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E Bojanowska and B Stempniak

To date, glucagon-like peptide 1(7-36) amide (tGLP-1) has been found to affect the neurohypophysial and cardiovascular functions in normotensive and normovolaemic rats. The aim of the present study was to investigate possible effects of tGLP-1 on the mean arterial blood pressure and the release of vasopressin and oxytocin under conditions of blood volume depletion in the rat. In the first series of experiments, the animals were injected i.p. with either 0.15 M saline or 30% polyethylene glycol (PEG). PEG caused an 18% reduction of blood volume 1 h after injection. No significant changes in the mean arterial blood pressure were found in either normo- or hypovolaemic rats during the experiment. tGLP-1 injected i.c.v. at a dose of 1 microg/5 microl 1 h after the i.p. injection increased similarly the arterial blood pressure in normo- and hypovolaemic rats. The plasma vasopressin/oxytocin concentrations were markedly elevated in hypovolaemic animals and tGLP-1 further augmented the release of both hormones. In the second study, hypovolaemia was induced by double blood withdrawal. The haemorrhage resulted in a marked decrease of the mean arterial blood pressure and in the elevated plasma vasopressin/oxytocin concentrations. tGLP-1 injected immediately after the second blood withdrawal increased the arterial blood pressure. In parallel, tGLP-1 enhanced significantly vasopressin and oxytocin secretion when compared with haemorrhaged, saline-injected rats. The results of this study indicate that tGLP-1 may affect the arterial blood pressure and the secretion of neurohypophysial hormones under pathological conditions brought about by blood volume depletion.

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BD Green, MH Mooney, VA Gault, N Irwin, CJ Bailey, P Harriott, B Greer, FP O'Harte, and PR Flatt

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.

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Isabella Artner, Yan Hang, Min Guo, Guoqiang Gu, and Roland Stein

factors have been shown to play fundamental roles in pancreas development and function, especially those linked to endocrine cell-specific expression of the hormones glucagon and insulin (reviewed by Sander & German 1997 , Servitja & Ferrer 2004

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Niamh X Cawley, Guida Portela-Gomes, Hong Lou, and Y Peng Loh

, we extend those findings and show yapsin 1-like immunoreactivity exclusively in human pancreatic islet α-cells and that purified yapsin 1 can generate glucagon by processing proglucagon. These results suggest the presence of a yapsin 1-like

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N M Whalley, L E Pritchard, D M Smith, and A White

Introduction Like many prohormones, proglucagon is processed in a cell type-specific manner. In the α-cells of the pancreas, proglucagon is processed to glucagon by prohormone convertase 2 (PC2), but it undergoes alternative processing in the L

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Alessandro Pocai

insulin. Recent work on understanding the physiological function of proglucagon-derived peptides has renewed interest in glucagon-based therapeutics. One of these peptides is glucagon-like peptide-1 (GLP1), which is secreted from the L cells of the

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Herbert A Schmid and Josef Brueggen

in clinical trials, as expected based on the physiological effect of natural somatostatin. Glucose homeostasis is a complex process regulated by the interactions of various hormones, including insulin, glucagon, and somatostatin (among others), plus

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Simon C Lee, Christine A Robson-Doucette, and Michael B Wheeler

Introduction Blood glucose homeostasis is maintained by the concerted and opposing actions of the hormones insulin and glucagon. Insulin release from the pancreatic β-cell promotes glucose utilization when blood glucose levels are high, while

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Tetsuhiro Kakimoto, Hirotaka Kimata, Satoshi Iwasaki, Atsushi Fukunari, and Hiroyuki Utsumi

, Yoon et al . 2003 ), suggesting that subjects with insulin resistance develop diabetes with the onset of β-cell dysfunction. Drugs to effectively increase insulin-secreting β-cells have been long-awaited. Glucagon-like peptide-1 (GLP-1), a member of