Quercetin/oleic acid-based G-protein-coupled receptor 40 ligands as new insulin secretion modulators
Abstract
Aim: Management of Type 2 diabetes mellitus by diet is achievable at the early stage of the disease; patients usually underestimate this approach and an appropriate drug therapy is required. Results: Starting from quercetin and oleic acid, that have effect on insulin secretion, a small set of hybrid molecules was synthesized. Insulin secretion was evaluated in both in vitro and ex vivo models. AV1 was able to enhance insulin secretion dose dependently, behaving as a conceivable agonist of G-protein-coupled receptor 40. Conclusion: AV1 represents an interesting tool that interacts with G-protein-coupled receptor 40. Further studies will be carried out to evaluate the exact binding mode, and also to enlarge the library of these antidiabetic agents.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 9-cis retinoic acid modulates myotrophin expression and its miR in physiological and pathophysiological cell models. Exp. Cell. Res. 354(1), 25–30 (2017).
- 2 . Pancreatic β-cell identity, glucose sensing and the control of insulin secretion. Biochem. J. 466(2), 203–218 (2015).
- 3 . Pancreatic regulation of glucose homeostasis. Exp. Mol. Med. 48(3), e219 (2016).
- 4 A European evidence-based guideline for the prevention of Type 2 diabetes. Horm. Metab. Res. 42(1), S3–S36 (2010).
- 5 Clinical practice guideline for the prevention, early detection, diagnosis, management and follow-up of Type 2 diabetes mellitus in adults. Colomb. Med. (Cali.) 47(2), 109–131 (2016).
- 6 . Severity of gastrointestinal side effects of metformin tablet compared to metformin capsule in Type 2 diabetes mellitus patients. J. Res. Pharm. Pract. 6(2), 73–76 (2017).
- 7 . Generalized intense pruritus during canagliflozin treatment: is it an adverse drug reaction? Curr. Drug Saf.
doi:10.2174/1574886311666160405110515 (2016) (Epub ahead of print). - 8 Clinical review of antidiabetic drugs: implications for Type 2 diabetes mellitus management. Front. Endocrinol. 8, 6 (2017). • Describes Type 2 diabetes mellitus and its therapies.
- 9 . An insight into anti-diabetic properties of dietary phytochemicals. Phytochem. Rev. 16(3), 535–553 (2017).
- 10 . Quercetin and derivatives: useful tools in inflammation and pain management. Future Med. Chem. 9(1), 79–93 (2017).
- 11 . Quercetin: a flavonol with multifaceted therapeutic applications? Fitoterapia 106, 256–271 (2015).
- 12 . Antidiabetic properties of dietary flavonoids: a cellular mechanism review. Nutr. Metab. 12, 60 (2015).
- 13 . Quercetin content in some food and herbal samples. Food Chem. 100(2), 699–704 (2007). •• Quercetin in diabetes: various relevant data.
- 14 . Quercetin in anti-diabetic research and strategies for improved quercetin bioavailability using polymer-based carriers – a review. RSC Adv. 5, 97547–97562 (2015).
- 15 Effect of lipase inhibition on gastric emptying of, and the glycemic and incretin responses to, an oil/aqueous drink in Type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 88(8), 3829–3834 (2003).
- 16 . Mediterranean diet rich in olive oil and obesity, metabolic syndrome and diabetes mellitus. Curr. Pharm. Des. 17(8), 769–777 (2011).
- 17 . Olive oil composition. In: Olive Oil Chemistry and Technology (2nd Edition). Boskou D (Ed.). Elsevier: Academic Press and AOCS Press, Amsterdam, the Netherlands, 282 (2006).
- 18 . Oleic acid modulates metabolic substrate channeling during glucose-stimulated insulin secretion via NAD(P)H oxidase. Endocrinology 152(10), 3614–3621 (2011).
- 19 G protein-coupled receptor (GPR)40-dependent potentiation of insulin secretion in mouse islets is mediated by protein kinase D1. Diabetologia 55(10), 2682–2692 (2012).
- 20 . Evaluation of the insulin releasing and antihyperglycaemic activities of GPR55 lipid agonists using clonal beta-cells, isolated pancreatic islets and mice. Br. J. Pharmacol. 170(5), 978–990 (2013).
- 21 The novel chemokine receptor, G-protein-coupled receptor 75, is expressed by islets and is coupled to stimulation of insulin secretion and improved glucose homeostasis. Diabetologia 56(11), 2467–2476 (2013).
- 22 . Emerging roles of GPER in diabetes and atherosclerosis. Trends Endocrinol. Metab. 26(4), 185–192 (2015).
- 23 Estrogen receptor activation reduces lipid synthesis in pancreatic islets and prevents β-cell failure in rodent models of Type 2 diabetes. J. Clin. Invest. 121(8), 3331–3342 (2011).
- 24 Identification of breast cancer inhibitors specific for G protein-coupled estrogen receptor (GPER)-expressing cells. ChemMedChem 12, 1–8 (2017).
- 25 Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature 422, 173–176 (2003). •• Fatty acids and G protein-coupled receptors (GPRs): an insight into diabetes.
- 26 . Free fatty acids increase cytosolic free calcium and stimulate insulin secretion from β cells through activation of GPR40. Mol. Cell. Endocrinol. 263, 173–180 (2007).
- 27 . The effects of TAK-875, a selective G protein-coupled receptor 40/free fatty acid 1 agonist, on insulin and glucagon secretion in isolated rat and human islets. J. Pharmacol. Exp. Ther. 340, 483–489 (2012).
- 28 . GPR40-induced insulin secretion by the novel agonist TAK-875: first clinical findings in patients with Type 2 diabetes. Diabetes Obes. Metab. 14, 271–278 (2012).
- 29 High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875. Nature 513, 124–127 (2014).
- 30 . GPR40 agonists for the treatment of Type 2 diabetes mellitus: The biological characteristics and the chemical space. Bioorg. Med. Chem. Lett. 26(23), 5603–5612 (2016).
- 31 . Long Y discovery of potent and orally bioavailable GPR40 full agonists bearing thiophen-2-ylpropanoic acid scaffold. J. Med. Chem. 60, 2697–2717 (2017).
- 32 Discovery of pyrrolidine-containing GPR40 agonists: stereochemistry effects a change in binding mode. J. Med. Chem. 60, 1417–1431 (2017).
- 33 Design, synthesis and structure–activity relationship studies of novel free fatty acid receptor 1 agonists bearing amide linker. Bioorg. Med. Chem. 25, 2445–2450 (2017).
- 34 Free fatty acid receptor 1 (GPR40) agonists containing spirocyclic periphery inspired by LY2881835. Bioorg. Med. Chem. 24, 5481–5494 (2016).
- 35 Novel free fatty acid receptor 1 (GPR40) agonists based on 1,3,4-thiadiazole-2-carboxamide scaffold. Bioorg. Med. Chem. 24, 2954–2963 (2016).
- 36 . Recent developments in the discovery of FFA1 receptor agonists as novel oral treatment for type 2 diabetes mellitus. Bioorg. Med. Chem. Lett. 24, 2991–3000 (2014).
- 37 . Characterizing pharmacological ligands to study the long-chain fatty acid receptors GPR40/FFA1 and GPR120/FFA4. Br. J. Pharmacol. 172, 3254–3265 (2015).
- 38 . Treatment of Type 2 diabetes by free fatty acid receptor agonists. Front. Endocrinol. 5, 137 (2014). •• TAK-875 and other GPR40 synthetic ligands.
- 39 Identification and pharmacological characterization of multiple allosteric binding sites on the free fatty acid 1 receptor. J. Mol. Pharm. 82, 843–859 (2012).
- 40 Activity of dietary fatty acids on FFA1 and FFA4 and characterisation of pinolenic acid as a dual FFA1/FFA4 agonist with potential effect against metabolic diseases. Br. J. Nutr. 113, 1677–1688 (2015).
- 41 . Free fatty acid receptors: structural models and elucidation of ligand binding interactions. BMC Struct. Biol. 15, 16 (2015).
- 42 . Oleic acid interacts with GPR40 to induce Ca2+ signaling in rat islet β cells: mediation by PLC and L-type Ca2+ channel and link to insulin release. Am. J. Physiol. Endocrinol. Metab. 289(4), E670–E677 (2005). •• GPR40 flat structure–activity relationships.
- 43 . Lipotoxicity in obesity: benefit of olive oil. In: Obesity and Lipotoxicity, Advances in Experimental Medicine and Biology 960. Engin AB, Engin A (Eds.), Springer International Publishing AG, Gewerbestrasse, Switzerland (2017).
- 44 Quercetin potentiates insulin secretion and protects INS-1 pancreatic β cells against oxidative damage via the ERK1/2 pathway. Br. J. Pharmacol. 161, 799–814 (2010). •• Oleic acid: why do we use it?
- 45 . Enhanced stability and intracellular accumulation of quercetin by protection of the chemically or metabolically susceptible hydroxyl groups with a pivaloxymethyl (POM) promoiety. J. Med. Chem. 53, 8597–8607 (2010).
- 46 . Electrochemical degradation of quercetin: isolation and structural elucidation of the degradation products. Electrochem. Commun. 9, 2246–2255 (2007).
- 47 . A DFT study of the reactivity of OH groups in quercetin and taxifolin antioxidants: the specificity of the 3-OH site. Food Chem. 97, 679–688 (2006).
- 48 ‘In vitro’ antioxidant and photoprotective properties and interaction with model membranes of three new quercetin esters. Eur. J. Pharm. Biopharm. 56, 167–174 (2003).
- 49 . Isolation of INS-1-derived cell lines with robust ATP-sensitive K+ channel-dependent and -independent glucose-stimulated insulin secretion. Diabetes 49(3), 424–430 (2000).
- 50 . Evaluation of the INS-1 832/13 cell line as a beta-cell based screening system to assess pollutant effects on beta-cell function. PLoS ONE 8(3), e60030 (2013).
- 51 Identification of 9-cis-retinoic acid as a pancreas-specific autacoid that attenuates glucose-stimulated insulin secretion. Proc. Natl Acad. Sci. USA 107(50), 21884–21889 (2010). •• Limitations of quercetin and valorization of our hybrid molecule.
- 52 . An efficient partial synthesis of 4′-O-methylquercetin via regioselective protection and alkylation of quercetin. Beilstein J. Org. Chem. 5, 60 (2009).
- 53 Schrödinger, LLC, www.schrodinger.com
- 54 . Beta cell mass and growth after syngeneic islet cell transplantation in normal and streptozocin diabetic C57BL/6 mice. J. Clin. Invest. 91, 780 (1993).
- 55 Synthesis, molecular characterization and preliminary antioxidant activity evaluation of quercetin fatty esters. J. Am. Oil. Chem. Soc. 90, 1751–1759 (2013). • Chemical synthesis and biological methods.
- 56 . Fatty acids, lipotoxicity and insulin secretion. Diabetologia 42, 128–138 (1999).
- 57 Quercetin induces insulin secretion by direct activation of L-type calcium channels in pancreatic beta cells. Br. J. Pharmacol. 169, 1102–1113 (2013).
- 58 . Mechanisms of oleic acid deterioration in insulin secretion: role in the pathogenesis of Type 2 diabetes. Life Sci. 77(17), 2071–2081 (2005).
- 59 . Ester-based precursors to increase the bioavailability of quercetin. J. Med. Chem. 50, 241–253 (2007).
- 60 . Metabolism and pharmacokinetics of 3,3′,4′,7-tetrahydroxyflavone (fisetin), 5-hydroxyflavone, and 7-hydroxyflavone and antihemolysis effects of fisetin and its serum metabolites. J. Agric. Food Chem. 57, 83–89 (2009).
- 61 Simultaneous action of the flavonoid quercetin on cytochrome P450 (CYP) 1A2, CYP2A6, N-acetyltransferase and xanthine oxidase activity in healthy volunteers. Clin. Exp. Pharmacol. Physiol. 36(8), 828–833 (2009). • About metabolism of quercetin.