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Dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1 which have extended metabolic stability and improved biological activity.
Diabetologia. 1998 Mar; 41(3):271-8.D

Abstract

Glucagon-like peptide 1 (GLP-1) has great potential in diabetes therapy due to its glucose-dependent stimulation of insulin secretion, but this is limited by its rapid degradation, primarily by dipeptidyl peptidase IV. Four analogues, N-terminally substituted with threonine, glycine, serine or alpha-aminoisobutyric acid, were synthesised and tested for metabolic stability. All were more resistant to dipeptidyl peptidase IV in porcine plasma in vitro, ranging from a t1/2 of 159 min (Gly8 analogue) to undetectable degradation after 6 h (Aib8 analogue; t1/2 for GLP-1 (7-36) amide, 28 min). During i. v. infusion in anaesthetised pigs, over 50% of each analogue remained undegraded compared to 22.7 % for GLP-1 (7-36) amide. In vivo, analogues had longer N-terminal t1/2 (intact peptides: means, 3.3-3.9 min) than GLP-1 (7-36) amide (0.9 min; p < 0.01), but these did not exceed the C-terminal t1/2 (intact plus metabolite: analogues, 3.5-4.4 min; GLP-1 (7-36) amide, 4.1 min). Analogues were assessed for receptor binding using a cell line expressing the cloned receptor, and for ability to stimulate insulin or inhibit glucagon secretion from the isolated perfused porcine pancreas. All bound to the receptor, but only the Aib8 and Gly8 analogues had similar affinities to GLP-1 (7-36) amide (IC50; Aib8=0.45 nmol/l; Gly8=2.8 nmol/l; GLP-1 (7-36) amide=0.78 nmol/l). All analogues were active in the isolated pancreas, with the potency order reflecting receptor affinities (Aib8 > Gly8 > Ser8 > Thr8). N-terminal modification of GLP-1 confers resistance to dipeptidyl peptidase IV degradation. Such analogues are biologically active and have prolonged metabolic stability in vivo, which, if associated with greater potency and duration of action, may help to realise the potential of GLP-1 in diabetes therapy.

Authors+Show Affiliations

Department of Medical Physiology, The Panum Institute, University of Copenhagen, Denmark.No 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

9541166

Citation

Deacon, C F., et al. "Dipeptidyl Peptidase IV Resistant Analogues of Glucagon-like Peptide-1 Which Have Extended Metabolic Stability and Improved Biological Activity." Diabetologia, vol. 41, no. 3, 1998, pp. 271-8.
Deacon CF, Knudsen LB, Madsen K, et al. Dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1 which have extended metabolic stability and improved biological activity. Diabetologia. 1998;41(3):271-8.
Deacon, C. F., Knudsen, L. B., Madsen, K., Wiberg, F. C., Jacobsen, O., & Holst, J. J. (1998). Dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1 which have extended metabolic stability and improved biological activity. Diabetologia, 41(3), 271-8.
Deacon CF, et al. Dipeptidyl Peptidase IV Resistant Analogues of Glucagon-like Peptide-1 Which Have Extended Metabolic Stability and Improved Biological Activity. Diabetologia. 1998;41(3):271-8. PubMed PMID: 9541166.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1 which have extended metabolic stability and improved biological activity. AU - Deacon,C F, AU - Knudsen,L B, AU - Madsen,K, AU - Wiberg,F C, AU - Jacobsen,O, AU - Holst,J J, PY - 1998/4/16/pubmed PY - 1998/4/16/medline PY - 1998/4/16/entrez SP - 271 EP - 8 JF - Diabetologia JO - Diabetologia VL - 41 IS - 3 N2 - Glucagon-like peptide 1 (GLP-1) has great potential in diabetes therapy due to its glucose-dependent stimulation of insulin secretion, but this is limited by its rapid degradation, primarily by dipeptidyl peptidase IV. Four analogues, N-terminally substituted with threonine, glycine, serine or alpha-aminoisobutyric acid, were synthesised and tested for metabolic stability. All were more resistant to dipeptidyl peptidase IV in porcine plasma in vitro, ranging from a t1/2 of 159 min (Gly8 analogue) to undetectable degradation after 6 h (Aib8 analogue; t1/2 for GLP-1 (7-36) amide, 28 min). During i. v. infusion in anaesthetised pigs, over 50% of each analogue remained undegraded compared to 22.7 % for GLP-1 (7-36) amide. In vivo, analogues had longer N-terminal t1/2 (intact peptides: means, 3.3-3.9 min) than GLP-1 (7-36) amide (0.9 min; p < 0.01), but these did not exceed the C-terminal t1/2 (intact plus metabolite: analogues, 3.5-4.4 min; GLP-1 (7-36) amide, 4.1 min). Analogues were assessed for receptor binding using a cell line expressing the cloned receptor, and for ability to stimulate insulin or inhibit glucagon secretion from the isolated perfused porcine pancreas. All bound to the receptor, but only the Aib8 and Gly8 analogues had similar affinities to GLP-1 (7-36) amide (IC50; Aib8=0.45 nmol/l; Gly8=2.8 nmol/l; GLP-1 (7-36) amide=0.78 nmol/l). All analogues were active in the isolated pancreas, with the potency order reflecting receptor affinities (Aib8 > Gly8 > Ser8 > Thr8). N-terminal modification of GLP-1 confers resistance to dipeptidyl peptidase IV degradation. Such analogues are biologically active and have prolonged metabolic stability in vivo, which, if associated with greater potency and duration of action, may help to realise the potential of GLP-1 in diabetes therapy. SN - 0012-186X UR - https://www.unboundmedicine.com/medline/citation/9541166/Dipeptidyl_peptidase_IV_resistant_analogues_of_glucagon_like_peptide_1_which_have_extended_metabolic_stability_and_improved_biological_activity_ L2 - https://doi.org/10.1007/s001250050903 DB - PRIME DP - Unbound Medicine ER -