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  • br Acknowledgements This work was supported by a fellowship

    2022-01-17


    Acknowledgements This work was supported by a fellowship to C.H. under the ‘100 Foreign Expert’ scheme of the Shanxi province government(R100456). Conflict of interest: Dr. Holscher is a named inventor on a patent submitted by Lancaster University on the use of dual GLP-1/GIP analogues in neurodegenerative. The other authors do not declare a conflict of interest.
    Introduction Glucose-dependent insulinotropic polypeptide (GIP) is a member of an extended family of structurally related regulatory peptides that includes glucagon, glucagon-like peptide-1(GLP-1), glucagon-like peptide-2, secretin, vasoactive monohydrochloride australia intestinal polypeptide, peptide histidine methionine, pituitary adenylate cyclase-activating peptide, and growth hormone-releasing hormone [1]. In addition, a gene encoding glucagon-related peptide with structural similarity to the Gila monster venom peptides, exendin-3 and -4 is present in the genomes of a range of tetrapod taxa but is absent from zebrafish and mammals [2], [3]. The peptides are related evolutionarily having arisen from an ancestral gene either by tandem duplications or as a result of ancient whole genome duplications (2R hypothesis) [4], [5]. The physiological effects of these peptides are mediated largely by interaction with a family of structurally and evolutionarily related class B (secretin–like) G-protein coupled receptors [6]. GIP was first isolated from a porcine intestinal extract as a 42-amino-acid peptide on the basis of its ability to inhibit gastric monohydrochloride australia production at supraphysiological concentrations [7]. Subsequently, the gene encoding the peptide has been identified in a range of mammalian species (reviewed in [1]), chicken [8], the frogs Xenopus tropicalis and Xenopus laevis [8], and in a teleost, the zebrafish Danio rerio [8]. A gene encoding a GIP-like sequence is present in the genome of the sea lamprey Petromyzon marinus but transcripts were not detected [9]. Similarly, a GIP-like molecule has not yet been identified in an elasmobranch but it is of interest that a mammalian GIP is a potent stimulant of cAMP production and chloride secretion in the rectal gland of the skate Leucoraja erinacea [10]. The predicted primary structure of zebrafish GIP (zfGIP) is only 31 amino acid residues and it has been speculated that the peptide is more similar to the ancestral gene product from which the glucagon family of peptides has arisen than are mammalian GIP peptides [9]. GIP is described as an incretin hormone in mammals owing to its ability to promote insulin release from pancreatic β-cells at physiologically relevant concentrations. GIP is released into the circulation from intestinal enteroendocrine K- cells in response to ingestion of nutrients and, along with GLP-1, is the major physiologic incretin in the human [11]. Recent research has indicated that functionally relevant GIP is also present in the pancreatic islet cells of mice [12]. In the zebrafish, RT-PCR and immunohistocemical studies have demonstrated that GIP expression in the intestine is restricted to cells located near the base of the vill and the peptide is located principally in endocrine cells of the pancreas [13]. This has led investigators to speculate that GIP may not function as an incretin in this species [13]. No gene that closely resembles the human GLP-1R gene has been found in the genomes of the zebrafish or other bony fish [6] and the fact that GLP-1 does not function as an incretin hormone in teleosts, rather as a glucagon-like stimulant of glycogenolysis and gluconeogenesis, is well established [14]. The aim of the present study was to assess whether synthetic zfGIP shows potential for development into a therapeutic agent for treatment of patients with Type 2 diabetes mellitus (T2DM) by investigating its insulinotropic properties in vitro using established insulin-producing cell lines and in vivo using NIH Swiss mice. The possibility that zfGIP may function as a dual- or triple agonist in a mammalian system was investigated using selective antagonists for GIP, GLP-1, and glucagon receptors and by using cells transfected with the human glucagon receptor (CGCR) and the GLP-1 (GLP-1R) receptor and CRISPR/Cas9-engineered INS-1 cells from which the GIPR and GLP-1R had been deleted.