ATAC sequencing of zebrafish pancreatic beta-cells
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ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE152199 | GEO | 2021/12/31
REPOSITORIES: GEO
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Project description:The pancreatic beta-cells regulate blood glucose levels by secreting the hormone insulin in response to increasing glucose levels. Recent work has identified molecular and functional heterogeneity among the beta-cell community. To ontain an unbiased picture into the molecular heterogeneity present in zebrafish pancreatic cells, we performed droplet based next-generation sequencing of individual pancreatic cells. Using unsupervised clustering, we could identify all the major cell types present in the pancreas. Moreover, we could define sub-populations within the major cell-types, demonstrating the presence of molecular heterogeneity within nominally homogenous cell-populations.
2019-04-05 | GSE123662 | GEO
Project description:The NF-κB pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic beta cell dysfunction in the metabolic syndrome. While canonical NF-κB signaling is well studied, there is little information on the divergent non-canonical NF-κB pathway in the context of pancreatic islet dysfunction in diabetes. Here, we demonstrate that pharmacological activation of the non-canonical NF-κB inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. Further, we identify NIK as a critical negative regulator of beta cell function as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of non-canonical NF-κB components p100 to p52, and accumulation of RelB. Tumor necrosis factor α (TNFα) and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive beta cell intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the non-canonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to beta cell failure. These studies reveal that NIK contributes a central mechanism for beta cell failure in diet-induced obesity. We identify a role for Nuclear Factor inducing κB (NIK) in pancreatic beta cell failure. NIK activation disrupts glucose homeostasis in zebrafish in vivo and impairs glucose-stimulated insulin secretion in mouse and human islets in vitro. NIK activation also perturbs beta cell insulin secretion in a diet-induced obesity mouse model. These studies reveal that NIK contributes a central mechanism for beta cell failure in obesity. To uncover the role of NIK in pancreatic beta cells, we performed a gene expression microarray analysis comparing pancreatic islets with constitutive beta cell intrinsicNIK activation from the 16 week old mice (beta cell specific TRAF2 and TRAF2 knockout mice) to their controls (n=3 per group).
2015-06-18 | E-GEOD-68317 | biostudies-arrayexpress
Project description:The NF-κB pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic beta cell dysfunction in the metabolic syndrome. While canonical NF-κB signaling is well studied, there is little information on the divergent non-canonical NF-κB pathway in the context of pancreatic islet dysfunction in diabetes. Here, we demonstrate that pharmacological activation of the non-canonical NF-κB inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. Further, we identify NIK as a critical negative regulator of beta cell function as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of non-canonical NF-κB components p100 to p52, and accumulation of RelB. Tumor necrosis factor α (TNFα) and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive beta cell intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the non-canonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to beta cell failure. These studies reveal that NIK contributes a central mechanism for beta cell failure in diet-induced obesity. We identify a role for Nuclear Factor inducing κB (NIK) in pancreatic beta cell failure. NIK activation disrupts glucose homeostasis in zebrafish in vivo and impairs glucose-stimulated insulin secretion in mouse and human islets in vitro. NIK activation also perturbs beta cell insulin secretion in a diet-induced obesity mouse model. These studies reveal that NIK contributes a central mechanism for beta cell failure in obesity.
2015-06-18 | GSE68317 | GEO
Project description:Pancreatic β cell dysfunction greatly contributes to the pathogenesis of type 2 diabetes. MiR-21 has been shown to be induced in the islets of glucose intolerant patients and type 2 diabetic mice. However, the role of miR-21 in the regulation of pancreatic β cell function remains largely elusive. In the current study, we studied the pathway by which miR-21 regulates glucose-stimulated insulin secretion utilizing mice lacking miR-21 in their β cells (miR-21βKO). We found that miR-21βKO mice developed glucose intolerance due to impaired glucose-stimulated insulin secretion. Mechanistic studies revealed that miR-21 enhances glucose uptake and subsequently promotes insulin secretion by up-regulating Glut2 expression in a miR-21-Pdcd4-AP-1 dependent pathway. Over-expression of Glut2 in knockout islets resulted in rescue of the impaired glucose-stimulated insulin secretion. Furthermore, we demonstrated that delivery of miR-21 into the pancreas of type 2 diabetic db/db mice is able to promote Glut2 expression and significantly reduce blood glucose level. Taking together, our results reveal that miR-21 in islet β cell promotes insulin secretion and support a role for miR-21 in the adaptation of pancreatic β cell function in type 2 diabetes.
2022-05-16 | GSE191194 | GEO
Project description:Background: Tetraspanin-7 (Tspan7) is an islet autoantigen involved in autoimmune type 1 diabetes and known to regulate beta-cell L-type Ca2+ channel activity. However, the role of Tspan7 in pancreatic beta-cell function is not yet fully understood. Methods: Histological analyses were conducted using immunostaining. Whole-body metabolism was tested using glucose tolerance test. Islet hormone secretion was quantified using static batch incubation or dynamic perifusion. Beta-cell transmembrane currents, electrical activity and exocytosis were measured using whole-cell patch-clamping and capacitance measurements. Gene expression was studied using mRNA-sequencing and quantitative PCR. Results: Tspan7 is expressed in insulin-containing granules of pancreatic beta-cells. Tspan7-knockout mice (Tspan7 y/- mouse) exhibit reduced body weight and ad libitum plasma glucose but normal glucose tolerance. Tspan7y/- islets have normal insulin content and glucose- or tolbutamide-stimulated insulin secretion. Depolarisation-triggered Ca2+ current was enhanced in Tspan7y/- beta-cells, but beta-cell electrical activity and depolarisation-evoked exocytosis were unchanged suggesting that exocytosis was less sensitive to Ca2+. TSPAN7 knockdown (KD) in human pseudo-islets led to a significant reduction in high K+-stimulated insulin secretion. Transcriptomic analyses show that TSPAN7 KD in human pseudo-islets correlated with changes in genes involved in hormone secretion, apoptosis and ER stress. Consistent with rodent beta-cells, exocytotic Ca2+ sensitivity was reduced in a human beta cell line (EndoC-H1) following Tspan7 KD. Conclusion: Tspan7 is involved in the regulation of Ca2+-dependent exocytosis in beta-cells. Its function is more significant in human beta-cells than their rodent counterparts
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Project description:Background: Tetraspanin-7 (Tspan7) is an islet autoantigen involved in autoimmune type 1 diabetes and known to regulate beta-cell L-type Ca2+ channel activity. However, the role of Tspan7 in pancreatic beta-cell function is not yet fully understood. Methods: Histological analyses were conducted using immunostaining. Whole-body metabolism was tested using glucose tolerance test. Islet hormone secretion was quantified using static batch incubation or dynamic perifusion. Beta-cell transmembrane currents, electrical activity and exocytosis were measured using whole-cell patch-clamping and capacitance measurements. Gene expression was studied using mRNA-sequencing and quantitative PCR. Results: Tspan7 is expressed in insulin-containing granules of pancreatic beta-cells. Tspan7-knockout mice (Tspan7 y/- mouse) exhibit reduced body weight and ad libitum plasma glucose but normal glucose tolerance. Tspan7y/- islets have normal insulin content and glucose- or tolbutamide-stimulated insulin secretion. Depolarisation-triggered Ca2+ current was enhanced in Tspan7y/- beta-cells, but beta-cell electrical activity and depolarisation-evoked exocytosis were unchanged suggesting that exocytosis was less sensitive to Ca2+. TSPAN7 knockdown (KD) in human pseudo-islets led to a significant reduction in high K+-stimulated insulin secretion. Transcriptomic analyses show that TSPAN7 KD in human pseudo-islets correlated with changes in genes involved in hormone secretion, apoptosis and ER stress. Consistent with rodent beta-cells, exocytotic Ca2+ sensitivity was reduced in a human beta cell line (EndoC-bH1) following Tspan7 KD. Conclusion: Tspan7 is involved in the regulation of Ca2+-dependent exocytosis in beta-cells. Its function is more significant in human beta-cells than their rodent counterparts
2022-10-10 | GSE213729 | GEO
Project description:Pancreatic islets adapt to the increase in insulin demand during pregnancy by up-regulating beta cell proliferation, insulin synthesis, and lowering the threshold of glucose-stimulated insulin secretion. In vitro studies suggest that pregnancy hormones, such as placental lactogens and prolactin, both act through the prolactin receptor, are required for these adaptation. Furhtermore, we found that transgenic mice with heterogenous prolactin receptor null mutation are glucose intolerant, with a lower beta-cell mass and lower insulin levels. The goal here is to discover novel targets of prolactin receptor signaling in pancreatic beta cells during pregnancy.
2019-02-01 | GSE125350 | GEO
Project description:Aim: To investigate the compensatory role of α-cell-derived paracrine signaling through glucagon and GLP-1 receptors in maintaining β-cell function when insulin secretion is compromised. Methods: A β-cell-specific Nox4 knockout mouse (Nox4βKO), which displays defective glucose-stimulated insulin secretion, was used to assess adaptive changes in pancreatic islets. We analyzed islet composition, hormone secretion dynamics, receptor expression profiles, and downstream signaling pathways. Methodologies included immunocytochemistry, flow cytometry, RNA sequencing, cAMP assays, and functional insulin/glucagon secretion assays using both isolated islets and pancreatic slices across different glucose levels and receptor-modulating conditions. Results: Prediabetic Nox4βKO islets showed increased α-cell numbers, expansion of bihormonal cells, and elevated production of glucagon and GLP-1. Receptor profiling revealed a shift in receptor usage: whereas GLP-1R dominated in wild-type islets, GCGR signaling gained prominence in Nox4βKO islets. This restructuring appears to reflect an adaptive response to emerging β-cell dysfunction. Functional assays demonstrated that insulin secretion in prediabetic islets became increasingly reliant on glucagon-driven activation of GLP-1R and cAMP-dependent pathways. Transcriptomic and signaling data confirmed enhanced expression of cAMP-related intermediates and calcium-handling components, indicating partial preservation of insulin secretory capacity despite underlying defects. Conclusion: α-cell remodeling and flexible engagement of glucagon and GLP-1 receptors act as key compensatory mechanisms that help maintain insulin secretion during early β-cell stress. The context-dependent reordering of intra-islet receptor dominance highlights a coordinated multicellular adaptation in prediabetes and suggests that targeting intra-islet endocrine crosstalk may help preserve β-cell function in prediabetes and early type 2 diabetes.
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