Electrogenic Na+-coupled HCO3- cotransporter NBCe1 regulates pancreatic beta cell function in type 2 diabetes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA743061 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15015639_1.fastq.gz | Fastqsanger.gz | |||
| SRR15015639_2.fastq.gz | Fastqsanger.gz | |||
| SRR15015640_1.fastq.gz | Fastqsanger.gz | |||
| SRR15015640_2.fastq.gz | Fastqsanger.gz | |||
| SRR15015641_1.fastq.gz | Fastqsanger.gz |
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Project description:Pancreatic beta cell failure in type 2 diabetes (T2DM) is attributed in part to perturbations of the beta cell's transcriptional landscape resulting in the aberrant regulation of glucose-stimulated insulin secretion. Recent studies identified SLC4A4 (a gene encoding an electrogenic Na+-coupled HCO3- cotransporter and intracellular pH regulator, NBCe1) as one of the mis-expressed genes in beta cells of patients with T2DM. Thus, in the current study we set out to test the hypothesis that mis-expression of SLC4A4/NBCe1 in T2DM beta cells contributes to beta cell dysfunction and impaired glucose homeostasis. To address this hypothesis, we first confirmed induction of SLC4A4/NBCe1 expression in beta cells of patients with T2DM and demonstrated that its expression is associated with loss of beta cell transcriptional identity, intracellular alkalinization, and beta cell dysfunction. In addition, we generated a beta cell selective Slc4a4/NBCe1 knockout mouse model and report that these mice are protected from diet-induced metabolic stress and beta cell failure. Importantly, improved glucose tolerance and enhanced beta cell function in Slc4a4/NBCe1 deficient mice was due to augmented mitochondrial function and increased expression of genes regulating beta cell identity and function. These results suggest that increased beta cell expression of SLC4A4/NBCe1 in T2DM plays a contributory role in promotion of beta cell failure and should be considered as a potential novel therapeutic target.
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Project description:The electrogenic sodium bicarbonate cotransporter 1, NBCe1 (SLC4A4), is the major bicarbonate transporter expressed in astrocytes. It is highly sensitive for bicarbonate, and the main regulator of intracellular-, extracellular-, and synaptic pH, thereby modulating neuronal excitability. However, despite these essential functions, the molecular mechanisms underlying NBCe1-mediated astrocytic response to extracellular pH changes are mostly unknown. Using primary cortical astrocyte cultures we have investigated the effect of long-term extracellular metabolic alkalosis on regulation of NBCe1 using functional assays and phosphoproteomic analysis.
2019-07-15 | PXD014034 | Pride
Project description:Pancreatic β cell failure in type 2 diabetes mellitus (T2DM) is attributed to perturbations of the β cell's transcriptional landscape resulting in impaired glucose-stimulated insulin secretion. Recent studies identified SLC4A4 (a gene encoding an electrogenic Na+-coupled HCO3- cotransporter and intracellular pH regulator, NBCe1) as one of the misexpressed genes in β cells of patients with T2DM. Thus, in the current study, we set out to test the hypothesis that misexpression of SLC4A4/NBCe1 in T2DM β cells contributes to β cell dysfunction and impaired glucose homeostasis. To address this hypothesis, we first confirmed induction of SLC4A4/NBCe1 expression in β cells of patients with T2DM and demonstrated that its expression was associated with loss of β cell transcriptional identity, intracellular alkalinization, and β cell dysfunction. In addition, we generated a β cell-selective Slc4a4/NBCe1-KO mouse model and found that these mice were protected from diet-induced metabolic stress and β cell dysfunction. Importantly, improved glucose tolerance and enhanced β cell function in Slc4a4/NBCe1-deficient mice were due to augmented mitochondrial function and increased expression of genes regulating β cell identity and function. These results suggest that increased β cell expression of SLC4A4/NBCe1 in T2DM plays a contributory role in promotion of β cell failure and should be considered as a potential therapeutic target.
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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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Project description:The purpose of this study was to investigate the hypothesis that cardiomyocyte-specific loss of the electrogenic NBCe1 Na+-HCO3- cotransporter is cardioprotective during in vivo ischemia-reperfusion (IR) injury. An NBCe1 (Slc4a4 gene) cardiac conditional knockout mouse (KO) model was prepared by gene targeting. Cardiovascular performance of wild-type (WT) and cardiac-specific NBCe1 KO mice was analyzed by intraventricular pressure measurements, and changes in cardiac gene expression were determined by RNA Seq analysis. Response to in vivo I/R injury was analyzed after 30 minutes occlusion of the left anterior descending artery followed by 3 hours of reperfusion. Loss of NBCe1 in cardiac myocytes did not impair cardiac contractility or relaxation and caused only limited changes in gene expression patterns, such as those for electrical excitability. However, following ischemia and reperfusion, KO heart sections exhibited significantly fewer apoptotic nuclei than WT sections. These studies indicate that cardiac-specific loss of NBCe1 does not impair cardiovascular performance, causes only minimal changes in gene expression patterns, and protects against I/R injury in vivo.
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