Tetraspanin-2 promotes glucotoxic apoptosis by regulating JNK/β-catenin signaling pathway in human pancreatic β-cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE76189 | GEO | 2015/12/21
SECONDARY ACCESSION(S): PRJNA306583
REPOSITORIES: GEO
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Project description:Redox signaling mediated by reversible oxidative cysteine thiol modifications is crucial for driving cellular adaptation to dynamic environmental changes, maintaining homeostasis, and ensuring proper function. This is particularly critical in pancreatic β-cells, which are highly metabolically active and play a specialized role in whole organism glucose homeostasis. Glucose stimulation in β-cells triggers signals leading to insulin secretion, including changes in ATP/ADP ratio and intracellular calcium levels. Additionally, lipid metabolism and reactive oxygen species (ROS) signaling are essential for β-cell function and health. We employed IodoTMT isobaric labeling combined with tandem mass spectrometry to elucidate redox signaling pathways in pancreatic β-cells.
2024-09-30 | PXD052765 | Pride
Project description:Objective: Redox signaling mediated by reversible oxidative cysteine thiol modifications is crucial for driving cellular adaptation to dynamic environmental changes, maintaining homeostasis, and ensuring proper function. This is particularly critical in pancreatic β-cells, which are highly metabolically active and play a specialized role in whole organism glucose homeostasis. Glucose stimulation in β-cells triggers signals leading to insulin secretion, including changes in ATP/ADP ratio and intracellular calcium levels. Additionally, lipid metabolism and reactive oxygen species (ROS) signaling are essential for β-cell function and health. Methods: We employed IodoTMT isobaric labeling combined with tandem mass spectrometry to elucidate redox signaling pathways in pancreatic β-cells. Results: Glucose stimulation significantly increases ROS levels in β-cells, leading to targeted reversible oxidation of proteins involved in key metabolic pathways such as glycolysis, the tricarboxylic acid (TCA) cycle, pyruvate metabolism, oxidative phosphorylation, protein processing in the endoplasmic reticulum (ER), and insulin secretion. Furthermore, the glucose-induced increase in reversible cysteine oxidation correlates with the presence of other post-translational modifications, including acetylation and phosphorylation. Conclusions: Proper functioning of pancreatic β-cell metabolism relies on fine-tuned regulation, achieved through a sophisticated system of diverse post-translational modifications that modulate protein functions. Our findings demonstrate that glucose induces the production of ROS in pancreatic β-cells, leading to targeted reversible oxidative modifications of proteins. Furthermore, protein activity is modulated by acetylation and phosphorylation, highlighting the complexity of the regulatory mechanisms in β-cell function.
2024-09-15 | GSE274980 | GEO
Project description:Reactive oxygen species (ROS) have been implicated as mediators of pancreatic β-cell damage. While β-cells are thought to be vulnerable to oxidative damage, we have shown, using inhibitors and acute depletions, that thioredoxin reductase, thioredoxin, and peroxiredoxins are the primary mediators of antioxidant defense in β-cells. However, the role of this antioxidant cycle in maintaining redox homeostasis and β-cell survival in vivo remains unclear. Here, we generated mice with a β-cell specific knockout of thioredoxin reductase 1 (Txnrd1.fl/fl; Ins1.Cre/+, βKO). Despite blunted glucose-stimulated insulin secretion, knockout mice maintain normal whole body glucose homeostasis. Unlike pancreatic islets with acute Txnrd1 inhibition, βKO islets do not demonstrate increased sensitivity to continuous ROS. RNA-sequencing analysis revealed that Txnrd1-deficient β-cells have increased expression of Nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated genes, and altered expression of genes involved in heme and glutathione metabolism, suggesting an adaptive response. Txnrd1-deficient β-cells also have decreased expression of factors controlling β-cell function and identity which may explain the mild functional impairment. Together, these results suggest that Txnrd1-knockout β-cells compensate for loss of this essential antioxidant pathway by increasing expression of Nrf2-regulated antioxidant genes, allowing for protection from excess ROS at the expense of normal β-cell function and identity.
2022-07-05 | GSE200965 | GEO
Project description:Purpose: Test the role of ChREBPbeta in pancreatic beta cells using tools that distinguish ChREBPalpha and ChREBPbeta and loss and gain of function experiments, confirming its role in glucose toxicity and finding mitigation strategies. Methods: INS-1 832/13 cells cultured in 2 mM or 11 mM glucose were transduced with adenoviruses expressing GFP as control or ChREBPbeta. After 48 h, RNA was isolated and amplified via the NuGEN Ovation RNA-Seq System V2 prior to RNA sequencing. Human islets from non-diabetic and T2D subjects were transduced with adenovirus ZSGreen and cell sorted. RNA was isolated and subjected to RNAseq. Results: Overexpression of ChREBPbeta led to increased expression of cell cycle and apoptotic genes and a decrease in beta cell maturity genes. T2D human beta cells expressed an increased ratio of ChREBPbeta to ChREBPalpha compared to non-diabetics. Conclusions: ChREBPbeta is necessary for adaptive beta cell expansion, but drives glucose toxicity when overexpressed, mimicking the graded effect of Myc overexpression in beta cells.
2022-06-02 | GSE197864 | GEO
Project description:In this study, we investigated the molecular and cellular mechanisms of verapamil treatment on β-cell function and survival using MIN6 cells. Verapamil's molecular processes were studied using transcriptomic data. MTT, cell count, and flow cytometry assessed cell proliferation, growth, and cycle. MIN6 cell function was assessed by glucose-stimulated insulin release and total insulin content. Seahorse and metabolic stress kits examined metabolic activity and oxygen consumption rate. The protective impact of verapamil on MIN6 cells was evaluated by challenging the verapamil treated cell with streptozotocin, T1D-cytomix, or T2D-cytomix cocktail. Our results demonstrate that verapamil treatment induced higher proliferation of MIN6 cells, altered expression of various proteins and genes, improved insulin secretion in hyperglycemic conditions, increased basal and maximal respiration levels, along with β-cell survival against streptozotocin, T1D-, or T2D-cytomix-induced toxicity, and rendered a protective effect.
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Project description:Glucose-stimulated insulin secretion (GSIS) is suppressed through α-adrenergic receptor stimulation by catecholamines, epinephrine and norepinephrine, in pancreatic β-cells. Previous work has elucidated a bevy of adrenergic regulatory mechanisms beyond traditional Gi-coupled signaling including regulation of ion channels and interactions with exocytotic machinery. Glucose oxidation may also be an important site for adrenergic regulation of GSIS, but the link between epinephrine and glucose oxidation in β-cells is undefined. Here, we evaluate whether adrenergic stimulation decreases oxidative metabolism in β cells. Oxygen consumption rates were determined for Min6 and isolated rat islets in 20mM glucose complete media, then epinephrine was added at either 0 nM (vehicle control) or 100nM, followed by 10uM yohimbine (a selective Adrα2A antagonist). To identify glucose oxidation as the primary metabolic pathway affected by epinephrine, oxidation of 14C(U)-labeled glucose was determined in Min6 cells with epinephrine or vehicle. Oxygen consumption and glucose oxidation experiments were conducted in the presence of cAMP and insulin secretion blockers, respectively. Proteomics was performed on Min6 cells exposed to epinephrine for 4 hours and compared to controls. Epinephrine, but not vehicle, reduced (P<0.01) oxygen consumption rates in rat islets and Min6 cells to 64 ± 6% and 65 ± 1% of baseline, respectively, and yohimbine restored oxygen consumption to rates not different from baseline. In Min6 cells incubated with epinephrine rates of 14C glucose oxidation were reduced (P<0.01) 66 ± 4% compared to vehicle controls. These results demonstrate that acute epinephrine exposure suppresses glucose oxidation in β cells via the specific adrenergic receptor, Adrα2A, and indicate a new role for adrenergic regulation in GSIS.
2019-11-08 | PXD006330 | Pride
Project description:Recent studies have uncovered thousands of long non-coding RNAs (lncRNAs) in human pancreatic β cells. β cell lncRNAs are often cell type specific and exhibit dynamic regulation during differentiation or upon changing glucose concentrations. Although these features hint at a role of lncRNAs in β cell gene regulation and diabetes, the function of β cell lncRNAs remains largely unknown. In this study, we investigated the function of β cell-specific lncRNAs and transcription factors using transcript knockdowns and co-expression network analysis. This revealed lncRNAs that function in concert with transcription factors to regulate β cell-specific transcriptional networks. We further demonstrate that the lncRNA PLUTO affects local 3D chromatin structure and transcription of PDX1, encoding a key β cell transcription factor, and that both PLUTO and PDX1 are downregulated in islets from donors with type 2 diabetes or impaired glucose tolerance. These results implicate lncRNAs in the regulation of β cell-specific transcription factor networks.
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Project description:Rhodacyanine, a series of cyanines derived from rhodanine, exerts anticancer effects. This study intended to uncover the biological mechanism underlying the anticancer effects of a a fluorinated rhodacyanine in HeLa cervical cancer cells. Initially, the cytotoxic activities of 15 compounds were screened, Rho-7 exhibited the most effective compound against Hela cell growth with IC50 values at 0.03 µM. Interestingly, Rho-7-targeted mitochondrial damage leads to cancer cell death by increasing reactive oxygen species (ROS) levels. Additionally, Rho-7 can trigger Hela cells to undergo apoptosis and cell cycle arrest at the G2/M phase. Rho-7 could downregulate the expression of anti-apoptotic Mcl-1 genes or upregulate the level of pro-apoptotic Bad and Bik genes. Our findings suggest that the anticancer activity of Rho-7 involve ROS generation, cell cycle arrest and apoptotic induction, as well as alteration of pro-and anti-apoptotic genes, displaying a therapeutic potential of Rho-7 in cervical cancer treatment.
2024-01-01 | GSE251969 | GEO
Project description:The functional mass of insulin-secreting pancreatic β cells expands to maintain glucose homeostasis in the face of nutrient excess, in part via replication of existing β cells. To decipher the underlying molecular mechanisms, we assessed β-cell proliferation in isolated rat islets exposed to glucose and oleate or palmitate for 48 h and analyzed the transcriptional response by single-cell RNA sequencing. Unsupervised clustering of pooled β cells identified subpopulations, including proliferating β cells. β-cell proliferation increased in response to oleate but not palmitate. Both fatty acids enhanced the expression of genes involved energy metabolism and mitochondrial activity. Comparison of proliferating vs. non-proliferating β cells and pseudotime ordering suggested the involvement of reactive oxygen species (ROS) and peroxiredoxin signaling. Accordingly, the antioxidant N-acetyl cysteine and the peroxiredoxin inhibitor Conoidin A both blocked oleate-induced β-cell proliferation. Our data reveal a key role for ROS signaling in β-cell proliferation in response to nutrients.
2022-01-21 | GSE193857 | GEO
Project description:Diabetes is a global health problem caused primarily by the inability of pancreatic β-cells to secrete adequate levels of insulin. The molecular mechanisms underlying the progressive failure of β-cells to respond to glucose in type-2 diabetes remain unresolved. Using a combination of transcriptomics and proteomics, we find significant dysregulation of major metabolic pathways in islets of diabetic βV59M mice, a non-obese, eulipidaemic diabetes model. Multiple genes/proteins involved in glycolysis/gluconeogenesis are upregulated, whereas those involved in oxidative phosphorylation are downregulated. In isolated islets, glucose-induced increases in NADH and ATP are impaired and both oxidative and glycolytic glucose metabolism are reduced. INS-1 β-cells cultured chronically at high glucose show similar changes in protein expression and reduced glucose-stimulated oxygen consumption: targeted metabolomics reveals impaired metabolism. These data indicate hyperglycaemia induces metabolic changes in β-cells that markedly reduce mitochondrial metabolism and ATP synthesis. We propose this underlies the progressive failure of β-cells in diabetes.
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