title: Naturally-occurring TGR5 agonists modulating glucagon-like peptide-1 biosynthesis and secretion.
abstract: Selective GLP-1 secretagogues represent a novel potential therapy for type 2 diabetes mellitus. This study examined the GLP-1 secretory activity of the ethnomedicinal plant, Fagonia cretica, which is postulated to possess anti-diabetic activity. After extraction and fractionation extracts and purified compounds were tested for GLP-1 and GIP secretory activity in pGIP/neo STC-1 cells. Intracellular levels of incretin hormones and their gene expression were also determined. Crude F. cretica extracts stimulated both GLP-1 and GIP secretion, increased cellular hormone content, and upregulated gene expression of proglucagon, GIP and prohormone convertase. However, ethyl acetate partitioning significantly enriched GLP-1 secretory activity and this fraction underwent bioactivity-guided fractionation. Three isolated compounds were potent and selective GLP-1 secretagogues: quinovic acid (QA) and two QA derivatives, QA-3β-O-β-D-glycopyranoside and QA-3β-O-β-D-glucopyranosyl-(28→1)-β-D-glucopyranosyl ester. All QA compounds activated the TGR5 receptor and increased intracellular incretin levels and gene expression. QA derivatives were more potent GLP-1 secretagogues than QA. This is the first time that QA and its naturally-occurring derivatives have been shown to activate TGR5 and stimulate GLP-1 secretion. These data provide a plausible mechanism for the ethnomedicinal use of F. cretica and may assist in the ongoing development of selective GLP-1 agonists.
authors.affiliation: Department of Biochemistry, Bahauddin Zakariya University, Multan, Pakistan; Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan. Electronic address: lailashah9@gmail.com.
authors.forename: Laila
authors.initials: L
authors.lastname: Jafri
authors.affiliation: University Institute of Biochemistry & Biotechnology (UIBB), PMAS-Arid Agriculture University Rawalpindi, Murree Road, Rawalpindi, Pakistan; Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan. Electronic address: samreen.qau@gmail.com.
authors.forename: Samreen
authors.initials: S
authors.lastname: Saleem
authors.affiliation: Institute for Global Food Security, School of Biological Sciences, Queens University Belfast, Stranmillis Road, Belfast BT9 5AG, Northern Ireland, UK. Electronic address: dcalderwood01@qub.ac.uk.
authors.forename: Danielle
authors.initials: D
authors.lastname: Calderwood
authors.affiliation: Institute for Global Food Security, School of Biological Sciences, Queens University Belfast, Stranmillis Road, Belfast BT9 5AG, Northern Ireland, UK. Electronic address: agillespie14@qub.ac.uk.
authors.forename: Anna
authors.initials: A
authors.lastname: Gillespie
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan. Electronic address: bushramirza@qau.edu.pk.
authors.forename: Bushra
authors.initials: B
authors.lastname: Mirza
authors.affiliation: Institute for Global Food Security, School of Biological Sciences, Queens University Belfast, Stranmillis Road, Belfast BT9 5AG, Northern Ireland, UK. Electronic address: b.green@qub.ac.uk.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Green
mesh_terms: D002460:Cell Line; D019858:Enteroendocrine Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005749:Gastric Inhibitory Polypeptide / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D052216:Glucagon-Like Peptide 1 / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D006027:Glycosides / Q000302:isolation & purification / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D054795:Incretins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D035261:Plant Components, Aerial / Q000737:chemistry; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D052336:Proglucagon / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics; D043484:Proprotein Convertases / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014315:Triterpenes / Q000302:isolation & purification / Q000494:pharmacology; D028461:Zygophyllaceae / Q000737:chemistry*
chemical_list: C473772:GPBAR1 protein, human; D006027:Glycosides; D007004:Hypoglycemic Agents; D054795:Incretins; D010936:Plant Extracts; D043562:Receptors, G-Protein-Coupled; D014315:Triterpenes; D052336:Proglucagon; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; C472605:quinovic acid; D043484:Proprotein Convertases
keywords: GIP; GLP-1; Incretin; Secretagogue; TGR5