2 diabetes (T2D), but it is unknown whether impaired proteostasis in T2D is generalized or has special features. Here, we report a robust accumulation of misfolded proteins within the mitochondria of human pancreatic islets from patients with T2D and elucidate its impact on β cell viability. Quantitative proteomics studies of protein aggregates surprisingly reveal that islets from donors with T2D have a signature more closely resembling mitochondrial rather than ER protein misfolding. Loss of the matrix protease LONP1, a vital component of the mitochondrial proteostatic machinery whose expression is reduced in β cells of donors with T2D, yields mitochondrial protein misfolding and reduced respiratory function, ultimately leading to β cell apoptosis and hyperglycemia. Intriguingly, LONP1 gain of function ameliorates mitochondrial protein misfolding and restores human β cell survival following glucolipotoxicity via a protease-independent effect requiring LONP1-mtHSP70 chaperone activity. Thus, LONP1 promotes β cell survival and prevents hyperglycemia by facilitating mitochondrial protein folding. These observations open novel insights into the nature of proteotoxicity that promotes β cell loss during the pathogenesis of T2D that could be considered as future therapeutic targets.
2025-06-05 | PXD060404 | Pride
Project description:Pancreatic islet beta cell heterogeneity has been identified, which plays a pivotal role in the pathological alterations of pancreatic islets in type 2 diabetes (T2D) mice. However, pathological alterations of beta cells in type 2 diabetes (T2D) mice remain to be investigated. We isolated pancreatic islets from the control and T2D mice and conducted scRNA-seq analysis using the 10x Genomics platform. Pathological alterations of beta cells in T2D were also explored.
2022-04-09 | GSE200531 | GEO
Project description:Objectives: Glycine acts in an autocrine positive feedback loop in human β cells through its ionotropic receptors (GlyRs). In type 2 diabetes (T2D), islet GlyR activity is impaired by unknown mechanisms. We sought to investigate if the GlyR dysfunction in T2D is replicated by hyperglycemia per se, and to further characterize its action in β cells and the islets. Methods: GlyR-mediated currents were measured using whole-cell patch-clamp in human β cells from donors with or without T2D, or after high glucose culture. We also correlated glycine-induced current amplitude with transcript expression levels through patch-seq. The expression of the GlyR α1, α3, and β subunit mRNA splice variants was compared between islets from donors with and without T2D, and after high glucose culture. Insulin secretion from human islets was measured in the presence or absence of the GlyR antagonist strychnine. Results: Gene expression of GlyRs was decreased in islets from T2D donors along with smaller GlyR-mediated currents in the β cells. Glycine-induced currents are also reduced in islets from donors without diabetes after 48 hours of culture in high glucose, along with reducedα1 subunit expression and increased α3 subunit expression. Glycine-evoked currents are highly heterogeneous between different β cells within and between donors; inversely correlated with donor HbA1c; and significantly correlated to the expression of 99 different transcripts. Finally, glucose-stimulated insulin secretion is decreased in the presence of strychnine.
2024-12-02 | GSE280267 | GEO
Project description:Type 2 diabetes (T2D) is a common metabolic disease due to insufficient insulin secretion by pancreatic beta cells in the context of insulin resistance. Islet molecular pathology reveals a role for protein misfolding in beta cell dysfunction and loss with islet amyloid derived from islet amyloid polypeptide (IAPP), a protein co-expressed and co-secreted with insulin. The most toxic form of misfolded IAPP is intracellular membrane disruptive toxic oligomers present in beta cells in T2D and in beta cells of mice transgenic for human IAPP (hIAPP). Prior work revealed a high degree of overlap of transcriptional changes in islets from T2D and pre-diabetic 9-10-week-old mice transgenic for hIAPP with most changes being pro-survival adaptations and therefore of limited therapeutic guidance. Here we investigated islets from hIAPP transgenic mice at an earlier age (6 weeks) to screen for potential mediators of hIAPP toxicity that precede predominance of pro-survival signaling. We identified early suppression of cholesterol synthesis and trafficking along with aberrant intra-beta cell cholesterol and lipid deposits, and impaired cholesterol trafficking to cell membranes. These findings align with comparable lipid deposits present in beta cells in T2D and increased vulnerability to develop T2D in individuals taking medications that suppress cholesterol synthesis.
2024-07-03 | GSE256432 | GEO
Project description:Recent advances in the understanding of the genetics of type 2 diabetes (T2D) susceptibility have focused attention on the regulation of transcriptional activity within the pancreatic beta-cell. MicroRNAs (miRNAs) represent an important component of regulatory control, and have proven roles in the development of human disease and control of glucose homeostasis. We set out to establish the miRNA profile of human pancreatic islets and of enriched beta-cell populations, and to explore their potential involvement in T2D susceptibility. We used Illumina small RNA sequencing to profile the miRNA fraction in three preparations each of primary human islets and of enriched beta-cells generated by fluorescence-activated cell sorting. In total, 366 miRNAs were found to be expressed (i.e. >100 cumulative reads) in islets and 346 in beta-cells; of the total of 384 unique miRNAs, 328 were shared. A comparison of the islet-cell miRNA profile with those of 15 other human tissues identified 40 miRNAs predominantly expressed (i.e. >50% of all reads seen across the tissues) in islets. Several highly-expressed islet miRNAs, such as miR-375, have established roles in the regulation of islet function, but others (e.g. miR-27b-3p, miR-192-5p) have not previously been described in the context of islet biology. As a first step towards exploring the role of islet-expressed miRNAs and their predicted mRNA targets in T2D pathogenesis, we looked at published T2D association signals across these sites. We found evidence that predicted mRNA targets of islet-expressed miRNAs were globally enriched for signals of T2D association (p-values <0.01, q-values <0.1). At six loci with genome-wide evidence for T2D association (AP3S2, KCNK16, NOTCH2, SCL30A8, VPS26A, and WFS1) predicted mRNA target sites for islet-expressed miRNAs overlapped potentially causal variants. In conclusion, we have described the miRNA profile of human islets and beta-cells and provide evidence linking islet miRNAs to T2D pathogenesis. Examination of the miRNA profiles in 3 preparations of isolated pancreatic islets and 3 preparations of FACS-enriched pancreatic beta-cells
2013-06-07 | E-GEOD-47720 | biostudies-arrayexpress