Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

GLP-1 receptor signaling increases PCSK1 and beta-cell features in human alpha-cells

ABSTRACT: Glucagon-like peptide-1 (GLP-1) is an incretin hormone that potentiates glucose stimulated insulin secretion. GLP-1 is classically produced by gut L cells; however, under certain circumstances alpha-cells can express the prohormone convertase required for proglucagon processing to GLP-1, prohormone convertase 1/3 (PC1/3), and can produce GLP-1. However, the mechanisms through which this occurs are poorly defined. Understanding the mechanisms by which alpha-cell PC1/3 expression can be activated may reveal new targets for diabetes treatment. Here, we demonstrate that the GLP-1 receptor (GLP-1R) agonist, liraglutide, increases alpha-cell GLP-1 expression in a beta cell GLP-1R-dependent manner. We demonstrate that this effect of liraglutide is translationally relevant in human islets through application of a new scRNA-sequencing technology, DART-seq. We find that the effect of liraglutide to increase alpha-cell PC1/3 mRNA expression occurs in a sub-cluster of alpha-cells and is associated with increased expression of other beta-cell-like genes, which we confirm by IHC. Finally, we find that the effect of liraglutide to increase bi-hormonal insulin+ glucagon+ cells is mediated by the beta-cell GLP-1R in mice. Together, our data validate a new high-sensitivity method for scRNA-sequencing in human islets and identify a novel GLP-1 mediated pathway regulating human alpha-cell function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE163744 | GEO | 2020/12/24

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

Acute effects of liraglutides on gene expression in the hearts of mice with experimental myocardial infarction

Project description:Glucagon-like peptide-1 receptor (GLP-1R) agonists reduce the rates of major cardiovascular events, including myocardial infarction in people with type 2 diabetes, and decrease infarct size while preserving ventricular function in preclinical studies. Nevertheless, the precise cellular sites of GLP-1R expression that mediate the cardioprotective actions of GLP-1 in the setting of ischemic cardiac injury are uncertain. Here, cardiac gene expression profiles regulated by liraglutide were examined using RNA-Seq to interrogate mouse atria and both non-infarcted and non-infarcted ventricular tissue after acute coronary artery ligation.

2022-11-21 | GSE217736 | GEO

RNA-Seq analysis on the liver of mice treated with high-fat diet and liraglutide

Project description:GLP-1 based diabetes drugs are effective to reduce hepatic lipid accumulation beyong glycemic control. As GLP-1 receptor (GLP-1R) is not expressed in hepatocytes, the mechanism behind the beneficial effects of GLP-1 based drugs on the liver remained elusive. Several studies have shown that the expression of hepatic fibroblast growth factor 21 (FGF21) can be stimulated by GLP-1-based drugs. Therefore, the present study aimed to assess such stimulation in mice and in mouse primary hepatocytes, determine whether hepatic FGF21 mediates functions of the GLP-1R agonist liraglutide, and to explore the potential mechanisms of liraglutide regulating the expression of FGF21. In high-fat diet induced obese mice, we observed hepatic and plasma FGF21 elevation, improved glucose disposal, and reduced plasma triglyceride levels by liraglutide treatment. Moreover, RNA-sequencing on the liver suggested that Fgf21 was the most upregulated gene after liraglutide treatment. In liver-specific FGF21 knock-out mice on high-fat and high-fructose diet, the body-weight gain attenuation and lipid homeostatic effects of liraglutide was lost or significantly reduced. These studies implied that hepatic FGF21 was the critical mediator of liraglutide-induced metabolic improvement.

2021-03-16 | GSE168937 | GEO

BI 456906: a dual glucagon-like peptide-1/glucagon agonist promoting bodyweight reduction

Project description:Glucagon and glucagon-like peptide-1 (GLP-1) are hormones involved in energy homeostasis. GLP-1 receptor (GLP-1R) agonism reduces food intake and delays gastric emptying, and glucagon receptor (GCGR) agonism increases energy expenditure by thermogenesis. BI 456906 is a subcutaneous, once-weekly injectable dual GLP-1R/GCGR agonist in development for the treatment of obesity or non-alcoholic steatohepatitis. Here we show that BI 456906 is a potent dual agonist with an extended half-life in human plasma. Key GLP-1R-mediated mechanisms of reduced food intake, delayed gastric emptying and improved glucose tolerance were confirmed in GLP-1R knockout mice. GCGR activity was confirmed by reduced plasma amino acids, increased hepatic expression of nicotinamide N-methyltransferase and increased energy expenditure. BI 456906 produced greater bodyweight reductions than maximally efficacious semaglutide doses and modulated gene expression, including genes involved in amino acid metabolism. BI 456906 is a potent dual agonist that produces bodyweight-lowering effects through both GLP-1R and GCGR agonism.

2022-12-09 | GSE211105 | GEO

Combination of an ACLY inhibitor with a GLP-1R agonist exerts additive benefits on NASH and hepatic fibrosis [NASH Custom panel]

Project description:Increased liver de novo lipogenesis (DNL) is a hallmark of nonalcoholic steatohepatitis (NASH). A key enzyme controlling DNL upregulated in NASH is ATP citrate lyase (ACLY). In mice, inhibition of ACLY reduces liver steatosis, ballooning and fibrosis and inhibits activation of hepatic stellate cells. Glucagon like peptide-1 receptor (GLP-1R) agonists lower body mass, insulin resistance and steatosis without improving fibrosis. Here, we find that combining an inhibitor of liver ACLY, bempedoic acid, and the GLP-1R agonist liraglutide reduces liver steatosis, hepatocellular ballooning, and hepatic fibrosis in a mouse model of NASH. Liver RNA analyses revealed additive downregulation of pathways that are predictive of NASH resolution, reductions in the expression of prognostically significant genes compared to clinical NASH samples, and a predicted gene signature profile that supports fibrosis resolution. These findings support further investigation of this combinatorial therapy to treat obesity, insulin resistance, hypercholesterolemia, steatohepatitis, and fibrosis in people with NASH.

2023-08-09 | GSE240409 | GEO

Combination of an ACLY inhibitor with a GLP-1R agonist exerts additive benefits on NASH and hepatic fibrosis [Fibrosis panel]

2023-08-09 | GSE240406 | GEO

GIPR agonism and antagonism decrease body weight and food intake via different mechanisms of action.

Project description:Agonists and antagonists of the glucose-dependent insulinotropic polypeptide receptor (GIPR) enhance body weight loss induced by glucagon-like peptide-1 receptor (GLP-1R) agonism. But while GIPR agonism decreases body weight and food intake in a GLP-1R-independent manner via GABAergic GIPR+ neurons, it remains unclear whether GIPR antagonism affects energy metabolism via a similar mechanism. Here we show that the body weight and food intake reducing effects of GIPR antagonism vanish in mice with global loss of either Gipr or Glp-1r but are preserved in mice with loss of Gipr in either GABAergic or peripheral neurons. RNA-sequencing shows opposing effects of GIPR agonism and antagonism in the hindbrain, with antagonism, but not agonism, mimicking GLP-1R signaling, and with GIPR antagonism and GLP-1R agonism both regulating gene programs implicated in synaptic plasticity. Collectively, we show that GIPR agonism and antagonism decrease body weight via different mechanisms, with GIPR antagonism, unlike agonism, depending on functional GLP-1R signaling.

2025-03-12 | GSE288514 | GEO

GPCR signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics

Project description:G protein-coupled receptors are important drug targets that engage and activate signaling transducers in multiple cellular compartments. Delineating therapeutic signaling from signaling associated with adverse events is an important step towards rational drug design. The glucagon-like peptide-1 receptor (GLP-1R) is a validated target for the treatment of diabetes and obesity, but drugs that target this receptor are a frequent cause of adverse events. Using recently developed biosensors, we explored the ability of GLP-1R to activate 15 pathways in 4 cellular compartments and demonstrate that modifications aimed at improving the therapeutic potential of GLP-1R agonists greatly influence compound efficacy, potency and safety in a pathway- and compartment-selective manner. These findings, together with comparative structure analysis, time-lapse microscopy and phosphoproteomics, reveal unique signaling signatures for GLP-1R agonists at the level of receptor conformation, functional selectivity and location bias, thus associating signaling neighborhoods with functionally distinct cellular outcomes and clinical consequences.

2023-10-11 | PXD037472 | Pride

Effects of the glucagon-like 1 receptor agonist exendin-4 on activated gut intraepithelial lymphocytes

Project description:Gut intraepithelial lymphocytes (IELs) are one of the few immune cell populations in the body that expresses glucagon-like 1 receptors (GLP-1R). To test the potential effects of GLP-1 on gut IEL function, we performed bulk RNA-seq on gut IELs isolated from C57BL/6J mice treated with anti-CD3 and with or without exendin-4 for 3 hours.

2022-08-29 | GSE202453 | GEO

Effects of semaglutide on the gut microbiota of high-fat diet-fed mice lacking GLP-1Rs in T cells

Project description:Gut intraepithelial lymphocytes (IELs) are one of the few immune cell populations in the body that expresses glucagon-like 1 receptors (GLP-1R). To test the potential effects of GLP-1 on the gut microbiota through the gut IEL GLP-1R, we performed 16s rRNA seq on the DNA isolated from the fecal pellet of Lck-Cre; Glp1rfl/fl mice (Glp1rTcell-/-) or controls (Glp1rTcell+/+) fed a high-fat diet (HFD) for 12 weeks followed by 1 week of HFD plus semaglutide (10 ug/kg) or vehicle treatment. Fecal pellets from a group of age-matched, sex-matched control mice were included as a chow control group.

2022-08-29 | GSE202452 | GEO

GLP-1R/GCGR dual agonism dissipates hepatic steatosis to restore insulin sensitivity and rescue pancreatic β-cell function in obese mice

Project description:Early drivers of Type 2 diabetes mellitus (T2D) include ectopic fat accumulation, especially in the liver, that significantly impairs insulin sensitivity. In a T2D setting, GLP-1R/GCGR dual agonists have been shown to reduce glycaemia, body weight and hepatic steatosis. We utilized cotadutide, a well characterized GLP-1R/GCGR dual-agonist, to demonstrate improved insulin sensitivity during hyperinsulinemic euglycemic clamp following sub-chronic dosing in male, diet-induced obese mice. Phosphoproteomic analyses of insulin stimulated liver from cotadutide treated diet-induced obese (DIO) mice identified novel phosphorylation sites on key insulin signalling pathway proteins associated with improved insulin sensitivity. Cotadutide or GCGR monoagonist treatment also resulted in specific increased brown adipose tissue (BAT) insulin-stimulated glucose uptake, while GLP-1R monoagonist only showed a weak effect. BAT from cotadutide treated mice had induction of UCP-1 protein, increased mitochondrial area and a transcriptomic profile of increased fat oxidation and mitochondrial activity. Finally, the cotadutide-induced improvement in insulin sensitivity was associated with reduced insulin secretion from isolated pancreatic islet β-cells indicating reduced insulin secretory demand. Thus, GLP-1R/GCGR dual agonism provides multimodal efficacy to decrease hepatic steatosis and consequently improve insulin sensitivity, in concert with recovery of endogenous β-cell function and reduced insulin demand. This substantiates GLP-1R/GCGR dual-agonism as a novel and effective T2D treatment

2025-03-28 | PXD057744 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data