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Biological activities of glucagon-like peptide-1 analogues in vitro and in vivo.
Biochemistry. 2001 Mar 06; 40(9):2860-9.B

Abstract

Studies support a role for glucagon-like peptide 1 (GLP-1) as a potential treatment for diabetes. However, since GLP-1 is rapidly degraded in the circulation by cleavage at Ala(2), its clinical application is limited. Hence, understanding the structure-activity of GLP-1 may lead to the development of more stable and potent analogues. In this study, we investigated GLP-1 analogues including those with N-, C-, and midchain modifications and a series of secretin-class chimeric peptides. Peptides were analyzed in CHO cells expressing the hGLP-1 receptor (R7 cells), and in vivo oral glucose tolerance tests (OGTTs) were performed after injection of the peptides in normal and diabetic (db/db) mice. [D-Ala(2)]GLP-1 and [Gly(2)]GLP-1 showed normal or relatively lower receptor binding and cAMP activation but exerted markedly enhanced abilities to reduce the glycemic response to an OGTT in vivo. Improved biological effectiveness of [D-Ala(2)]GLP-1 was also observed in diabetic db/db mice. Similarly, improved biological activity of acetyl- and hexenoic-His(1)-GLP-1, glucagon((1-5)-, glucagon((1-10))-, PACAP(1-5)-, VIP(1-5)-, and secretin((1-10))-GLP-1 was observed, despite normal or lower receptor binding and activation in vitro. [Ala(8/11/12/16)] substitutions also increased biological activity in vivo over wtGLP-1, while C-terminal truncation of 4-12 amino acids abolished receptor binding and biological activity. All other modified peptides examined showed normal or decreased activity in vitro and in vivo. These results indicate that specific N- and midchain modifications to GLP-1 can increase its potency in vivo. Specifically, linkage of acyl-chains to the alpha-amino group of His(1) and replacement of Ala(2) result in significantly increased biological effects of GLP-1 in vivo, likely due to decreased degradation rather than enhanced receptor interactions. Replacement of certain residues in the midchain of GLP-1 also augment biological activity.

Authors+Show Affiliations

Department of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11258897

Citation

Xiao, Q, et al. "Biological Activities of Glucagon-like Peptide-1 Analogues in Vitro and in Vivo." Biochemistry, vol. 40, no. 9, 2001, pp. 2860-9.
Xiao Q, Giguere J, Parisien M, et al. Biological activities of glucagon-like peptide-1 analogues in vitro and in vivo. Biochemistry. 2001;40(9):2860-9.
Xiao, Q., Giguere, J., Parisien, M., Jeng, W., St-Pierre, S. A., Brubaker, P. L., & Wheeler, M. B. (2001). Biological activities of glucagon-like peptide-1 analogues in vitro and in vivo. Biochemistry, 40(9), 2860-9.
Xiao Q, et al. Biological Activities of Glucagon-like Peptide-1 Analogues in Vitro and in Vivo. Biochemistry. 2001 Mar 6;40(9):2860-9. PubMed PMID: 11258897.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Biological activities of glucagon-like peptide-1 analogues in vitro and in vivo. AU - Xiao,Q, AU - Giguere,J, AU - Parisien,M, AU - Jeng,W, AU - St-Pierre,S A, AU - Brubaker,P L, AU - Wheeler,M B, PY - 2001/3/22/pubmed PY - 2001/5/22/medline PY - 2001/3/22/entrez SP - 2860 EP - 9 JF - Biochemistry JO - Biochemistry VL - 40 IS - 9 N2 - Studies support a role for glucagon-like peptide 1 (GLP-1) as a potential treatment for diabetes. However, since GLP-1 is rapidly degraded in the circulation by cleavage at Ala(2), its clinical application is limited. Hence, understanding the structure-activity of GLP-1 may lead to the development of more stable and potent analogues. In this study, we investigated GLP-1 analogues including those with N-, C-, and midchain modifications and a series of secretin-class chimeric peptides. Peptides were analyzed in CHO cells expressing the hGLP-1 receptor (R7 cells), and in vivo oral glucose tolerance tests (OGTTs) were performed after injection of the peptides in normal and diabetic (db/db) mice. [D-Ala(2)]GLP-1 and [Gly(2)]GLP-1 showed normal or relatively lower receptor binding and cAMP activation but exerted markedly enhanced abilities to reduce the glycemic response to an OGTT in vivo. Improved biological effectiveness of [D-Ala(2)]GLP-1 was also observed in diabetic db/db mice. Similarly, improved biological activity of acetyl- and hexenoic-His(1)-GLP-1, glucagon((1-5)-, glucagon((1-10))-, PACAP(1-5)-, VIP(1-5)-, and secretin((1-10))-GLP-1 was observed, despite normal or lower receptor binding and activation in vitro. [Ala(8/11/12/16)] substitutions also increased biological activity in vivo over wtGLP-1, while C-terminal truncation of 4-12 amino acids abolished receptor binding and biological activity. All other modified peptides examined showed normal or decreased activity in vitro and in vivo. These results indicate that specific N- and midchain modifications to GLP-1 can increase its potency in vivo. Specifically, linkage of acyl-chains to the alpha-amino group of His(1) and replacement of Ala(2) result in significantly increased biological effects of GLP-1 in vivo, likely due to decreased degradation rather than enhanced receptor interactions. Replacement of certain residues in the midchain of GLP-1 also augment biological activity. SN - 0006-2960 UR - https://www.unboundmedicine.com/medline/citation/11258897/Biological_activities_of_glucagon_like_peptide_1_analogues_in_vitro_and_in_vivo_ L2 - https://dx.doi.org/10.1021/bi0014498 DB - PRIME DP - Unbound Medicine ER -