Glucagon as a target for the treatment of type 2 diabetes

Expert Opinion on Therapeutic Targets

Volumn 9, Issue 3, 2005, Pages 593-600

  Sloop, Kyle W ^a   Michael, M Dodson ^a   Moyers, Julie S ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

Glucagon; Glucagon receptor (GCGR); Glucose homeostatis; Type 2 diabetes

Indexed keywords

2 (4 PYRIDYL) 5 (4 CHLOROPHENYL) 3 (5 BROMO 2 PROPYLOXYPHENYL)PYROLE; 2 (BENZIMIDAZOL 2 YLTHIO) 1 (3,4 DIHYDROXYPHENYL) 1 ETHANONE; 2 PYRIDYL 3,5 DIARYLPYRROLE DERIVATIVE; 5 HYDROXYALKYL 4 PHENYLPYRIDINE DERIVATIVE; 6,7 DICHLORO 2 [N (3 DIMETHYLAMINOPROPYL) N METHYLAMINO] 3 STYRYLQUINOXALINE; [1 (2,3,5,6 TETRAMETHYLBENZYL) 1H INDOL 4 YLMETHYLENE]HYDRAZIDE 3 CYANO 4 HYDROXYBENZOIC ACID; ALKYLIDENE HYDRAZIDE DERIVATIVE; ANTISENSE OLIGODEOXYNUCLEOTIDE; BAY 27 9955; CPD 1; GLUCAGON; GLUCAGON ANTIBODY; GLUCAGON RECEPTOR; GLUCAGON RECEPTOR ANTAGONIST; GLUCOSE; GLYCOGEN; GW 4123X; INSULIN; L 168049; NATURAL PRODUCT; NNC 25 2504; PEPTIDE DERIVATIVE; QUINOXALINE DERIVATIVE; UNCLASSIFIED DRUG;

DRUG HALF LIFE; DRUG SYNTHESIS; DRUG TARGETING; GLUCAGON BLOOD LEVEL; GLUCONEOGENESIS; GLUCOSE BLOOD LEVEL; GLYCOGEN LIVER LEVEL; HUMAN; HYPERGLYCEMIA; HYPOGLYCEMIA; IN VIVO STUDY; INSULIN BLOOD LEVEL; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PROTEIN TARGETING; REVIEW; STRUCTURE ACTIVITY RELATION;

ANIMALS; DIABETES MELLITUS, TYPE 2; GLUCAGON; HUMANS; HYPOGLYCEMIC AGENTS; RECEPTORS, GLUCAGON;

EID: 21244431627     PISSN: 14728222     EISSN: None     Source Type: Journal    
DOI: 10.1517/14728222.9.3.593     Document Type: Review

References (61)

1. ALFORD FP, BLOOM SR, NABARRO JD: Glucagon metabolism in man, studies on the metabolic clearance rate and the plasma acute disappearance time of glucagon in normal and diabetic subjects. J. Clin. Endocrinol Metab. (1976) 42(5):830-838.
2. IKEDA T, TERASAWA H, ISHIMURA M et al.: Hepatic extraction and hepatic action of insulin, glucagon, and epinephrine in bivascularly perfused rat liver. Jpn. J. Physiol. (1993) 43(3):371-378.
3. KLETZIEN RF, WEBER CA, STUMPO DJ: Coordinate regulation of gluconeogenesis by the glucocorticoids and glucagon: evidence for acute and chronic regulation by glucagon. J. Cell. Physiol. (1981) 109(1):83-90.
4. POLONSKY K, JASPAN J, EMMANOUEL D, HOLMES K, MOOSSA AR: Differences in the hepatic and renal extraction of insulin and glucagon in the dog: evidence for saturability of insulin metabolism. Acta Endocrinol. (Copenh) (1983) 102(3):420-427.
5. DOBBINS RL, DAVIS SN, NEAL DW et al al.: Compartmental modeling of glucagon kinetics in the conscious dog. Metabolism (1995) 44(4):452-459.
6. DEACON CF, KELSTRUP M, TREBBIEN R et al.: Differential regional metabolism of glucagon in anesthetized pigs. Am. J. Physiol. Endocrinol. Metab. (2003) 285(3):E552-E560.
7. BARTHEL A, SCHMOLL D: Novel concepts in insulin regulation of hepatic gluconeogenesis. Am. J. Physiol. Endocrinol. Metab. (2003) 285(4):E685-E692.
8. DEFRONZO RA, FERRANNINI E, SIMONSON DC: Fasting hyperglycemia in non-insulin-dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake. Metabolism (1989) 38(4):387-395.
9. CONSOLI A, NURJHAN N, CAPANI F, GERICH J: Predominant role of gluconeogenesis in increased hepatic glucose production in NIDDM. Diabetes (1989) 38(5):550-557.
10. BUTLER PC, RIZZA RA: Contribution to postprandial hyperglycemia and effect on initial splanchnic glucose clearance of hepatic glucose cycling in glucose-intolerant or NIDDM patients. Diabetes (1991) 40(1):73-81.
11. ROUILLE Y, MARTIN S, STEINER DF: Differential processing of proglucagon by the subrilisin-like prohormone convertases PC2 and PC3 to generate either glucagon or glucagon-like peptide. J. Biol. Chem. (1995) 270(44):26488-26496.
12. ROUILLE Y, BIANCHI M, IRMINGER JC, HALBAN PA: Role of the prohormone convertase PC2 in the processing of proglucagon to glucagon. FEBS Lett. (1997) 413(1):119-123.
13. WEBB GC, AKBAR MS, ZHAO C, SWIFT HH, STEINER DF: Glucagon replacement via micro-osmotic pump corrects by hypoglycemia and alpha-cell hyperplasia in prohormone convertase 2 knockout mice. Diabetes (2002) 51(2):398-405.
14. VINCENT M, GUZ Y, ROZENBERG M et al.: Abrogation of protein convertase 2 activity results in delayed islet cell differentiation and maturation, increased alpha-cell proliferation, and islet neogenesis. Endocrinology (2003) 144(9):4061-4069.
15. ROUILLE Y, KANTENGWA S, IRMINGER JC, HALBAN PA: Role of the prohormone convertase PC3 in the processing of proglucagon to glucagon-like peptide 1. J. Biol. Chem. (1997) 272(52):32810-32816.
16. GROMADA J, BOKVIST K, DING WG et al.: Adrenaline stimulates glucagon secretion in pancreatic A-cells by increasing the Ca2+ current and the number of granules close to the L-type Ca2+ channels. J. Gen. Physiol. (1997) 110(3):217-228.
17. DING WG, RENSTROM E, RORSMAN P, BUSCHARD K, GROMADA J: Glucagon-like peptide I and glucose-dependent insulinotropic polypeptide stimulate Ca2+-induced secretion in rat alpha-cells by a protein kinase A-mediated mechanism. Diabetes (1997) 46(5):792-800.
18. MEIER JJ, GALLWITZ B, SIEPMANN N et al.: Gastric inhibitory polypeptide (GIP) dose-dependently stimulates glucagon secretion in healthy human subjects at euglycaemia. Diabetologia (2003) 46(6):798-801.
19. ABRAHAMSEN N, LUNDGREN K, NISHIMURA E: Regulation of glucagon receptor mRNA in cultured primary rat hepatocytes by glucose and cAMP. J. Biol. Chem. (1995) 270(26):15853-15857.
20. BURCELIN R, MREJEN C, DECAUX JF et al.: In vivo and in vitro regulation of hepatic glucagon receptor mRNA concentration by glucose metabolism. J. Biol. Chem. (1998) 273(14):8088-8093.
21. HUYPENS P, LING Z, PIPELEERS D, SCHUIT F: Glucagon receptors on human islet cells contribute to glucose competence of insulin release. Diabetologia (2000) 43(8):1012-1019.
22. GRAPENGIESSER E, DANSK H, HELLMAN B: Synchronization of pancreatic beta-cell rhythmicity after glucagon induction of Ca2+ transients. Cell Calcium (2003) 34(1):49-53.
23. MA X, ZHANG Y, GROMADA J et al.: Glucagon stimulates exocytosis in mouse and rat pancreatic alpha-cells by binding to glucagon receptors. Mol. Endocrinol. (2005) 19(1):198-212.
24. REAVEN GM, CHEN YD, GOLAY A, SWISLOCKI AL, JASPAN JB: Documentation of hyperglucagonemia throughout the day in nonobese and obese patients with noninsulin-dependent diabetes mellitus. J. Clin. Endocrinol. Metab. (1987) 64(1):106-110.
25. BARON AD, SCHAEFFER L, SHRAGG P, KOLTERMAN OG: Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in Type II diabetics. Diabetes (1987) 36(3):274-283.
26. SHAH P, BASU A, BASU R, RIZZA R: Impact of lack of suppression of glucagon on glucose tolerance in humans. Am. J. Pbysiol. (1999) 277(2 Pt 1):E283-E290.
27. SHAH P, VELLA A, BASU A et al.: Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with Type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. (2000) 85(11):4053-4059.
28. CONSOLI A: Role of liver in pathophysiology of NIDDM. Diabetes Care (1992) 15(3):430-441.
29. LARSSON H, AHREN B: Failure to adequately adapt reduced insulin sensitivity with increased insulin secretion in women with impaired glucose tolerance. Diabetologia (1996) 39(9):1099-1107.
30. BURCELIN R, KATZ EB, CHARRON MJ: Molecular and cellular aspects of the glucagon receptor: role in diabetes and metabolism. Diabetes Metab. (1996) 22(6):373-396.
31. BIRNBAUMER L, POHL SL: Relation of glucagon-specific binding sites to glucagon-dependent stimulation of adenylyl cyclase activity in plasma membranes of rat liver. J. Biol. Chem. (1973) 248(6):2056-2061.
32. JOHNSON DG, GOEBEL CU, HRUBY VJ, BREGMAN MD, TRIVEDI D: Hyperglycemia of diabetic rats decreased by a glucagon receptor antagonist. Science (1982) 215(4536):1115-1116.
33. AHN JM, MEDEIROS M, TRIVEDI D, HRUBY VJ: Development of potent truncated glucagon antagonists. J. Med. Chem. (2001a) 44(9):1372-1379.
34. AHN JM, MEDEIROS M, TRIVEDI D, HRUBY VJ: Development of potent glucagon antagonists: structure-activity relationship study of glycine at position 4. J. Pept. Res. (2001b) 58(2):151-158.
35. BRAND CL, ROLIN B, JORGENSEN PN et al.: Immunoneutralization of endogenous glucagon with monoclonal glucagon antibody normalizes hyperglycaemia in moderately streptozotocin-diabetic rats. Diabetologia (1994) 37(10):985-993.
36. BRAND CL, JORGENSEN PN, SVENDSEN I, HOLST JJ: Evidence for a major role for glucagon in regulation of plasma glucose in conscious, nondiabetic, and alloxan-induced diabetic rabbits. Diabetes (1996) 45(8):1076-1083.
37. BRAND CL, HANSEN B, GRONEMAN S, BOYSEN M, HOLST JJ: Sub-chronic glucagon neutralisation improves diabetes in ob/ob mice. Diabetes (2000) 49(Suppl. 1):A81.
38. MCCORMACK JG, WESTERGAARD N, KRISTIANSEN M, BRAND CL, LAU J: Pharmacological approaches to inhibit endogenous glucose production as a means of anti-diabetic therapy. Curr. Pharm. Des. (2001) 7(14):1451-1474.
39. MADSEN P, KNUDSEN LB, WIBERG FC, CARR RD: Discovery and structure-activity relationship of the first non-peptide competitive human glucagon receptor antagonists. J. Med. Chem. (1998) 41(26):5150-5157.
40. COLLINS JL, DAMBEK PJ, GOLDSTEIN SW, FARACI WS: CP-99,711: A Non-Peptide Glucagon Receptor Antagonist. Bioorg. Med. Chem. Lett. (1992) 2:915-918.
41. CASCIERI MA, KOCH GE, BER E et al.: Characterization of a novel, non-peptidyl antagonist of the human glucagon receptor. J. Biol. Chem. (1999) 274(13):8694-8697.
42. CHANG LL, SIDLER KL, CASCIERI MA et al.: Substituted imidazoles as glucagon receptor antagonists. Bioorg. Med. Chem. Lett (2001) 11(18):2549-2553.
43. DE LASZLO SE, HACKER C, LI B et al.: Potent, orally absorbed glucagon receptor antagonists. Bioorg. Med. Chem. Lett. (1999) 9(5):641-646.
44. LADOUCEUR GH, COOK JH, DOHERTY EM et al.: Discovery of 5-hydroxyalkyl-4-phenylpyridines as a new class of glucagon receptor antagonists. Bioorg. Med. Chem. Lett. (2002) 12(3):461-464.
45. LING A, PLEWE M, GONZALEZ J et al.: Human glucagon receptor antagonists based on alkylidene hydrazides. Bioorg. Med. Chem. Lett. (2002) 12(4):663-666.
46. SHIAO LL, CASCIERI MA, TRUMBAUER M, CHEN H, SULLIVAN KA: Generation of mice expressing the human glucagon receptor with a direct replacement vector. Transgenic Res. (1999) 8(4):295-302.
47. DALLAS-YANG Q, SHEN X, STROWSKI M et al.: Hepatic glucagon receptor binding and glucose-lowering in vivo by peptidyl and non-peptidyl glucagon receptor antagonists. Eur. J. Pharmacol. (2004) 501(1-3):225-234.
48. PETERSEN KF, SULLIVAN JT: Effects of a novel glucagon receptor antagonist (Bay 27-9955) on glucagon-stimulated glucose production in humans. Diabetologia (2001) 44(11):2018-2024.
49. MADSEN P, LING A, PLEWE M et al.: Optimization of alkylidene hydrazide based human glucagon receptor antagonists. Discovery of the highly potent and orally available 3-cyano-4-hydroxybenzoic acid [1-(2,3,5,6-tetramethylbenzyl)-1H-indol -4-ylmethylenelhydrazide. J. Med. Chem. (2002) 45(26):5755-5775.
50. HANDLON AL, AKWABI-AMEYAW A, BROWN K et al.: Glucagon receptor antagonists for the treatment of Type 2 diabetes. 226th American Chemical Society National Meeting, New York City, NY, USA (2003):MEDI-164.
51. QURESHI SA, RIOS CANDELORE M, XIE D et al.: A novel glucagon receptor antagonist inhibits glucagon-mediated biological effects. Diabetes (2004) 53(12):3267-3273.
52. PARKER JC, MCPHERSON RK, ANDREWS KM et al.: Effects of skyrin, a receptor-selective glucagon antagonist, in rat and human hepatocytes. Diabetes (2000) 49(12):2079-2086.
53. POTTERAT O, WAGNER K, GEMMECKER G et al.: BI-32169, a bicyclic 19-peptide with strong glucagon receptor antagonist activity from Streptomyces sp. J. Nat. Prod. (2004) 67(9):1528-1531.
54. PARKER JC, ANDREWS KM, ALLEN MR, STOCK JL, MCNEISH JD: Glycemic control in mice with targeted disruption of the glucagon receptor gene. Biochem. Biophys. Res. Commun. (2002) 290(2):839-843.
55. GELLING RW, DU XQ, DICHMANN DS et al.: Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc. Natl. Acad. Sci. USA (2003) 100(3):1438-1443.
56. LIANG Y, OSBORNE MC, MONIA BP et al.: Reduction in glucagon receptor expression by an antisense oligonucleotide ameliorates diabetic syndrome in db/db mice. Diabetes (2004) 53(2):410-417.
57. SLOOP KW, CAO JX, SIESKY AM et al.: Hepatic and glucagon-like peptide-1-mediated reversal of diabetes by glucagon receptor antisense oligonucleotide inhibitors. J. Clin. Invest. (2004) 113(11):1571-1581.
58. ZHANG H, COOK J, NICKEL J et al.: Reduction of liver Fas expression by an antisense oligonucleotide protects mice from fulminant hepatitis. Nat. Biotechnol. (2000) 18(8):862-867.
59. YU RZ, ZHANG H, GEARY RS et al.: Pharmacokinetics and pharmacodynamics of an antisense phosphorothioate oligonucleotide targeting Fas mRNA in mice. J. Pharmacol. Exp. Ther. (2001) 296(2):388-395.
60. JIANG G, ZHANG BB: Glucagon and regulation of glucose metabolism. Am. J. Physiol. Endocrinol. Metab. (2003) 284(4):E671-E678.
61. HERZIG S, HEDRICK S, MORANTTE I et al.: CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-gamma. Nature (2003) 426(6963):190-193.