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UBC Theses and Dissertations

Marine invertebrate and bacterial extract library screens for novel modulators of the glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors Merchant, Catherine


Type 2 diabetes is often associated with obesity and is characterized by high blood-glucose levels due to inadequate insulin secretion and/or action. One current treatment for type 2 diabetes and the associated obesity involves multiple daily injections of a peptide-drug targeting the glucagon-like peptide-1 receptor (GLP-1R). GLP-1R activation stimulates glucose-dependent insulin secretion from β-cells, inhibits glucose-dependent glucagon (GCG) secretion from α-cells, slows gastric emptying and suppresses appetite, which normalizes blood-glucose levels and causes weight loss. Another hormone involved in glucose and fat metabolism, glucose-dependent insulinotropic polypeptide (GIP), stimulates glucose-dependent insulin secretion from β-cells and the storage of fat in adipocytes. As such, both GIP receptor (GIPR) agonists and antagonists have been demonstrated to display therapeutic potential to treat diabetes and obesity. However, glucagon-like peptide-1 (GLP-1) and GIP based treatments could be improved if oral drugs were discovered to replace the current injectable medications. In order to discover novel molecules that mimic these effects, we have screened marine invertebrate and bacterial extract compounds, as they generally contain functionally diverse and biologically active small molecules and are a source of many new drugs. A cell-based bioassay capable of measuring GLP-1R or GIPR activity via a luciferase reporter system was used to screen these compounds for receptor activity. Over 2000 compounds were screened in each of four separate bioassays (GLP-1R agonist screen, GLP-1R allosteric modulator screen, GIPR agonist screen and GIPR allosteric modulator/antagonist screen). These screens resulted in the identification of a GIPR antagonist, halistanol sulphate. Halistanol sulphate was demonstrated to be a selective antagonist of the GIPR as it concentration-dependently decreased activity in the GIP bioassay in the presence of GIP, but not in the absence of GIP or in the presence of GLP-1 in the GLP-1 bioassay. In addition, halistanol sulphate was shown to concentration-dependently block 125I-GIP binding to the GIPR, but only block 125I-GLP-1 and 125I-glucagon binding to their respective receptors at very high concentrations. Finally, halistanol sulphate also demonstrated the ability to modulate incretin induced insulin secretion from perifused mouse islets. Thus, halistanol sulphate displays potent antagonistic activity towards the GIPR in vitro, but still requires in vivo characterization.

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