دورية أكاديمية
أعرض في EDS

CRISPR/Cas9 gene editing demonstrates metabolic importance of GPR55 in the modulation of GIP release and pancreatic beta cell function.

التفاصيل البيبلوغرافية
العنوان: CRISPR/Cas9 gene editing demonstrates metabolic importance of GPR55 in the modulation of GIP release and pancreatic beta cell function.
المؤلفون: McCloskey AG; School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland., Miskelly MG; School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland., Moore CBT; School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland., Nesbit MA; School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland., Christie KA; Center for Genomic Medicine, Massachusetts General Hospital & Harvard Medical School, 185 Cambridge St. Boston, MA 02115, USA., Owolabi AI; School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland., Flatt PR; School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland., McKillop AM; School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland. Electronic address: am.mckillop@ulster.ac.uk.
المصدر: Peptides [Peptides] 2020 Mar; Vol. 125, pp. 170251. Date of Electronic Publication: 2020 Jan 07.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Elsevier Science Inc Country of Publication: United States NLM ID: 8008690 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-5169 (Electronic) Linking ISSN: 01969781 NLM ISO Abbreviation: Peptides Subsets: MEDLINE
أسماء مطبوعة: Publication: New York, NY : Elsevier Science Inc.
Original Publication: Fayetteville, N. Y., Ankho International.
مواضيع طبية MeSH: Diabetes Mellitus, Experimental/*metabolism , Gastric Inhibitory Polypeptide/*metabolism , Gene Editing/*methods , Glucagon-Like Peptide 1/*metabolism , Insulin-Secreting Cells/*metabolism , Receptors, Cannabinoid/*metabolism, Animals ; CRISPR-Cas Systems ; Cell Line ; Diabetes Mellitus, Experimental/genetics ; Diabetes Mellitus, Experimental/physiopathology ; Disease Models, Animal ; Humans ; Male ; Mice ; Receptors, Cannabinoid/chemistry ; Receptors, Cannabinoid/genetics
مستخلص: G-protein coupled receptor-55 (GPR55), an endocannabinoid receptor, is a novel anti-diabetic target. This study aimed to assess the metabolic functionality of GPR55 ligands using CRISPR/Cas9 gene editing to determine their regulatory role in beta cell function and incretin-secreting enteroendocrine cells. A clonal Gpr55 knockout beta cell line was generated by CRISPR/Cas9 gene editing to investigate insulin secretion and Gpr55 signalling. Acute effects of GPR55 agonists were investigated in high fat fed (HFD) diabetic HsdOla:TO (Swiss TO) mice. Atypical and endogenous endocannabinoid ligands (10 -7 -10 -4 M) stimulated insulin secretion (p < 0.05-0.001) in rodent (BRIN-BD11) and human (1.1B4) beta cells, with 2-2.7-fold (p < 0.001) increase demonstrated in BRIN-BD11 cells (10 -4 M). The insulinotropic effect of Abn-CBD (42 %), AM251 (30 %) and PEA (53 %) were impaired (p < 0.05) in Gpr55 knockout BRIN-BD11 cells, with the secretory effect of O-1602 completely abolished (p < 0.001). Gpr55 ablation abolished the release of intracellular Ca 2+ upon treatment with O-1602, Abn-CBD and PEA. Upregulation of insulin mRNA by Abn-CBD and AM251 (1.7-3-fold; p < 0.01) was greatly diminished (p < 0.001) in Gpr55 null cells. Orally administered Abn-CBD and AM251 (0.1 μmol/kgBW) improved GIP (p < 0.05-p < 0.01), GLP-1 (p < 0.05-p < 0.001), glucose tolerance (p < 0.001) and circulating insulin (p < 0.05-p < 0.001) in HFD diabetic mice. Abn-CBD in combination therapy with DPP-IV inhibitor (Sitagliptin) resulted in greater improvement in glucose tolerance (p < 0.05) and insulin release (p < 0.05). Antagonism of Gpr55 in-vivo attenuated the glucoregulatory effects of Abn-CBD (p < 0.05). Conclusively, GPR55 agonists enhance insulin, GIP and GLP-1 release, thereby promoting GPR55 agonist monotherapy and combinational therapy as a novel approach for the treatment of type-2-diabetes.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
فهرسة مساهمة: Keywords: CRISPR/Cas9; Cannabinoid; GIP; GLP-1; GPR55; Insulin
المشرفين على المادة: 0 (GPR55 protein, mouse)
0 (Receptors, Cannabinoid)
59392-49-3 (Gastric Inhibitory Polypeptide)
89750-14-1 (Glucagon-Like Peptide 1)
تواريخ الأحداث: Date Created: 20200111 Date Completed: 20210208 Latest Revision: 20210208
رمز التحديث: 20240628
DOI: 10.1016/j.peptides.2019.170251
PMID: 31923454
قاعدة البيانات: MEDLINE
الوصف
تدمد:1873-5169
DOI:10.1016/j.peptides.2019.170251