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Age-dependent human β cell proliferation induced by GLP-1 and calcineurin signaling

ABSTRACT: We developed an engraftment strategy to examine age-associated human islet cell replication and found that Ex-4, an agonist of GLP-1R, stimulates human β cell proliferation in juvenile, but not adult islets. We showed that this β cell proliferative response to Ex-4 requires Cn/NFAT signaling.

OTHER RELATED OMICS DATASETS IN: PRJNA392445

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE100660 | GEO | 2017/10/18

SECONDARY ACCESSION(S): PRJNA392445

REPOSITORIES: GEO

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

Project description: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.

2020-12-24 | GSE163744 | GEO

Effects of exendin-4 in Brunner's glands of male GLP-1R-/- and wild-type control mice

Project description:To gain insight into the biological functions of the highly expressed GLP-1R in Brunnerâs glands, transcriptome analyses were conducted in male GLP-1R-/- and wild-type control mice. Analyses were performed 6 hours after a single s.c. dose of exendin-4 (1.0mg/kg s.c.), following 18 hours of two doses of exendin-4 (1.0 mg/kg s.c., administered at 0 and 9 hours), and in untreated controls. Brunnerâs glands were isolated by laser capture micro dissection and extracted total RNA was used for microarray profiling. A total of 18 samples consisting of laser captured microdissected Brunner's glands from individual male GLP-1R-/- and wild-type (CD-1) mice. Before the isolation of Brunner's glands, mice were dosed with exendin-4 for 6 and 18 hours. The extracted total RNA from Brunner's glands were compared by full transcriptome profiling.

2016-07-01 | E-GEOD-80119 | biostudies-arrayexpress

Effects of exendin-4 in Brunner's glands of male GLP-1R-/- and wild-type control mice

Project description:To gain insight into the biological functions of the highly expressed GLP-1R in Brunner’s glands, transcriptome analyses were conducted in male GLP-1R-/- and wild-type control mice. Analyses were performed 6 hours after a single s.c. dose of exendin-4 (1.0mg/kg s.c.), following 18 hours of two doses of exendin-4 (1.0 mg/kg s.c., administered at 0 and 9 hours), and in untreated controls. Brunner’s glands were isolated by laser capture micro dissection and extracted total RNA was used for microarray profiling.

2016-07-01 | GSE80119 | GEO

Behavioural and neurochemical mechanisms underpinning the synergistic feeding-suppressive effect of GLP-1/CCK combinatorial therapy

Project description:Combinatorial therapies are under intense investigation for the development of more efficient anti-obesity drugs, however little is known about how they act in brain to produce enhanced satiety and weight loss. Here we used a multidisciplinary strategy to decipher the central mechanisms engaged downstream from the co-administration of GLP-1R and CCK1R agonists, an efficient combination therapy in obese rodents. The nucleus of the solitary tract (NTS) contained one of the few neuronal populations synergistically activated in response to GLP-1R and CCK1R co-agonism. None of the previously categorized NTS neuronal subpopulations relevant to feeding behaviour were synergistically activated. However, using PhosphoTRAP, we obtained the molecular signature of NTS and ARH neurons synergistically regulated by the GLP-1R and CCK1R co-agonism and identified NTS/AP Calcrl+ neurons and ARH Adcyap1r1+ neurons as targets of this treatment. Collectively these studies advance our understanding of the central mechanisms involved in the synergistic appetite- and weight-suppressive effect of a combinatorial therapy.

2019-08-16 | GSE135862 | 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

Microarray was used to detect the expression of lncRNAs and mRNAs in INS-1 cells treated with GLP-1RA Geniposide for 24 hours.

Project description:Studies have shown that long noncoding RNAs (lncRNAs) can be widely involved in various physiological and pathological processes. In recent years, there have been many studies on GLP-1 receptor agonists (GLP-1RA) regulating islet β cells function and mass of type 2 diabetes (T2DM) patients. However, the function of lncRNAs in this process have not been fully elucidated. In this study, lncRNA microarray was used to identify the differently expressed (DE) lncRNAs and mRNAs in β cells exposed to Geniposide, which is a GLP-1RA. 308 lncRNAs and 128 mRNAs were detected with a set filter fold change≥1.5 and P-value<0.05. Gene Ontology and KEGG pathway analysis were performed to assess the underlying functions of DE mRNAs. Co-expression network of DE lncRNAs and mRNAs was constructed based on Pearson coefficient of expression level. And hub mRNAs were selected through String database and Cytoscape plugin Cytohubba. Additionally, a ceRNA network was constructed among the co-expressed lncRNAs and hub mRNAs. This study reveals key mRNAs involved in the regulation of GLP-1RA on β cells function and mass. More importantly, screening out lncRNAs that play an importance regulatory role in this process. This original research could provide valuable information for the further investigation between lncRNAs and GLP-AR in the protection of β cells.

2020-10-06 | GSE138744 | GEO

Biased agonism and signal transduction mediated by β-arrestin1/2 at the glucagon-like peptide 1 receptor

Project description:proteomics profiling was conducted in GLP-1R stable cell line upon ligands stimulation with or without β-arrestin1/2 overexpression.

2023-02-18 | PXD040259 | iProX

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

Age-dependent human β cell proliferation induced by GLP-1 and calcineurin signaling

Project description:Age-dependent human β cell proliferation induced by GLP-1 and calcineurin signaling

| PRJNA392445 | ENA

VGF-derived peptide attenuates development of type 2 diabetes via enhancement of islet beta cell survival and function survival and function

Project description:Deterioration of functional islet β-cell mass is the final step in progression to Type 2 diabetes. We previously reported that overexpression of Nkx6.1 in rat islets has the dual effects of enhancing glucose-stimulated insulin secretion (GSIS) and increasing β-cell replication. Here we show that Nkx6.1 strongly upregulates the prohormone VGF in rat islets and that VGF is both necessary and sufficient for Nkx6.1-mediated enhancement of GSIS. Moreover, the VGF-derived peptide TLQP-21 potentiates GSIS in rat and human islets and improves glucose tolerance in vivo. Chronic injection of TLQP-21 in pre-diabetic ZDF rats preserves islet mass and slows diabetes onset. TLQP-21 prevents islet cell apoptosis by a pathway similar to that used by GLP-1, but independent of the GLP-1, GIP, or VIP receptors. Unlike GLP-1, TLQP-21 does not inhibit gastric emptying or increase heart rate. We conclude that a TLQP-21 is a novel agent for enhancing islet β-cell survival and function.

2012-05-10 | GSE37852 | GEO

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