N-terminal His(7)-modification of glucagon-like peptide-1(7-36) amide generates dipeptidyl peptidase IV-stable analogues with potent antihyperglycaemic activity
Open accessAbstract
Glucagon-like peptide-1(7-36)amide (GLP-1) possesses several unique and beneficial effects for the potential treatment of type 2 diabetes. However, the rapid inactivation of GLP-1 by dipeptidyl peptidase IV (DPP IV) results in a short half-life in vivo (less than 2 min) hindering therapeutic development. In the present study, a novel His(7)-modified analogue of GLP-1, N-pyroglutamyl-GLP-1, as well as N-acetyl-GLP-1 were synthesised and tested for DPP IV stability and biological activity. Incubation of GLP-1 with either DPP IV or human plasma resulted in rapid degradation of native GLP-1 to GLP-1(9-36)amide, while N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 were completely resistant to degradation. N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 bound to the GLP-1 receptor but had reduced affinities (IC(50) values 32.9 and 6.7 nM, respectively) compared with native GLP-1 (IC(50) 0.37 nM). Similarly, both analogues stimulated cAMP production with EC(50) values of 16.3 and 27 nM respectively compared with GLP-1 (EC(50) 4.7 nM). However, N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 exhibited potent insulinotropic activity in vitro at 5.6 mM glucose (P<0.05 to P<0.001) similar to native GLP-1. Both analogues (25 nM/kg body weight) lowered plasma glucose and increased plasma insulin levels when administered in conjunction with glucose (18 nM/kg body weight) to adult obese diabetic (ob/ob) mice. N-pyroglutamyl-GLP-1 was substantially better at lowering plasma glucose compared with the native peptide, while N-acetyl-GLP-1 was significantly more potent at stimulating insulin secretion. These studies indicate that N-terminal modification of GLP-1 results in DPP IV-resistant and biologically potent forms of GLP-1. The particularly powerful antihyperglycaemic action of N-pyroglutamyl-GLP-1 shows potential for the treatment of type 2 diabetes.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
T2DM treatment with incretins focuses on modified analogues or receptor agonists, including exenatide.
“their application in T2DM treatment focuses on modified analogues320, 321, 322, 323, 324, 325 or receptor agonists, including the well-known, short-acting exenatide.326, 327, 328”
From Pancreatic regulation of glucose homeostasis. (2016) · cites this paper as [322]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Biochemical and Biophysical Research Communications
Rc, A. N., On Filamentous Bacteriophage, M., Hoffmann, S., & Willbold, D. (1960) · Nature · doi:10.1038/186124d0 · Cited by 6,690 · see citing works
A role for glucagon-like peptide-1 in the central regulation of feeding
Turton, M. D., O'Shea, D., Gunn, I., Beak, S. A., Edwards, C. M. B., Meeran, K., Choi, S. J., Taylor, G. M., Heath, M. M., Lambert, P. D., et al. (1996) · Nature · doi:10.1038/379069a0 · Cited by 1,950 · see citing works
Stewart, J. M. (1976) · Journal of Macromolecular Science Part A - Chemistry · doi:10.1080/00222337608068099 · Cited by 1,770 · see citing works
Nauck, M. A., Heimesaat, M. M., Orskov, C., Holst, J. J., Ebert, R., & Creutzfeldt, W. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116186 · Cited by 1,651 · see citing works
Salacinski, P., McLean, C., Sykes, J. E., Clement‐Jones, V., & Lowry, P. J. (1981) · Analytical Biochemistry · doi:10.1016/0003-2697(81)90703-x · Cited by 1,129 · see citing works
Eng, J., Kleinman, W. A., Singh, L., Singh, G., & Raufman, J. P. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)42531-8 · Cited by 1,000 · see citing works
Thorens, B. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.18.8641 · Cited by 906 · see citing works
Drucker, D. J., Philippe, J., Mojsov, S., Chick, W. L., & Habener, J. F. (1987) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.84.10.3434 · Cited by 903 · see citing works
Mojsov, S., Weir, G. C., & Habener, J. F. (1987) · Journal of Clinical Investigation · doi:10.1172/jci112855 · Cited by 882 · see citing works
Deacon, C. F., Nauck, M. A., Toft-Nielsen, M.-B., Pridal, L., Willms, B., & Holst, J. J. (1995) · Diabetes · doi:10.2337/diabetes.44.9.1126 · Cited by 878 · see citing works
Scrocchi, L. A., Brown, T. J., Maclusky, N., Brubaker, P. L., Auerbach, A. B., Joyner, A. L., & Drucker, D. J. (1996) · Nature Medicine · doi:10.1038/nm1196-1254 · Cited by 793 · see citing works
European Journal of Clinical Investigation
Holgate, S. T. (2010) · European Journal of Clinical Investigation · doi:10.1111/(issn)1365-2362 · Cited by 645 · see citing works
Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor
Bullock, B. P., Heller, R. S., & Habener, J. F. (1996) · Endocrinology · doi:10.1210/endo.137.7.8770921 · Cited by 618 · see citing works
Holz, G. G., Kiihtreiber, W. M., & Habener, J. F. (1993) · Nature · doi:10.1038/361362a0 · Cited by 594 · see citing works
The Multiple Actions of GLP-1 on the Process of Glucose-Stimulated Insulin Secretion
MacDonald, P. E., El-kholy, W., Riedel, M. J., Salapatek, A. M. F., Light, P. E., & Wheeler, M. B. (2002) · Diabetes · doi:10.2337/diabetes.51.2007.s434 · Cited by 590 · see citing works
Biological actions and therapeutic potential of the glucagon-like peptides
Drucker, D. J. (2002) · Gastroenterology · doi:10.1053/gast.2002.31068 · Cited by 500 · see citing works
Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes.
Holst, J. J., & Deacon, C. F. (1998) · Diabetes · doi:10.2337/diabetes.47.11.1663 · Cited by 487 · see citing works
Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers
Edwards, C. M. B., Stanley, S. A., Davis, R. P., Brynes, A. E., Frost, G. S., Seal, L., Ghatei, M. A., & Bloom, S. R. (2001) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2001.281.1.e155 · Cited by 464 · see citing works
Perfetti, R., Zhou, J., Doyle, M. E., & Egan, J. M. (2000) · Endocrinology · doi:10.1210/endo.141.12.7806 · Cited by 442 · see citing works
Abnormal plasma glucose and insulin responses in heterozygous lean (ob/+) mice
Flatt, P. R., & Bailey, C. J. (1981) · Diabetologia · doi:10.1007/bf00252768 · Cited by 406 · see citing works
Self-citationMcClenaghan, N. H., Barnett, C. R., Ah-Sing, E., Abdel‐Wahab, Y. H. A., O'Harte, F. P. M., Yoon, T.-W., Swanston-Flatt, S. K., & Flatt, P. R. (1996) · Diabetes · doi:10.2337/diab.45.8.1132 · Cited by 352 · see citing works
Self-citationCampos, R. V., Lee, Y. C., & Drucker, D. J. (1994) · Endocrinology · doi:10.1210/endo.134.5.8156917 · Cited by 342 · see citing works
Zhou, J., Wang, X., Piñeyro, M. A., & Egan, J. (1999) · Diabetes · doi:10.2337/diabetes.48.12.2358 · Cited by 319 · see citing works
Exendin-4 Decelerates Food Intake, Weight Gain, and Fat Deposition in Zucker Rats
Szayna, M., Doyle, M. E., Betkey, J. A., Holloway, H. W., Spencer, R. G. S., Greig, N. H., & Egan, J. M. (2000) · Endocrinology · doi:10.1210/endo.141.6.7490 · Cited by 303 · see citing works
Insulinotropic Action of Glucagonlike Peptide-I-(7–37) in Diabetic and Nondiabetic Subjects
Nathan, D. M., Schreiber, E., Fogel, H., Mojsov, S., & Habener, J. F. (1992) · Diabetes Care · doi:10.2337/diacare.15.2.270 · Cited by 289 · see citing works
Knudsen, L. B., & Pridal, L. (1996) · European Journal of Pharmacology · doi:10.1016/s0014-2999(96)00795-9 · Cited by 248 · see citing works
Handbook of Mathematical Tables and Formulas
W., J. W., & Burington, R. S. (1973) · Mathematics of Computation · doi:10.2307/2005538 · Cited by 224 · see citing works
Hui, H., Wright, C. V. E., & Perfetti, R. (2001) · Diabetes · doi:10.2337/diabetes.50.4.785 · Cited by 224 · see citing works
Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes
Drucker, D. J. (2003) · Expert Opinion on Investigational Drugs · doi:10.1517/eoid.12.1.87.21250 · Cited by 204 · see citing works
Kolligs, F. T., Fehmann, H.-C., Göke, R., & Göke, B. (1995) · Diabetes · doi:10.2337/diab.44.1.16 · Cited by 185 · see citing works
Determination of glucose by an automatic analyser
Stevens, J. F. (1971) · Clinica Chimica Acta · doi:10.1016/0009-8981(71)90332-9 · Cited by 166 · see citing works
Merrifield, R. B. (1973) · Springer eBooks · doi:10.1007/978-1-4613-4571-8_16 · Cited by 154 · see citing works
Initiation of Increased Pancreatic Islet Growth in Young Normoglycemic Mice (Umea +/?)*
Edvell, A., & Lindström, P. (1999) · Endocrinology · doi:10.1210/endo.140.2.6514 · Cited by 151 · see citing works
Gault, V. A., O'Harte, F. P. M., Harriott, P., Mooney, M., Green, B., & Flatt, P. R. (2003) · Diabetologia · doi:10.1007/s00125-002-1028-x · Cited by 134 · see citing works
Self-citationA Novel Form of Dipeptidylpeptidase IV Found in Human Serum.
Duke‐Cohan, J. S., Morimoto, C., Rocker, J. A., et al. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.23.14107 · Cited by 118 · see citing works
Biological Activities of Glucagon-Like Peptide-1 Analogues in Vitro and in Vivo
Xiao, Q., Giguere, J., Parisien, M., Jeng, W., St-Pierre, S. A., Brubaker, P. L., & Wheeler, M. B. (2001) · Biochemistry · doi:10.1021/bi0014498 · Cited by 106 · see citing works
Bailey, C. J., Flatt, P. R., & Atkins, T. W. (1982) · PubMed · Cited by 98 · see citing works
Self-citationGlucagon‐like peptide‐1 (GLP‐1): a trial of treatment in non‐insulin‐dependent diabetes mellitus
Todd, J. F., Wilding, J. P. H., Edwards, C. M. B., KHAN, F. A., Ghatei, M. A., & Bloom, S. R. (1997) · European Journal of Clinical Investigation · doi:10.1046/j.1365-2362.1997.1490691.x · Cited by 87 · see citing works
McClenaghan, N. H., Barnett, C. R., Ah-Sing, E., et al. (1996) · Diabetes · doi:10.2337/diabetes.45.8.1132 · Cited by 86 · see citing works
Campos, R. V. (1994) · Endocrinology · doi:10.1210/en.134.5.2156 · Cited by 66 · see citing works
GLP-1-analogues resistant to degradation by dipeptidyl-peptidase IV in vitro
Gallwitz, B., Ropeter, T., Morys‐Wortmann, C., Mentlein, R., Siegel, E. G., & Schmidt, W. E. (2000) · Regulatory Peptides · doi:10.1016/s0167-0115(99)00095-6 · Cited by 64 · see citing works
Deacon, C. F., & Holst, J. J. (2002) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(02)00359-5 · Cited by 56 · see citing works
Hassan, M., Eskilsson, A., Nilsson, C., Jonsson, C., Jacobsson, H., Refai, E., Larsson, S., & Efendić, S. (1999) · Nuclear Medicine and Biology · doi:10.1016/s0969-8051(98)00121-8 · Cited by 56 · see citing works
Kolligs, F., Fehmann, H. C., Göke, R., et al. (1995) · Diabetes · doi:10.2337/diabetes.44.1.16 · Cited by 53 · see citing works
O'Harte, F. P. M. (2000) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/s0304-4165(99)00214-7 · Cited by 44 · see citing works
Self-citationInitiation of Increased Pancreatic Islet Growth in Young Normoglycemic Mice (Umea +/?)
Edvell, A. (1999) · Endocrinology · doi:10.1210/en.140.2.778 · Cited by 44 · see citing works
Comparison of dipeptidyl peptidase IV prepared from pig liver and kidney
Fukasawa, K. M., Fukasawa, K., Hiraoka, B. Y., & Harada, M. (1981) · Biochimica et Biophysica Acta (BBA) - Enzymology · doi:10.1016/0005-2744(81)90141-8 · Cited by 38 · see citing works
O'Harte, F. P. M., Gray, A. M., Abdel‐Wahab, Y. H. A., & Flatt, P. R. (1997) · Peptides · doi:10.1016/s0196-9781(97)00201-5 · Cited by 37 · see citing works
Self-citationO'Harte, F. P. M., Abdel‐Wahab, Y. H. A., Conlon, J. M., & Flatt, P. R. (1998) · Diabetologia · doi:10.1007/s001250051050 · Cited by 34 · see citing works
Self-citationPancreatic and extrapancreatic effects of GLP-1.
Valverde, I., Villanueva-Peñacarrillo, M., & Malaisse, W. J. (2002) · PubMed · Cited by 30 · see citing works
O'Harte, F. P. M., Mooney, M., Kelly, C., McKillop, A. M., & Flatt, P. R. (2001) · Regulatory Peptides · doi:10.1016/s0167-0115(00)00125-7 · Cited by 27 · see citing works
Self-citationMiguel, J. C., Abdel-Wahab, Y., Green, B., Mathias, P., & Flatt, P. (2003) · Biochemical Pharmacology · doi:10.1016/s0006-2952(02)01482-x · Cited by 24 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Pancreatic regulation of glucose homeostasis.
Röder, P. V., Wu, B., Liu, Y., & Han, W. (2016) · Experimental & Molecular Medicine · doi:10.1038/emm.2016.6 · Cited by 985 · see citing works
Green, B., Gault, V., O'Harte, F., & Flatt, P. (2004) · Current Pharmaceutical Design · doi:10.2174/1381612043382774 · Cited by 111 · see citing works
Self-citationPeptide therapeutics for CNS indications
McGonigle, P. (2012) · Biochemical Pharmacology · doi:10.1016/j.bcp.2011.10.014 · Cited by 95 · see citing works
Sun, L., Zheng, Z.-M., Shao, C.-S., Zhang, Z.-Y., Li, M.-W., Wang, L., Wang, H., Zhao, G.-H., & Wang, P. (2022) · Pharmaceuticals · doi:10.3390/ph15060740 · Cited by 17 · see citing works
- Authors
- Green, B., Mooney, M., Gault, V., Irwin, N., Bailey, C., Harriott, P., Greer, B., O'Harte, F., & Flatt, P.
- Affiliations
- University of Ulster (GB)
- Queen's University Belfast (GB)
- Venue
- Journal of Endocrinology
- Publisher
- Bioscientifica
- Published
- 2004-03-01
- Volume
- 180
- Issue
- 3
- Pages
- 379-388
- ISSN
- 0022-0795 (ISSN-L)
- 1479-6805
- OpenAlex
- W2114369058
- Cited by
- 57
- References
- 52
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2022: 4 · 2021: 6 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 3 · 2016: 3 · 2015: 2 · 2014: 1 · 2012: 3
- FWCI
- 2.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Aston Publications Explorer (Aston University) (submittedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Funders
- Ulster University
- Université de Lausanne
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Health Sciences › Medicine › Oncology › Peptidase Inhibition and Analysis
- Keywords
- glucagon-like peptide-1(7-36)amide, N-terminal modification, antidiabetic activity, insulin secretion, cAMP signaling, type 2 diabetes, peptide analogues, ob/ob mice
- MeSH terms
- Cyclic AMP, Animals, Cell Line, Transformed, Diabetes Mellitus, Glucagon-Like Peptides, Glucagon, Cricetinae, Hypoglycemic Agents, Insulin, Mesocricetus, Mice, Obese, Peptide Fragments, Protein Precursors, Pyrrolidonecarboxylic Acid, Dipeptidyl Peptidase 4, Mice, Glucagon-Like Peptide 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
