MRNA expression in islets isolated from wild type and SHPKO mice fed chow or western diet
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE20518 | GEO | 2010/02/24
SECONDARY ACCESSION(S): PRJNA125243
REPOSITORIES: GEO
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Project description:SHP (small heterodimer partner; NR0B2) belongs to the nuclear hormone receptor superfamily, which regulates numerous developmental and metabolic cellular functions. To study physiological function of SHP, we generated congenic SHP-/- mice on C57Bl/6 background. When the congenic SHP-/- mice were challenged with a western diet (harlan, TD.88137) for 22 weeks, they were resistant to diet induced obesity and hepatic steatosis compared to WT controls. However, their hepatic insulin sensitivity was compromised when assessed with phospho-Akt levels after insulin injection. Therefore, we investigated hepatic gene expression using illumina beadchip array to explore mechanisms underneath the unique liver physiology in SHP-/- mice. Livers were collected from C57Bl/6 wild type and C57Bl/6 SHP-/- mice fed chow or western diet. The 1 microgram of total RNA obtained from individual mouse (n=4 per group) and subjected to illumina beadchip gene expression profiling.
2012-05-16 | E-GEOD-38013 | biostudies-arrayexpress
Project description:SHP (small heterodimer partner; NR0B2) belongs to the nuclear hormone receptor superfamily, which regulates numerous developmental and metabolic cellular functions. To study physiological function of SHP, we generated congenic SHP-/- mice on C57Bl/6 background. When the congenic SHP-/- mice were challenged with a western diet (harlan, TD.88137) for 22 weeks, they were resistant to diet induced obesity and hepatic steatosis compared to WT controls. However, their hepatic insulin sensitivity was compromised when assessed with phospho-Akt levels after insulin injection. Therefore, we investigated hepatic gene expression using illumina beadchip array to explore mechanisms underneath the unique liver physiology in SHP-/- mice.
2012-05-17 | GSE38013 | GEO
Project description:After the discovery of insulin a century ago, extensive work has been done to unravel the molecular network regulating insulin secretion. Here, we performed a chemical screen and identified AZD7762, a compound that potentiates glucose-stimulated insulin secretion (GSIS) of human β cell line, healthy and type 2 diabetic (T2D) human islets, and primary cynomolgus macaque islets. In vivo studies in diabetic mouse models and cynomolgus macaques demonstrated that AZD7762 enhances GSIS and improves glucose tolerance. Furthermore, genetic manipulation confirmed that ablation of CHEK2 in human β cells results in increased insulin secretion. Consistently, high-fat-diet fed Chk2-/- mice show elevated insulin secretion and improved glucose clearance. Finally, an untargeted metabolic profiling demonstrated the key role of the CHEK2-PP2A-PLK1-G6PD-PPP pathway in insulin secretion. This study successfully identifies a previously unknown insulin secretion regulating pathway that is conserved across rodents, cynomolgus macaques and human β cells in both healthy and T2D conditions.
2023-10-25 | GSE239335 | GEO
Project description:Objective Notch signaling is re-activated in β cells from obese mice, and is causal to β cell dysfunction. Notch activity is determined in part by expression of transmembrane ligand availability in a neighboring cell. We hypothesized that β cell expression of Jagged1 determines the maladaptive Notch response and resultant β cell dysfunction in obese mice. Methods We assessed expression of Notch pathway components in diet-induced obese (DIO) or leptin receptor-deficient (db/db) mice, and performed single cell RNA sequencing (scRNAseq) in islets from patients with and without type 2 diabetes (T2D). We generated and performed glucose tolerance testing in inducible, β cell-specific Jagged1 gain-of- and loss-of-function mice. We also tested effects of monoclonal neutralizing antibodies to Jagged1 in glucose-stimulated insulin secretion (GSIS) assays in isolated islets. Results Jag1 was the only Notch ligand that tracked with increased Notch activity in DIO and db/db mice. Consistently, JAG1 tracked with Notch activity in metabolically inflexible β cells enriched in patients with T2D. Neutralizing antibodies to block Jagged1 in islets isolated from DIO and db/db mice potentiated GSIS ex vivo. To demonstrate if β cell Jagged1 is sufficient to cause glucose tolerance in vivo, we generated inducible β cell-specific Jag1 transgenic mice (β-Jag1TG), which showed impaired glucose intolerance due to reduced GSIS. However, β cell-specific Jagged1 loss-of-function (β-Jag1KO) did not protect against HFD-induced insulin secretory defects or glucose intolerance. Conclusions Jagged1 is increased in islets from obese mice and in patients with T2D, and neutralizing Jagged1 antibodies lead to improved GSIS, suggesting that inhibition of Jagged1-Notch signaling may have therapeutic benefit. However, genetic loss-of-function experiments suggest that β cells are not a likely source of the Jagged1 signal.
2024-02-23 | GSE249170 | GEO
Project description:The Ras-related Rap1A GTPase is implicated in pancreas β-cell insulin secretion, and is stimulated by the cAMP sensor Epac2, a guanine exchange factor and activator of Rap1 GTPase. In this study we examined the differential proteomic profiles by nanoLC-ESI-MS/MS of pancreata from C57BL/6 Rap1A-deficient (Null) and control wild-type (WT) mice, to assess targets of Rap1A potentially involved in insulin regulation. We identified 77 overlapping identifier proteins in both groups, 8 distinct identifier proteins in Null versus 56 distinct identifier proteins in WT mice pancreas. Functional enrichment analysis showed 4 of the 8 Null unique proteins, ERO1-like protein β (Ero1lβ), triosephosphate isomerase (TP1), 14-3-3 protein γ and kallikrein-1, were exclusively involved in insulin biogenesis, with role in insulin metabolism. Specifically, the mRNA expression of Ero1lβ and TP1 was significantly (p<0.05) increased in Null versus WT pancreas. Rap1A-deficiency significantly affected glucose tolerance during the first 15-30 min of glucose challenge, but showed no impact on insulin sensitivity. Ex vivo glucose-stimulated insulin secretion (GSIS) studies on isolated Null islets showed significantly impaired GSIS. Furthermore, in GSIS-impaired islets, the cAMP-Epac2-Rap1A pathway was significantly compromised as compared to WT. Altogether, these studies underscore an essential role of Rap1A GTPase in pancreas physiological function
2024-10-17 | PXD052896 | Pride
Project description:Extracellular vesicles are membranous nanoparticles that convey signaling between cells, tissues and organs. By applying fluorescence tracing and SILAC-labeling paired with (phospho)proteomics, we identified the transfer of functional insulinotropic protein cargo via adipocyte-derived extracellular vesicles (AdEVs) from adipose tissue to pancreatic ß-cells in vivo and in vitro. AdEV-derived proteins were targets for phosphorylation, increased the overall abundances and phosphosite dynamics of insulinotropic GPCR/cAMP/PKA pathways and amplified 1st-phase glucose-stimulated insulin secretion (GSIS) in murine islets. Notably, insulinotropic effects were restricted to AdEVs from obese and insulin resistant, but not lean mice, which was consistent with differential protein loads and AdEV luminal morphologies. Pre-treatment with AdEVs from obese mice amplified insulin secretion and glucose tolerance in mice independent from hyperglycemia. These data suggest that secreted AdEVs can inform pancreatic ß-cells about adipose tissue insulin resistance in order to amplify GSIS in times of increased insulin demand.
2023-03-11 | PXD037809 | Pride
Project description:Glucagon and insulin are counter-regulatory pancreatic hormones that precisely control blood glucose homeostasis1. Type 2 diabetes mellitus (T2DM) is characterized by inappropriately elevated blood glucagon2-5 levels as well as insufficient glucose stimulated insulin secretion (GSIS) by pancreatic ß-cells6. Early in the pathogenesis of T2DM, hyperglucagonemia is observable antecedent to ß-cell dysfunction7-9; and in mice, liver-specific activation of glucagon receptor-dependent signaling results in impaired GSIS10. However, the mechanistic relationship between hyperglucagonemia, hepatic glucagon action, and ß-cell dysfunction remains poorly understood. Here we show that glucagon action stimulates hepatic production of the neuropeptide kisspeptin1, which acts in an endocrine manner on ß-cells to suppress GSIS. In vivo glucagon administration acutely stimulates hepatic kisspeptin1 production, and kisspeptin1 is increased in livers from humans with T2DM and from mouse models of diabetes mellitus. Synthetic kisspeptin1 potently suppresses GSIS in vivo and in vitro from normal isolated islets, which express the kisspeptin1 receptor Kiss1R. Administration of a Kiss1R antagonist in diabetic Leprdb/db mice potently augments GSIS and reduces glycemia. Our observations indicate in the pathogenesis of T2DM an endocrine mechanism sequentially linking hyperglucagonemia via hepatic kisspeptin1 production to impaired insulin secretion. In addition, our findings suggest Kiss1R antagonism as a therapeutic avenue to improve ß-cell function in T2DM. Total RNA from L-Δprkar1a KO mice compared to control D-glucose mice
2014-04-01 | E-GEOD-48815 | biostudies-arrayexpress
Project description:The pancreas plays a critical role in maintaining glucose homeostasis through the secretion of hormones from the islets of Langerhans. Glucose-stimulated insulin secretion (GSIS) by the pancreatic beta-cell is the main mechanism for reducing elevated plasma glucose.
Here we present a systematic modeling workflow for the development of kinetic pathway models using the Systems Biology Markup Language (SBML). An important factor was the reproducibility and exchangeability of the model, which allowed the use of various existing tools.
The workflow was applied to construct a novel data-driven kinetic model of GSIS in the pancreatic beta-cell based on experimental and clinical data from 39 studies spanning 50 years of pancreatic, islet, and beta-cell research in humans, rats, mice, and cell lines. The model consists of detailed glycolysis and phenomenological equations for insulin secretion coupled to cellular energy state, ATP dynamics and (ATP/ADP ratio).
Key findings of our work are that in GSIS there is a glucose-dependent increase in almost all intermediates of glycolysis. This increase in glycolytic metabolites is accompanied by an increase in energy metabolites, especially ATP and NADH. One of the few decreasing metabolites is ADP, which, in combination with the increase in ATP, results in a large increase in ATP/ADP ratios in the beta-cell with increasing glucose. Insulin secretion is dependent on ATP/ADP, resulting in glucose-stimulated insulin secretion.
2024-01-18 | MODEL2401110001 | BioModels
Project description:β-Cell dysfunction, manifested as impaired glucose-stimulated insulin secretion (GSIS), and β-cell loss, which presents as dedifferentiation, inhibited transcriptional identity and death, are the hallmarks of type 2 diabetes. Trimethylamine N-oxide (TMAO), a gut microbiota metabolite, has been shown to play a role in cardiovascular disease. Here, we found that plasma TMAO levels are elevated in both diabetic mice and human subjects and that TMAO at a similar concentration to that found in diabetes could directly decrease β-cell GSIS in both MIN6 cells and primary islets from mice or humans. Elevation of TMAO levels through choline diet feeding impairs GSIS, the β-cell proportion, and glucose tolerance. TMAO inhibits calcium transients through NLRP3 inflammasome-related inflammatory cytokines and induced Serca2 loss, and a Serca2 agonist reversed the effect of TMAO on β-cell function in vitro and in vivo. Additionally, long-term TMAO exposure promotes β-cell ER stress, dedifferentiation, and apoptosis and inhibits β-cell transcriptional identity. Inhibition of TMAO production through either genetic knockdown or antisense oligomers of Fmo3, the TMAO-producing enzyme, improves β-cell GSIS, the β-cell proportion, and glucose tolerance in both db/db and choline diet-fed mice. These observations elucidate a novel role for TMAO in β-cell dysfunction and maintenance, and inhibition of TMAO could be a new approach for the treatment of type 2 diabetes.
2024-02-23 | GSE243083 | GEO
Project description:Defective glucose-stimulated insulin secretion (GSIS) and β-cell senescence are hallmarks in diabetes. The mitochondrial enzyme pyruvate carboxylase (PC) has been shown to promote GSIS and β-cell proliferation in the clonal β-cell lines, yet its physiological relevance remains unknown. Here, we provide animal and human data showing a role of PC in protecting β-cells against senescence and maintaining GSIS under different physiological and pathological conditions. β-cell-specific deletion of PC impaired GSIS and induced β-cell senescence in the mouse models under either a standard chow diet or prolonged high-fat diet feeding. Transcriptomic analysis indicated that p53-related senescence and cell cycle arrest are activated in PC-deficient islets. Overexpression of PC inhibited hyperglycemia- and aging-induced p53-related senescence in human and mouse islets as well as INS-1E β-cells, whereas knockdown of PC provoked senescence. Mechanistically, PC interacted with MDM2 to prevent its degradation via the MDM2 binding motif, which in turn restricts the p53-dependent senescent program in β-cells. On the contrary, the regulatory effects of PC on GSIS and the tricarboxylic acid (TCA) anaplerotic flux are p53-independent. We illuminate a function of PC in controlling β-cell senescence through the MDM2–p53 axis.
2024-10-10 | GSE278865 | GEO