Anti-Diabetic Efficacy and Impact on Amino Acid Metabolism of GRA1, a Novel Small-Molecule Glucagon Receptor Antagonist

PLoS ONE

Volumn 7, Issue 11, 2012, Pages

  Mu, James ^a   Qureshi, Sajjad A ^a   Brady, Edward J ^a   Muise, Eric S ^a   Candelore, Mari Rios ^a   Jiang, Guoqiang ^a   Li, Zhihua ^a   Wu, Margaret S ^a   Yang, Xiaodong ^a   Dallas Yang, Qing ^a   Miller, Corey ^a   Xiong, Yusheng ^a   Langdon, Ronald B ^a   Parmee, Emma R ^a   Zhang, Bei B ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE AMINOTRANSFERASE; ALANINE GLYOXYLATE AMINOTRANSFERASE 2 LIKE 1; AMINO ACID; AMINOADIPATE SEMIALDEHYDE SYNTHASE; ANTIDIABETIC AGENT; ARGINOSUCCINATE LYASE; ASPARTATE AMINOTRANSFERASE ISOENZYME 1; CARRIER PROTEIN; CHOLESTEROL; DESFLUOROSITAGLIPTIN; DIPEPTIDYL PEPTIDASE IV INHIBITOR; ENZYME; EXCITATORY AMINO ACID TRANSPORTER 2; FATTY ACID; GLUCAGON; GLUCAGON LIKE PEPTIDE 1; GLUCAGON RECEPTOR ANTAGONIST; GLUCOSE; GRA 1; HEMOGLOBIN A1C; INSULIN; LOW DENSITY LIPOPROTEIN CHOLESTEROL; N [4 [1 [3 (2 FLUORO 5 TRIFLUOROMETHYLPHENYL) 5 (6 METHOXYNAPHTH 2 YL) 1H PYRAZOL 1 YL]ETHYL]BENZOYL] BETA ALANINE; NON LOW DENSITY LIPOPROTEIN CHOLESTEROL; ORNITHINE OXOACID AMINOTRANSFERASE; PHENYLALANINE 4 MONOOXYGENASE; SERINE DEHYDRATASE; SOLUTE CARRIER FAMILY 7 MEMBER 2; TRIACYLGLYCEROL; TYROSINE AMINOTRANSFERASE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

AASS GENE; AGXT2L1 GENE; AMINO ACID METABOLISM; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIDIABETIC ACTIVITY; AREA UNDER THE CURVE; ARG1 GENE; ARTICLE; ASL GENE; BCKDHB GENE; BODY WEIGHT; CHOLESTEROL BLOOD LEVEL; CHRONIC DRUG ADMINISTRATION; COMBINATION CHEMOTHERAPY; CONCENTRATION RESPONSE; CONTROLLED STUDY; DDC GENE; DIABETES MELLITUS; DISEASE MODEL; DISEASE SEVERITY; DOSE RESPONSE; DOWN REGULATION; DRUG BLOOD LEVEL; DRUG DOSE COMPARISON; DRUG EFFICACY; DRUG POTENCY; DRUG POTENTIATION; DRUG SELECTIVITY; FATTY ACID BLOOD LEVEL; FH GENE; FOOD INTAKE; GCK GENE; GCKR GENE; GENE; GENE EXPRESSION PROFILING; GLS2 GENE; GLUCAGON BLOOD LEVEL; GLUCOSE BLOOD LEVEL; GLYCOGENOLYSIS; GOT1 GENE; GPT GENE; HPD GENE; INSULIN BLOOD LEVEL; KMO GENE; LIPID LIVER LEVEL; LIVER CELL; LIVER PERFUSION; MONOTHERAPY; MOUSE; NONHUMAN; OAT GENE; PAH GENE; PROTEIN BLOOD LEVEL; PROTEIN EXPRESSION; RECEPTOR OCCUPANCY; RHESUS MONKEY; SDS GENE; SDSL GENE; SINGLE DRUG DOSE; SLC1A2 GENE; SLC7A2 GENE; TAT GENE; TRANSGENIC MOUSE; TRIACYLGLYCEROL BLOOD LEVEL;

ADMINISTRATION, ORAL; ANIMALS; BETA-ALANINE; DOSE-RESPONSE RELATIONSHIP, DRUG; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION; GLUCAGON; GLYCOGEN; GLYCOGENOLYSIS; HEPATOCYTES; HORMONES; HUMANS; HYPOGLYCEMIC AGENTS; IODINE RADIOISOTOPES; LIVER; MACACA MULATTA; MICE; MICE, INBRED C57BL; MICE, TRANSGENIC; MODELS, CHEMICAL; PYRAZOLES; RECEPTORS, GLUCAGON;

MACACA MULATTA; MURINAE; MUS;

EID: 84869805184     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0049572     Document Type: Article

References (45)

1. Unger RH, Aguilar-Parada E, Muller WA, Eisentraut AM, (1970) Studies of pancreatic alpha cell function in normal and diabetic subjects. J Clin Invest 49: 837-848.
2. Burcelin R, Katz EB, Charron MJ, (1996) Molecular and cellular aspects of the glucagon receptor: role in diabetes and metabolism. Diabetes Metab 22: 373-396.
3. Jiang G, Zhang BB, (2003) Glucagon and regulation of glucose metabolism. Am J Physiol Endocrinol Metab 284: E671-678.
4. Unger RH, (1978) Role of glucagon in the pathogenesis of diabetes: the status of the controversy. Metabolism 27: 1691-1709.
5. Toft I, Gerich JE, Jenssen T, (2002) Autoregulation of endogenous glucose production during hyperglucagonemia. Metabolism 51: 1128-1134.
6. Unger RH, Cherrington AD, (2012) Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J Clin Invest 122: 4-12.
7. Zhang BB, Moller DE, (2000) New approaches in the treatment of type 2 diabetes. Curr Opin Chem Biol 4: v461-467.
8. Sloop KW, Michael MD, Moyers JS, (2005) Glucagon as a target for the treatment of Type 2 diabetes. Expert Opin Ther Targets 9: 593-600.
9. Bagger JI, Knop FK, Holst JJ, Vilsboll T, (2011) Glucagon antagonism as a potential therapeutic target in type 2 diabetes. Diabetes Obes Metab 13: 965-971.
10. Lok S, Kuijper JL, Jelinek LJ, Kramer JM, Whitmore TE, et al. (1994) The human glucagon receptor encoding gene: structure, cDNA sequence and chromosomal localization. Gene 140: 203-209.
11. Parker JC, Andrews KM, Allen MR, Stock JL, McNeish JD, (2002) Glycemic control in mice with targeted disruption of the glucagon receptor gene. Biochem Biophys Res Commun 290: 839-843.
12. Gelling RW, Du XQ, Dichmann DS, Romer J, Huang H, et al. (2003) Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci U S A 100: 1438-1443.
13. Liang Y, Osborne MC, Monia BP, Bhanot S, Gaarde WA, et al. (2004) Reduction in glucagon receptor expression by an antisense oligonucleotide ameliorates diabetic syndrome in db/db mice. Diabetes 53: 410-417.
14. Sloop KW, Cao JX, Siesky AM, Zhang HY, Bodenmiller DM, et al. (2004) Hepatic and glucagon-like peptide-1-mediated reversal of diabetes by glucagon receptor antisense oligonucleotide inhibitors. J Clin Invest 113: 1571-1581.
15. Conarello SL, Jiang G, Mu J, Li Z, Woods J, et al. (2007) Glucagon receptor knockout mice are resistant to diet-induced obesity and streptozotocin-mediated beta cell loss and hyperglycaemia. Diabetologia 50: 142-150.
16. Petersen KF, Sullivan JT, (2001) Effects of a novel glucagon receptor antagonist (Bay 27-9955) on glucagon-stimulated glucose production in humans. Diabetologia 44: 2018-2024.
17. Qureshi SA, Rios Candelore M, Xie D, Yang X, Tota LM, et al. (2004) A novel glucagon receptor antagonist inhibits glucagon-mediated biological effects. Diabetes 53: 3267-3273.
18. Rivera N, Everett-Grueter CA, Edgerton DS, Rodewald T, Neal DW, et al. (2007) A novel glucagon receptor antagonist, NNC 25-0926, blunts hepatic glucose production in the conscious dog. J Pharmacol Exp Ther 321: 743-752.
19. Winzell MS, Brand CL, Wierup N, Sidelmann UG, Sundler F, et al. (2007) Glucagon receptor antagonism improves islet function in mice with insulin resistance induced by a high-fat diet. Diabetologia 50: 1453-1462.
20. Mu J, Jiang G, Brady E, Dallas-Yang Q, Liu F, et al. (2011) Chronic treatment with a glucagon receptor antagonist lowers glucose and moderately raises circulating glucagon and glucagon-like peptide 1 without severe alpha cell hypertrophy in diet-induced obese mice. Diabetologia 54: 2381-2391.
21. Shen DM, Brady EJ, Candelore MR, Dallas-Yang Q, Ding VD, et al. (2011) Discovery of novel, potent, selective, and orally active human glucagon receptor antagonists containing a pyrazole core. Bioorg Med Chem Lett 21: 76-81.
22. Flakoll PJ, Borel MJ, Wentzel LS, Williams PE, Lacy DB, et al. (1994) The role of glucagon in the control of protein and amino acid metabolism in vivo. Metabolism 43: 1509-1516.
23. Charlton MR, Adey DB, Nair KS, (1996) Evidence for a catabolic role of glucagon during an amino acid load. J Clin Invest 98: 90-99.
24. Yang J, MacDougall ML, McDowell MT, Xi L, Wei R, et al. (2011) Polyomic profiling reveals significant hepatic metabolic alterations in glucagon-receptor (GCGR) knockout mice: implications on anti-glucagon therapies for diabetes. BMC Genomics 12: 281.
25. Lee Y, Wang MY, Du XQ, Charron MJ, Unger RH, (2011) Glucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice. Diabetes 60: 391-397.
26. Xiong Y, Guo J, Candelore MR, Liang R, Miller C, et al. (2012) Discovery of a novel glucagon receptor antagonist N-[(4-{(1S)-1-[3-(3, 5-Dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbo nyl]-beta-alanine (MK-0893) for the treatment of type II diabetes. J Med Chem doi:10.1021/jm300579z.
27. Shiao LL, Cascieri MA, Trumbauer M, Chen H, Sullivan KA, (1999) Generation of mice expressing the human glucagon receptor with a direct replacement vector. Transgenic Res 8: 295-302.
28. Coleman DL, Hummel KP, (1973) The influence of genetic background on the expression of the obese (Ob) gene in the mouse. Diabetologia 9: 287-293.
29. Dallas-Yang Q, Shen X, Strowski M, Brady E, Saperstein R, et al. (2004) Hepatic glucagon receptor binding and glucose-lowering in vivo by peptidyl and non-peptidyl glucagon receptor antagonists. Eur J Pharmacol 501: 225-234.
30. Cohen SM, Duffy JL, Miller C, Kirk BA, Candelore MR, et al. (2006) Direct observation (NMR) of the efficacy of glucagon receptor antagonists in murine liver expressing the human glucagon receptor. Bioorg Med Chem 14: 1506-1517.
31. Mu J, Woods J, Zhou YP, Roy RS, Li Z, et al. (2006) Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic beta-cell mass and function in a rodent model of type 2 diabetes. Diabetes 55: 1695-1704.
32. Zhao W, Fong O, Muise ES, Thompson JR, Weingarth D, et al. (2010) Genome-wide expression profiling revealed peripheral effects of cannabinoid receptor 1 inverse agonists in improving insulin sensitivity and metabolic parameters. Mol Pharmacol 78 (3):: 350-359.
33. Reaven GM, Chen YD, Golay A, Swislocki AL, Jaspan JB, (1987) Documentation of hyperglucagonemia throughout the day in nonobese and obese patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 64: 106-110.
34. Shah P, Vella A, Basu A, Basu R, Schwenk WF, et al. (2000) Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab 85: 4053-4059.
35. Yan H, Gu W, Yang J, Bi V, Shen Y, et al. (2009) Fully human monoclonal antibodies antagonizing the glucagon receptor improve glucose homeostasis in mice and monkeys. J Pharmacol Exp Ther 329: 102-111.
36. Shen DM, Lin S, Parmee ER, (2011) A survey of small molecule glucagon receptor antagonists from recent patents (2006-2010). Expert Opin Ther Pat 21: 1211-1240.
37. Duffy JL, Kirk BA, Konteatis Z, Campbell EL, Liang R, et al. (2005) Discovery and investigation of a novel class of thiophene-derived antagonists of the human glucagon receptor. Bioorg Med Chem Lett 15: 1401-1405.
38. Shen DM, Zhang F, Brady EJ, Candelore MR, Dallas-Yang Q, et al. (2005) Discovery of novel, potent, and orally active spiro-urea human glucagon receptor antagonists. Bioorg Med Chem Lett 15: 4564-4569.
39. Kim RM, Chang J, Lins AR, Brady E, Candelore MR, et al. (2008) Discovery of potent, orally active benzimidazole glucagon receptor antagonists. Bioorg Med Chem Lett 18: 3701-3705.
40. Cryer PE, (2008) Hypoglycemia: still the limiting factor in the glycemic management of diabetes. Endocr Pract 14: 750-756.
41. Engel SS, Xu L, Andryuk PJ, Davies MJ, Amatruda J, et al. (2011) Efficacy and tolerability of MK-0893, a glucagon receptor antagonist (GRA), in patients with type 2 diabetes (T2DM). Diabetes 60: A85.
42. Ruddy M, Pramanik B, Lunceford SL, Cilissen C, Stoch A, et al. (2011) Inhibition of glucagon-induced hyperglycemia predicts glucose lowering efficacy of a glucagon receptor antagonist, MK-0893, in type 2 diabetes (T2DM). Diabetes 60: A85.
43. Engel SS, Teng R, Edwards RJ, Davies MJ, Kaufman KD, et al. (2011) Efficacy and safety of the glucagon receptor antagonist, MK-0893, in combination with metformin or sitagliptin in patients with type 2 diabetes mellitus 47th EASD Abstract 191.
44. Eldor R, Glaser B, Fraenkel M, Doviner V, Salmon A, et al. (2011) Glucagonoma and the glucagonoma syndrome- cumulative experience with an elusive endocrine tumour. Clin Endocrinol (Oxf) 74: 593-598.
45. Hebert SL, Nair KS, (2010) Protein and energy metabolism in type 1 diabetes. Clin Nutr 29: 13-17.