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dc.contributor.authorO'Harte, Finbarr P. M.
dc.contributor.authorParthsarathy, Vadivel
dc.contributor.authorHogg, Christopher
dc.contributor.authorFlatt, Peter R.
dc.date.accessioned2018-08-16T13:55:30Z
dc.date.available2018-08-16T13:55:30Z
dc.date.issued2018-02-03
dc.identifier.citationO'Harte, Finbarr, Parthsarathy, Vadivel, Hogg, C and Flatt, Peter (2018) Apelin-13 analogues show potent in vitro and in vivo insulinotropic and glucose lowering actions. Peptides, 100 . pp. 219-228.
dc.identifier.issn0196-9781
dc.identifier.doi10.1016/j.peptides.2017.12.004
dc.identifier.urihttp://hdl.handle.net/10545/622904
dc.description.abstractNine structurally modified apelin-13 analogues were assessed for their in vitro and acute in vivo antidiabetic potential. Stability was assessed in mouse plasma and insulinotropic efficacy tested in cultured pancreatic BRIN-BD11 cells and isolated mouse pancreatic islets. Intracellular Ca2+ and cAMP production in BRIN-BD11 cells was determined, as was glucose uptake in 3T3-L1 adipocytes. Acute antihyperglycemic effects of apelin analogues were assessed following i.p. glucose tolerance tests (ipGGT, 18 mmol/kg) in normal and diet-induced-obese (DIO) mice and on food intake in normal mice. Apelin analogues all showed enhanced in vitro stability (up to 5.8-fold, t½ = 12.8 h) in mouse plasma compared to native apelin-13 (t½ = 2.1 h). Compared to glucose controls, stable analogues exhibited enhanced insulinotropic responses from BRIN-BD11 cells (up to 4.7-fold, p < 0.001) and isolated mouse islets (up to 5.3-fold) for 10−7 M apelin-13 amide (versus 7.6-fold for 10−7 M GLP-1). Activation of APJ receptors on BRIN-BD11 cells increased intracellular Ca2+ (up to 3.0-fold, p < 0.001) and cAMP (up to 1.7-fold, p < 0.01). Acute ipGTT showed improved insulinotropic and glucose disposal responses in normal and DIO mice (p < 0.05 and p < 0.01, respectively). Apelin-13 amide and (pGlu)apelin-13 amide were the most effective analogues exhibiting acute, dose-dependent and persistent biological actions. Both analogues stimulated insulin-independent glucose uptake by differentiated adipocytes (2.9 to –3.3-fold, p < 0.05) and inhibited food intake (26-–33%, p < 0.001), up to 180 min in mice, versus saline. In contrast, (Ala13)apelin-13 and (Val13)apelin-13 inhibited insulin secretion, suppressed beta-cell signal transduction and stimulated food intake in mice. Thus, stable analogues of apelin-13 have potential for diabetes/obesity therapy.
dc.description.sponsorshipDepartment of Employment and Learning (DEL), Proof of Principle funding from Innovation Ulster at University of Ulsteren
dc.publisherElsevier
dc.relation.urlhttp://uir.ulster.ac.uk/39187/
dc.titleApelin-13 analogues show potent in vitro and in vivo insulinotropic and glucose lowering actions
dc.typeJournal article
dc.identifier.journalPeptides
dc.subject.keywordDiabetesen
dc.subject.keywordinsulinen
dc.subject.keywordGlucose homeostasisen
html.description.abstractNine structurally modified apelin-13 analogues were assessed for their in vitro and acute in vivo antidiabetic potential. Stability was assessed in mouse plasma and insulinotropic efficacy tested in cultured pancreatic BRIN-BD11 cells and isolated mouse pancreatic islets. Intracellular Ca2+ and cAMP production in BRIN-BD11 cells was determined, as was glucose uptake in 3T3-L1 adipocytes. Acute antihyperglycemic effects of apelin analogues were assessed following i.p. glucose tolerance tests (ipGGT, 18 mmol/kg) in normal and diet-induced-obese (DIO) mice and on food intake in normal mice. Apelin analogues all showed enhanced in vitro stability (up to 5.8-fold, t½ = 12.8 h) in mouse plasma compared to native apelin-13 (t½ = 2.1 h). Compared to glucose controls, stable analogues exhibited enhanced insulinotropic responses from BRIN-BD11 cells (up to 4.7-fold, p < 0.001) and isolated mouse islets (up to 5.3-fold) for 10−7 M apelin-13 amide (versus 7.6-fold for 10−7 M GLP-1). Activation of APJ receptors on BRIN-BD11 cells increased intracellular Ca2+ (up to 3.0-fold, p < 0.001) and cAMP (up to 1.7-fold, p < 0.01). Acute ipGTT showed improved insulinotropic and glucose disposal responses in normal and DIO mice (p < 0.05 and p < 0.01, respectively). Apelin-13 amide and (pGlu)apelin-13 amide were the most effective analogues exhibiting acute, dose-dependent and persistent biological actions. Both analogues stimulated insulin-independent glucose uptake by differentiated adipocytes (2.9 to –3.3-fold, p < 0.05) and inhibited food intake (26-–33%, p < 0.001), up to 180 min in mice, versus saline. In contrast, (Ala13)apelin-13 and (Val13)apelin-13 inhibited insulin secretion, suppressed beta-cell signal transduction and stimulated food intake in mice. Thus, stable analogues of apelin-13 have potential for diabetes/obesity therapy.


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