How glucagon-like is glucagon-like peptide-1?

Abstract

Summary. Although glucagon-like peptide-1 has the appearance of a glucagon-homologue that may be co-secreted with glucagon, synthetic glucagon-like peptide-l-(1-37) does not significantly affect plasma glucose and insulin concentrations when administered at high doses (100 and 400 ~tg) to cortisone-pretreated rabbits. This synthetic preparation thus lacks the primary metabolic effect of glucagon at the doses tested. An intra-or extra-pancreatic role of glucagon-like peptide-1 has yet to be discovered. Key words:Glucagon-like peptide-1, glucose, insulin, glucagon, bioassay.The nucleotide sequences of cDNA derived from hamster [1] and ox [2] glucagon mRNA and the human preproglucagon gene [3] show that pre-proglucagon contains two further glucagon-like peptides (GLP-1 and -2) C-terminal to the glucagon sequence. The amino-acid sequence of GLP-1 is completely conserved between the three mammalian species studied and shows a high degree of homology with similar deduced amino-acid sequences in angler-fish pre-proglucagons [4]. It is defined by delimiting pairs of basic amino-acid residues, that form potential cleavage points. GLP-1 thus has the appearance of a highly conserved biologically active peptide that may be co-secreted with glucagon, and it is possible that it has a modulating role in carbohydrate metabolism. In the first instance we have tested synthetic GLP-1 for its effect on plasma glucose and insulin concentrations in rabbits. Material and methodsSynthetic GLP-l-(1-37) was synthesized by a solid phase method [5] (Bachem, Torrance, CA, USA). It was tested for its effect on plasma glucose and insulin by a modification of the twin cross-over bioassay for glucagon [6], using crystalline glucagon (Novo Industri, Copenhagen, Denmark) as a standard. Twelve rabbits were injected (25 mg subcutaneously) on day 0 with cortisone acetate injection (British Pharmacopoeia; Cortistab, The Boots Company, Nottingham, UK). The assay was performed on days 2 and 3, the rabbits being deprived of food for 18 h before each part of the assay, but with free access to water. The peptides were dissolved immediately before each experiment in 1.6% (vol/vol) aqueous glycerine containing 0.2% (wt/vol) phenol, adjusted to pH 3 with HC1.The rabbits were randomized into four groups of three each, and they received a subcutaneous injection of 1 ml of diluent, as a control, followed after 60 min by either GLP-1 (400 gg or 100 gg) or glucagon (24 .ag or 6 ~xg) in the same volume. Blood samples (0.3 ml) were taken from a marginal ear vein at times -40, 0, 20 and 60 rain in relation to both the diluent and peptide injections. The next day, the experiment was repeated with a twin cross-over, so that rabbits that had received the higher dose of glucagon now received the lower dose of GLP-1. The blood samples were collected into fluoride-oxalate centrifuge tubes, containing dried aprotinin (200 Kallikrein Inhibitor Units; Trasylol, Bayer, Wuppertal, FRG), and centrifuged immediately at 1600 g for 10 min. The plasma was frozen on solid CO2 and st...

Glucagon-like peptide-1 but not glucagon-like peptide-2 stimulates insulin release from isolated rat pancreatic islets

“…In contrast to our findings, Ghiglione et al [20] failed to demonstrate a glucagon-like activity of GLP-1 in vivo in rabbits on blood glucose or plasma insulin levels, even at pharmacological doses. Two reasons could explain these negative results: First, due to the lack of interaction with the glucagon receptor in the liver [7] no effect on hepatic gluconeogenesis can be ex-pected.…”

The Structure-Function Relationship of GLP-1 Related Peptides in the Endocrine Function of the Canine Pancreas.

“…Although GLP-1(1-37) has similarities in 14 of the 37 amino acids compared with glucagon, this peptide did not elicit any insulinotropic action in anesthetized dogs, as originally reported by Ghiglione et al (1984). In contrast, a truncated peptide (7-37) revealed clearly an insulinotropic action in the present experiment, confirming the findings reported previously (Holst et al 1987 ;Mojsov et al 1987 ;Matsuyama et al 1988 ;(rskov et al 1988 ;Shima et al 1988 ;Kawai et al 1989 ;Suzuki et al 1989).…”

“…Although GLP-1 (1-37) has similarities in its amino acid sequence to glucagon, this peptide did not show any glucagon action, such as insulinotropic or glycogenolytic action (Ghiglione et al 1984). However, it has been reported that a truncated GLP-1 (7-37) elicited a strong insulin stimulating action (Mojsov et al 1987; Holst et al 1987; Shima et al 1988; Kawai et al 1989).…”

Glucagon‐like peptide‐1(7–36) amide is a new incretin/enterogastrone candidate

“…GLP-l(1-36) amide did not alter blood glucose or insulin levels in fasted canines [38]. Schmidt, Siege1 & Creutzfeldt obtained a weak stimulatory effect on insulin secretion in isolated rat pancreatic islets using supraphysiological concentrations of GLP-l(1-36) amide [39], while GLP-l(1-36) amide had no insulinotropic effect in the isolated perfused pig pancreas as shown by Orskov, Holst, Knuhtsen, Baldissera, Poulsen & Vagn Nielsen [14].…”