GPR43: An emerging target for the potential treatment of type 2 diabetes, obesity and insulin resistance

Current Opinion in Investigational Drugs

Volumn 11, Issue 4, 2010, Pages 385-393

  Tiwari, Atul ^a  

^a JUBILANT BIOSYS LTD   (India)

Author keywords

Adipose tissue; Free fatty acid receptor; GPCR; GPR43; Insulin resistance; Metabolic syndrome; Obesity; Short chain fatty acid; Type 2 diabetes

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; ALPHA GLUCOSIDASE INHIBITOR; ANTIDIABETIC AGENT; ANTIOBESITY AGENT; CANNABINOID 1 RECEPTOR ANTAGONIST; ESN 282; EXENDIN 4; FIBRIC ACID DERIVATIVE; G PROTEIN COUPLED RECEPTOR; G PROTEIN COUPLED RECEPTOR GPR43; GLUCAGON LIKE PEPTIDE 1; GPR109A AGONIST; GPR43 AGONIST; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; INSULIN; MEGLITINIDE; METFORMIN; NICOTINIC ACID; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA AGONIST; RIMONABANT; ROSIGLITAZONE; SULFONYLUREA; UNCLASSIFIED DRUG;

ANXIETY; DEPRESSION; DOSE RESPONSE; DRUG MECHANISM; DRUG SAFETY; DRUG TARGETING; DRUG TOLERABILITY; DYSLIPIDEMIA; FATTY ACID METABOLISM; FLUSHING; GASTROINTESTINAL SYMPTOM; GLUCOSE HOMEOSTASIS; HUMAN; HYPOGLYCEMIA; INSULIN RESISTANCE; LIPID METABOLISM; METABOLIC SYNDROME X; MOOD DISORDER; MUSCLE DISEASE; NAUSEA; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PANCREATITIS; PATHOPHYSIOLOGY; PROTEIN EXPRESSION; REVIEW; SIDE EFFECT; WEIGHT GAIN;

ANIMALS; DIABETES MELLITUS, TYPE 2; INSULIN RESISTANCE; OBESITY; RISK;

EID: 77950120729     PISSN: 14724472     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (65)

1. The IDF consensus worldwide definition of the metabolic syndrome: International Diabetes Federation, Brussels, Belgium (2006). www.idf.org/webdata/docs/IDF-Meta-def-final.pdf
2. Dunstan DW, Zimmet PZ, Welborn TA, De Courten MP, Cameron AJ, Sicree RA, Dwyer T, Colagiuri S, Jolley D, Knuiman M, Atkins R et al: The rising prevalence of diabetes and impaired glucose tolerance: The Australian Diabetes, Obesity and Lifestyle Study. Diabetes Care (2002) 25(5):829-834.
3. Isomaa B, Almgren P, Tuomi T, Forsén B, Lahti K, Nissén M, Taskinen MR, Groop L: Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care (2001) 24(4):683-689.
4. Stern M, Williams K, González-Villalpando C, Kunt KJ, Haffner SM: Does the metabolic syndrome improve identification of individuals at risk of type 2 diabetes and/or cardiovascular disease? Diabetes Care (2004) 27(11):2676-2681.
5. Narayan KMV, Boyle JP, Thompson TJ, Sorenson SW, Williamson DF: Lifetime risk for diabetes mellitus in the United States. JAMA (2003) 290(14):1884-1890.
6. Sawzdargo M, George SR, Nguyen T, Xu S, Kolakowski LF, O'Dowd BF: A cluster of four novel human G protein-coupled receptor genes occurring in close proximity to CD22 gene on chromosome 19q13.1. Biochem Biophys Res Commun (1997) 239(2):543-547.
7. Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, Daniels D, Muir AI, Wigglesworth MJ, Kinghorn I, Fraser NJ, Pike NB et al: The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem (2003) 278(13):11312-11319
8. Le Poul E, Loison C, Struyf S, Springael JY, Lannoy V, Decobecq ME, Brezillon S, Dupriez V, Vassart G, Van Damme J, Parmentier M et al: Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J Biol Chem (2003) 278(28):25481-25489.
9. Yonezawa T, Kobayashi Y, Obara Y: Short-chain fatty acids induce acute phosphorylation of the p38 mitogen-activated protein kinase/heat shock protein 27 pathway via GPR43 in the MCF-7 human breast cancer cell line. Cell Signal (2007) 19(1):185-193.
10. Nilsson NE, Kotarsky K, Owman C, Olde B: Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids. Biochem Biophys Res Commun (2003) 303(4):1047-1052
11. Euroscreen SA, Le Poul E, Detheux M, Brezillion S, Lannoy V, Parmentier M: Ligand for G-protein coupled receptor GPR43 and uses thereof. US-20080286806 (2008).
12. Hong YH, Nishimura Y, Hishikawa D, Tsuzuki H, Miyahara H, Gotoh C, Choi KC, Feng DD, Chen C, Lee HG, Katoh K et al: Acetate and propionate short chain fatty acids stimulate adipogenesis via GPCR43. Endocrinology (2005) 146(12): 5092-5099.
13. Reaven GM, Hollenbeck C, Jeng CY, Wu MS, Chen YD: Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 h in patients with NIDDM. Diabetes (1998) 37(8):1020-1024.
14. Paolisso G, Tataranni PA, Foley JE, Bogardus C, Howard BV, Ravussin E: A high concentration of fasting plasma nonesterified fatty acids is a risk factor for the development of NIDDM. Diabetologia (1995) 38(10):1213-1217.
15. Ge H, Li X, Weiszmann J, Wang P, Baribault H, Chen JL, Tian H, Li Y: Activation of G protein-coupled receptor 43 in adipocytes leads to inhibition of lipolysis and suppression of plasma free fatty acids. Endocrinology (2008) 149(9):4519-4526.
16. Lewis GF, Carpentier A, Adeli K, Giacca A: Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev (2002) 23(2):201-229.
17. Seip M, Trygstad O: Generalized lipodystrophy, congenital and acquired (lipoatrophy). Acta Paediatr Suppl (1996) 413:2-28.
18. Kim S, Huang LW, Snow KJ, Ablamunits V, Hasham MG, Young TH, Paulk AC, Richardson JE, Affourtit JP, Barak TS, Bult CJ et al: A mouse model of conditional lipodystrophy. Proc Natl Acad Sci USA (2007) 104(42):16627-16632.
19. Shimomura I, Hammer RE, Richardson JA, Ikemoto S, Bashmakov Y, Goldstein JL, Brown MS: Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP- 1c in adipose tissue: Model for congenital generalized lipodystrophy. Gene Dev (1998) 12(20):3182-3194.
20. Bays H, Mandarino L, DeFronzo RA: Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: Peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. J Clin Endocrinol Metab (2004) 89(2):463-478.
21. Savage DB, Tan GD, Acerini CL, Jebb SA, Agostini M, Gurnell M, Williams RL, Umpleby AM, Thomas EL, Bell JD, Dixon AK et al: Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-γ. Diabetes (2003) 52(4):910-917.
22. Haemmerle G, Zimmermann R, Hayn M, Theussl C, Waeg G, Wagner E, Sattler W, Magin TM, Wagner EF, Zechner R: Hormonesensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle and testis. J Biol Chem (2002) 277(7):4806-4815.
23. Wise A, Foord SM, Fraser NJ, Barnes AA, Elshourbagy N, Eilert M, Ignar DM, Murdock PR, Steplewski K, Green A, Brown AJ et al: Molecular identification of high and low affinity receptors for nicotinic acid. J Biol Chem (2003) 278(11):9869-9874.
24. Tunaru S, Kero J, Schaub A, Wufka C, Blaukat A, Pfeffer K, Offermanns S: PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect. Nat Med (2003) 9(3):352-355.
25. Soga T, Kamohara M, Takasaki J, Matsumoto S, Saito T, Ohishi T, Hiyama H, Matsuo A, Matsushime H, Furuichi K: Molecular identification of nicotinic acid receptor. Biochem Biophys Res Commun (2003) 303(1):364-369.
26. Tiwari A: Current and emerging paradigms in the therapeutic management of atherosclerosis. Expert Opin Ther Targets (2008) 12(12):1523-1546.
27. Malik S, Kashyap ML: Niacin, lipids and heart disease. Curr Cardiol Rep (2003) 5(6):470-476.
28. Carlson LA: Nicotinic acid: The broad-spectrum lipid drug. A 50th anniversary review. J Intern Med (2005) 258(2):94-114.
29. Pike NB, Wise A: Identification of a nicotinic acid receptor: Is this the molecular target for the oldest lipid-lowering drug? Curr Opin Investig Drugs (2004) 5(3):271-275.
30. Benyó Z, Gille A, Kero J, Csiky M, Suchánková MC, Nüsing RM, Moers A, Pfeffer K, Offermanns S: GPR109A (PUMA-G/HM74A) mediates nicotinic acid-induced flushing. J Clin Invest (2005) 115(12):3634-3640.
31. Pike NB: Flushing out the role of GPR109A (HM74A) in the clinical efficacy of nicotinic acid. J Clin Invest (2005) 115(12): 3400-3403.
32. Morrow JD, Awad JA, Oates JA, Roberts LJ 2nd: Identification of skin as a major site of prostaglandin D2 release following oral administration of niacin in humans. J Invest Dermatol (1992) 98(5):812-815.
33. Leibel RL, Hirsch J, Berry EM, Gruen RK: Alterations in adipocyte free fatty acid re-esterification associated with obesity and weight reduction in man. Am J Clin Nutr (1985) 42(2):198-206.
34. Xiong Y, Miyamoto N, Shibata K, Valasek MA, Motoike T, Kedzierski RM, Yanagisawa M: Short-chain fatty acids stimulate leptin production in adipocytes through the G proteincoupled receptor GPR41. Proc Natl Acad Sci USA (2004) 101(4): 1045-1050.
35. Cummings JH, Pomare EW, Branch WJ, Naylor CP, Macfarlane GT: Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut (1987) 28(10):1221-1227.
36. Regard JB, Kataoka H, Cano DA, Camerer E, Yin L, Zheng YW, Scanlan TS, Hebrok M, Coughlin SR: Probing cell type-specific functions of GI in vivo identifies GPCR regulators of insulin secretion. J Clin Invest (2007) 117(12):4034-4043.
37. Ahrén B: Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes. Nat Rev Drug Discov (2009) 8(5):369-385.
38. Arena Pharmaceuticals Inc (Leonard JM, Hayak Y): GPR43 and modulators thereof for the treatment of metabolic-related disorders. WO-2006036688 (2006).
39. Bergman EN: Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. Physiol Rev (1990) 70(2):567-590.
40. Macfarlane GT, Cummings JH: The colonic flora, fermentation, and large bowel digestive function. In: The Large Intestine: Physiology, Pathophysiology, and Disease. Phillips SF, Pemberton JH, Shorter RG (Eds), Raven Press, New York, NY, USA (1991):51-92.
41. Pomare EW, Branch WJ, Cummings JH: Carbohydrate fermentation in the human colon and its relation to acetate concentrations in venous blood. J Clin Invest (1985) 75(5): 1448-1454.
42. Rumessen JJ, Franck YS, Gudmand-Høyer E: Acetate in venous blood for determination of carbohydrate malabsorption. Eur J Clin Nutr (1992) 46(Suppl 2):S135-S136.
43. Euroscreen Drug Discovery. Programs Overview: Euroscreen SA, Brussels, Belgium (2008). www.euroscreen.com/ index.php/Programs-Overview.html
44. Bernard J, Hartiel AF, Brantis C, Hoveyda H, Fraser G: Identification of a small-molecule GPR43 agonist that Increases glucose uptake and inhibits lipolysis in adipocytes. American Diabetes Association Annual Meeting, New Orleans, LA, USA (2009) 69:Abs 1362-P.
45. Tazoe H, Otomo Y, Kaji I, Tanaka R, Karaki SI, Kuwahara A: Roles of short-chain fatty acids receptors, GPR41 and GPR43 on colonic functions. J Physiol Pharmacol (2008) 59(Suppl 2): 251-262.
46. Karaki S, Tazoe H, Hayashi H, Kashiwabara H, Tooyama K, Suzuki Y, Kuwahara A: Expression of the short-chain fatty acid receptor, GPR43, in the human colon. J Mol Histol (2008) 39(2):135-142.
47. Karaki S, Mitsui R, Hayashi H, Kato I, Sugiya H, Iwanaga T, Furness JB, Kuwahara A: Short-chain fatty acid receptor, GPR43, is expressed by enteroendocrine cells and mucosal mast cells in rat intestine. Cell Tissue Res (2006) 324(3): 353-360.
48. Mitsui R, Ono S, Karaki S, Kuwahara A: Neural and non-neural mediation of propionate-induced contractile responses in the rat distal colon. Neurogastroenterol Motil (2005) 17(4):585-594.
49. Fukumoto S, Tatewaki M, Yamada T, Fujimiya M, Mantyh C, Voss M, Eubanks S, Harris M, Pappas TN, Takahashi T: Short-chain fatty acids stimulate colonic transit via intraluminal 5-HT release in rats. Am J Physiol Regul Integr Comp Physiol (2003) 284(5):R1269-R1276.
50. Lin HC, Neevel C, Chen JH: Slowing intestinal transit by PYY depends on serotonergic and opioid pathways. Am J Physiol Gastrointest Liver Physiol (2004) 286(4):G558-G563.
51. Cuche G, Cuber JC, Malbert CH: Ileal short-chain fatty acids inhibit gastric motility by a humoral pathway. Am J Physiol Gastrointest Liver Physiol (2000) 279(5):G925-G930.
52. Dass NB, John AK, Bassil AK, Crumbley CW, Shehee WR, Maurio FP, Moore GB, Taylor CM, Sanger GJ: The relationship between the effects of short-chain fatty acids on intestinal motility in vitro and GPR43 receptor activation. Neurogastroenterol Motil (2007) 19(1):66-74.
53. Zhou J, Martin RJ, Tulley RT, Raggio AM, McCutcheon KL, Shen L, Danna SC, Tripathy S, Hegsted M, Keenan M: Dietary resistant starch upregulates total GLP-1 and PYY in a sustained day-long manner through fermentation in rodents. Am J Physiol Endocrinol Metab (2008) 295(5):E1160-E1166.
54. Avandia. European Public Assessment Report: European Medicines Agency, London, UK (2009). www.emea.europa.eu/ humandocs/Humans/EPAR/avandia/avandia.htm
55. Home PD, Pocock SJ, Nielsen HB, Curtis PS, Gomis R, Hanefeld M, Jones NP, Komajda M, McMurray JJ, RECORD Study Team: Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): A multicentre, randomised, open-label trial. Lancet (2009) 373(9861):2125-2135.
56. Evans JL, Rushakoff RJ: Oral pharmacological agents for type 2 diabetes: Sulfonylureas, meglitinides, metformin, thiazolidinediones, α-glucosidase inhibitors, and emerging approaches. Endotext.org, South Dartmouth, MA, USA (2002). www. endotext.org/diabetes/diabetes16/diabetes16.htm
57. Yki-Järvinen H: Thiazolidinediones. N Eng J Med (2004) 351(11):1106-1118.
58. Clarke T: Update 4 - Amylin reports four additional deaths with Byetta. Reuters, Boston, MA, USA (2008). www.reuters.com/ article/idUSN2636220320080826
59. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B: Medical management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care (2009) 32(1):193-203.
60. Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A: Efficacy and safety of the weight-loss drug rimonabant: A meta-analysis of randomised trials. Lancet (2007) 370(9600):1706-1713.
61. Tiwari A, Bansal V, Chugh A, Mookhtiar K: Statins and myotoxicity: A therapeutic limitation. Expert Opin Drug Saf (2006) 5(5): 651-666.
62. Skowronski R, Hollenbeck CB, Varasteh BB, Chen YD, Reaven GM: Regulation of non-esterified fatty acid and glycerol concentration by insulin in normal individuals and patients with type 2 diabetes. Diabet Med (1991) 8(4):330-333.
63. Campbell PJ, Carlson MG, Nurjhan N: Fat metabolism in human obesity. Am J Physiol (1994) 266(4 Pt 1):E600-E605.
64. Stoddart LA, Smith NJ, Jenkins L, Brown AJ, Milligan G: Conserved polar residues in transmembrane domains V, VI, and VII of free fatty acid receptor 2 and free fatty acid receptor 3 are required for the binding and function of short chain fatty acids. J Biol Chem (2008) 283(47):32913-32924.
65. Lee T, Schwandner R, Swaminath G, Weiszmann J, Cardozo M, Greenberg J, Jaeckel P, Ge H, Wang Y, Jiao X, Liu J et al: Identification and functional characterization of allosteric agonists for the G protein-coupled receptor FFA2. Mol Pharmacol (2008) 74(6):1599-1609.