J Korean Endocr Soc.  2006 Dec;21(6):437-447.

Glucagon-like Peptide-1 Analogue and Dipeptidyl Peptidase-IV Inhibitors

• Oh S

Abstract

No abstract available.

MeSH Terms

Glucagon-Like Peptide 1*
Glucagon-Like Peptide 1

Figure

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  Fig 1 Amino acid sequence of GLP-1 and incretin mimetics under development as antidiatetic drugs. Amino acids identical to the same position in the GLP-1 sequence are shown in light grey, amino acids different from the native molecule are displayed in darker grey.

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  Fig. 2 Structures of DPP-IV inhibitors.

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  Fig. 3 HbA1c concentrations during 12 weeks (core study, open symbols) and 1 year (extension study, closed symbols) treatment of type 2 diabetic patients with metformin alone (circles) or in combination with vildagliptin (50 mg once daily; triangles)[44].

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  Fig. 4 Means ± SE time courses of insulin secretion (pmol/L 30 min)/(mmol/L) (A), dynamic insulin sensitivity (OGIS, mL · min · -1 · m-2) (B), and adaptation index (nmolC-peptide mmolglucose-1 mL-1 · m-2) (C) at baseline (week 0) and after 12, 24, and 52 weeks of treatment with vildagliptin (50 mg once daily, n = 31) or placebo (n = 26) in metformin-treated type 2 diabetic subjects. D: Regression between change in adaptation index and change in A1C after 52 weeks of treatment with vildagliptin (●) or placebo (○). Asterisks indicate probability level of random difference between groups. *P < 0.05; **P < 0.01[45].

Reference

1. Holst JJ. Glucagon like peptide 1: a newly discovered gastrointestinal hormone. Gastroenterology. 1994. 107:1848–1855.

2. Fehmann HC, Goke R, Goke B. Cell and molecular biology of the incretin hormones glucagon-like peptide-I and glucose-dependent insulin releasing polypeptide. Endocr Rev. 1995. 16:390–410.

3. Xu G, Stoffers DA, Habener JF, Bonner-Weir S. Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes. 1999. 48:2270–2276.

4. Stoffers DA, Kieffer TJ, Hussain MA, Drucker DJ, Bonner-Weir S, Habener JF, Egan JM. Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas. Diabetes. 2000. 49:741–748.

5. Perfetti R, Zhou J, Doyle ME, Egan JM. Glucagon-like peptide-1 induces cell proliferation and pancreatic-duodenum homeobox-1 expression and increases endocrine cell mass in the pancreas of old, glucose-intolerant rats. Endocrinology. 2000. 141:4600–4605.

6. Orskov C, Holst JJ, Nielsen OV. Effect of truncated glucagon-like peptide-1 [proglucagon-(78-107) amide] on endocrine secretion from pig pancreas, antrum, and nonantral stomach. Endocrinology. 1988. 123:2009–2013.

7. Wettergren A, Schjoldager B, Mortensen PE, Myhre J, Christiansen J, Holst JJ. Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man. Dig Dis Sci. 1993. 38:665–673.

8. Nauck MA, Niedereichholz U, Ettler R, Holst JJ, Orskov C, Ritzel R, Schmiegel WH. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol. 1997. 273:E981–E988.

9. Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest. 1998. 101:515–520.

10. Naslund E, Barkeling B, King N, Gutniak M, Blundell JE, Holst JJ, Rossner S, Hellstrom PM. Energy intake and appetite are suppressed by glucagon-like peptide-1 (GLP-1) in obese men. Int J Obes Relat Metab Disord. 1999. 23:304–311.

11. Gutzwiller JP, Drewe J, Goke B, Schmidt H, Rohrer B, Lareida J, Beglinger C. Glucagon-like peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2. Am J Physiol. 1999. 276:R1541–R1544.

12. Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993. 36:741–744.

13. Nauck MA, Sauerwald A, Ritzel R, Holst JJ, Schmiegel W. Influence of glucagon-like peptide 1 on fasting glycemia in type 2 diabetic patients treated with insulin after sulfonylurea secondary failure. Diabetes Care. 1998. 21:1925–1931.

14. Toft-Nielsen MB, Damholt MB, Madsbad S, Hilsted LM, Hughes TE, Michelsen BK, Holst JJ. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab. 2001. 86:3717–3723.

15. Rachman J, Barrow BA, Levy JC, Turner RC. Near-normalisation of diurnal glucose concentrations by continuous administration of glucagon-like peptide-1 (GLP-1) in subjects with NIDDM. Diabetologia. 1997. 40:205–211.

16. Larsen J, Hylleberg B, Ng K, Damsbo P. Glucagon-like peptide-1 infusion must be maintained for 24 h/day to obtain acceptable glycemia in type 2 diabetic patients who are poorly controlled on sulphonylurea treatment. Diabetes Care. 2001. 24:1416–1421.

17. Deacon CF, Hughes TE, Holst JJ. Dipeptidyl peptidase IV inhibition potentiates the insulinotropic effect of glucagon-like peptide 1 in the anesthetized pig. Diabetes. 1998. 47:764–769.

18. Thorens B, Porret A, Buhler L, Deng SP, Morel P, Widmann C. Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor. Diabetes. 1993. 42:1678–1682.

19. Egan JM, Clocquet AR, Elahi D. The insulinotropic effect of acute exendin-4 administered to humans: comparison of nondiabetic state to type 2 diabetes. J Clin Endocrinol Metab. 2002. 87:1282–1290.

20. Fineman MS, Bicsak TA, Shen LZ, Taylor K, Gaines E, Varns A, Kim D, Baron AD. Effect on glycemic control of exenatide (synthetic exendin-4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes. Diabetes Care. 2003. 26:2370–2377.

21. Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004. 27:2628–2635.

22. Fineman MS, Shen LZ, Taylor K, Kim DD, Baron AD. Effectiveness of progressive dose-escalation of exenatide (exendin-4) in reducing dose-limiting side effects in subjects with type 2 diabetes. Diabetes Metab Res Rev. 2004. 20:411–417.

23. Egan JM, Meneilly GS, Elahi D. Effects of 1-mo bolus subcutaneous administration of exendin-4 in type 2 diabetes. Am J Physiol Endocrinol Metab. 2003. 284:E1072–E1079.

24. Toft-Nielson M, Madsbad S, Holst JJ. The effect of glucagon-like peptide I (GLP-I) on glucose elimination in healthy subjects depends on the pancreatic glucoregulatory hormones. Diabetes. 1996. 45:552–556.

25. Kolterman OG, Buse JB, Fineman MS, Gaines E, Heintz S, Bicsak TA, Taylor K, Kim D, Aisporna M, Wang Y, Baron AD. Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab. 2003. 88:3082–3089.

26. Rayner CK, Samsom M, Jones KL, Horowitz M. Relationships of upper gastrointestinal motor and sensory function with glycemic control. Diabetes Care. 2001. 24:371–381.

27. Dupre J, Behme MT, McDonald TJ. Exendin-4 normalized postcibal glycemic excursions in type 1 diabetes. J Clin Endocrinol Metab. 2004. 89:3469–3473.

28. 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. 64:106–110.

29. Mahler RJ, Adler ML. Clinical review 102: Type 2 diabetes mellitus: update on diagnosis, pathophysiology, and treatment. J Clin Endocrinol Metab. 1999. 84:1165–1171.

30. Agerso H, Jensen LB, Elbrond B, Rolan P, Zdravkovic M. The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. Diabetologia. 2002. 45:195–202.

31. Elbrond B, Jakobsen G, Larsen S, Agerso H, Jensen LB, Rolan P, Sturis J, Hatorp V, Zdravkovic M. Pharmacokinetics, pharmacodynamics, safety, and tolerability of a single-dose of NN2211, a long-acting glucagon-like peptide 1 derivative, in healthy male subjects. Diabetes Care. 2002. 25:1398–1404.

32. Juhl CB, Hollingdal M, Sturis J, Jakobsen G, Agerso H, Veldhuis J, Porksen N, Schmitz O. Bedtime administration of NN2211, a long-acting GLP-1 derivative, substantially reduces fasting and postprandial glycemia in type 2 diabetes. Diabetes. 2002. 51:424–429.

33. Ribel U, Larsen MO, Rolin B, Carr RD, Wilken M, Sturis J, Westergaard L, Deacon CF, Knudsen LB. NN2211: a long-acting glucagon-like peptide-1 derivative with anti-diabetic effects in glucose-intolerant pigs. Eur J Pharmacol. 2002. 451:217–225.

34. Rolin B, Larsen MO, Gotfredsen CF, Deacon CF, Carr RD, Wilken M, Knudsen LB. The long-acting GLP-1 derivative NN2211 ameliorates glycemia and increases beta-cell mass in diabetic mice. Am J Physiol Endocrinol Metab. 2002. 283:E745–E752.

35. Madsbad S, Schmitz O, Ranstam J, Jakobsen G, Matthews DR. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial. Diabetes Care. 2004. 27:1335–1342.

36. Nauck MA, Hompesch M, Filipczak R, Le TD, Zdravkovic M, Gumprecht J. Five weeks of treatment with the GLP-1 analogue liraglutide improves glycaemic control and lowers body weight in subjects with type 2 diabetes. Exp Clin Endocrinol Diabetes. 2006. 114:417–423.

37. Kim JG, Baggio LL, Bridon DP, Castaigne JP, Robitaille MF, Jette L, Benquet C, Drucker DJ. Development and characterization of a glucagon-like peptide 1-albumin conjugate: the ability to activate the glucagon-like peptide 1 receptor in vivo. Diabetes. 2003. 52:751–759.

38. Youn YS, Chae SY, Lee S, Jeon JE, Shin HG, Lee KC. Evaluation of therapeutic potentials of site-specific PEGylated glucagon-like peptide-1 isomers as a type 2 anti-diabetic treatment: Insulinotropic activity, glucose-stabilizing capability, and proteolytic stability. Biochem Pharmacol. 2007. 73:84–93.

39. Holst JJ, Deacon CF. Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes. Diabetes. 1998. 47:1663–1670.

40. Ahren B, Holst JJ, Martensson H, Balkan B. Improved glucose tolerance and insulin secretion by inhibition of dipeptidyl peptidase IV in mice. Eur J Pharmacol. 2000. 404:239–245.

41. Zander M, Madsbad S, Deacon CF, Holst JJ. The metabolite generated by dipeptidyl-peptidase 4 metabolism of glucagon-like peptide-1 has no influence on plasma glucose levels in patients with type 2 diabetes. Diabetologia. 2006. 49:369–374.

42. Ahren B, Simonsson E, Larsson H, Landin-Olsson M, Torgeirsson H, Jansson PA, Sandqvist M, Bavenholm P, Efendic S, Eriksson JW, Dickinson S, Holmes D. Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in type 2 diabetes. Diabetes Care. 2002. 25:869–875.

43. Ahren B, Landin-Olsson M, Jansson PA, Svensson M, Holmes D, Schweizer A. Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. J Clin Endocrinol Metab. 2004. 89:2078–2084.

44. Ahren B, Gomis R, Standl E, Mills D, Schweizer A. Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes. Diabetes Care. 2004. 27:2874–2880.

45. Ahren B, Pacini G, Foley JE, Schweizer A. Improved meal-related beta-cell function and insulin sensitivity by the dipeptidyl peptidase-IV inhibitor vildagliptin in metformin-treated patients with type 2 diabetes over 1 year. Diabetes Care. 2005. 28:1936–1940.

46. Ristic S, Byiers S, Foley J, Holmes D. Improved glycaemic control with dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes: vildagliptin (LAF237) dose response. Diabetes Obes Metab. 2005. 7:692–698.

47. Herman GA, Stevens C, Van Dyck K, Bergman A, Yi B, De Smet M, Snyder K, Hilliard D, Tanen M, Tanaka W, Wang AQ, Zeng W, Musson D, Winchell G, Davies MJ, Ramael S, Gottesdiener KM, Wagner JA. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther. 2005. 78:675–688.

48. Bergman AJ, Stevens C, Zhou Y, Yi B, Laethem M, De Smet M, Snyder K, Hilliard D, Tanaka W, Zeng W, Tanen M, Wang AQ, Chen L, Winchell G, Davies MJ, Ramael S, Wagner JA, Herman GA. Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers. Clin Ther. 2006. 28:55–72.

49. Herman GA, Bergman A, Stevens C, Kotey P, Yi B, Zhao P, Dietrich B, Golor G, Schrodter A, Keymeulen B, Lasseter KC, Kipnes MS, Snyder K, Hilliard D, Tanen M, Cilissen C, De Smet M, de Lepeleire I, Van Dyck K, Wang AQ, Zeng W, Davies MJ, Tanaka W, Holst JJ, Deacon CF, Gottesdiener KM, Wagner JA. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab. 2006. 91:4612–4619.

50. Augeri DJ, Robl JA, Betebenner DA, Magnin DR, Khanna A, Robertson JG, Wang A, Simpkins LM, Taunk P, Huang Q, Han SP, Abboa-Offei B, Cap M, Xin L, Tao L, Tozzo E, Welzel GE, Egan DM, Marcinkeviciene J, Chang SY, Biller SA, Kirby MS, Parker RA, Hamann LG. Discovery and preclinical profile of Saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem. 2005. 48:5025–5037.

51. Uwaifo GI, Ratner RE. Novel pharmacologic agents for type 2 diabetes. Endocrinol Metab Clin North Am. 2005. 34:155–197.