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N-terminally modified glucagon-like peptide-1(7-36) amide exhibits resistance to enzymatic degradation while maintaining its antihyperglycaemic activity in vivo

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O'Harte, Finbarr, Mooney, MH, Lawlor, A and Flatt, Peter (2000) N-terminally modified glucagon-like peptide-1(7-36) amide exhibits resistance to enzymatic degradation while maintaining its antihyperglycaemic activity in vivo. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, 1474 (1). pp. 13-22. [Journal article]

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Abstract

Glucagon-like peptide-1 (7-36)amide (tGLP-1) is inactivated by dipeptidyl peptidase (DPP) IV by removal of the NH2-terminal dipeptide His(7)-Ala(8). We examined the degradation of NH2-terminally modified His(7)-glucitol tGLP-1 and its insulin-releasing and antihyperglycaemic activity in vivo, tGLP-1 was degraded by purified DPP IV after 4 h (43% intact) and after 12 hi 89% was converted to GLP-1(9-36)amide. In contrast > 99% of His(7)-glucitol tGLP-1 remained intact at 12 h. His(7)-glucitol tGLP-1 was similarly resistant to plasma degradation in vitro. His7-glucitol tGLP-1 showed greater resistance to degradation in vivo (92% intact) compared to tGLP-1 (27% intact) 10 min after i.p. administration to Wistar rats. Glucose homeostasis was examined following i.p. injection of both peptides (12 nmol/kg) together with glucose (18 mmol/kg). Plasma glucose concentrations were significantly reduced and insulin concentrations elevated following peptides administration compared with glucose alone. The area under the curve (AUC) for glucose for controls (AUC 691 +/- 35 mM/min) was significantly lower after administration of tGLP-1 and His7-glucitol tGLP-1 (36 and 49% less; AUC; 440 +/- 40 and 353 +/- 31 mM/min, respectively; P < 0.01). This was associated with a significantly higher AUC for insulin (98-99% greater; AUC 834 +/- 6 and 838 +/- 39 ng/ml/min, respectively: P < 0.01) after tGLP-1 and His7-glucitol tGLP-1 administration compared to controls (421 +/- 30 ng/ml/min). In conclusion, His(7)-glucitol tGLP-1 resists plasma DPP IV degradation while retaining potent antihyperglycaemic and insulin-releasing activities in vivo. (C) 2000 Elsevier Science B.V. All rights reserved.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences
Faculty of Life and Health Sciences > School of Biomedical Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Diabetes
ID Code:3100
Deposited By:Professor Peter Flatt
Deposited On:13 Jan 2010 16:22
Last Modified:11 Jun 2010 12:42

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