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

Glucagon-like peptide-1 (7-36)amide (tGLP-1) is inactivated by dipeptidyl p eptidase (DPP) IV by removal of the NH2-terminal dipeptide His(7)-Ala(8). W e 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 tG LP-1 remained intact at 12 h. His(7)-glucitol tGLP-1 was similarly resistan t to plasma degradation in vitro. His7-glucitol tGLP-1 showed greater resis tance to degradation in vivo (92% intact) compared to tGLP-1 (27% intact) 1 0 min after i.p. administration to Wistar rats. Glucose homeostasis was exa mined following i.p. injection of both peptides (12 nmol/kg) together with glucose (18 mmol/kg). Plasma glucose concentrations were significantly redu ced and insulin concentrations elevated following peptides administration c ompared with glucose alone. The area under the curve (AUC) for glucose for controls (AUC 691 +/- 35 mM/min) was significantly lower after administrati on 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 sig nificantly 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 conclusio n, His(7)-glucitol tGLP-1 resists plasma DPP IV degradation while retaining potent antihyperglycaemic and insulin-releasing activities in vivo. (C) 20 00 Elsevier Science B.V. All rights reserved.