des-His1-[Glu9]-Glucagon (1-29) amide

Glucagon receptors on human islet cells contribute to glucose competence of insulin release.[Pubmed:10990079]

Diabetologia. 2000 Aug;43(8):1012-9.

AIMS/HYPOTHESIS: Synergism between glucose and cAMP in the stimulation of insulin secretion has been suggested to regulate beta cells. This study assessed the importance of an interaction between glucose and cAMP in the stimulation of insulin secretion from human islet cells by investigating expression and functional activity of receptors recognising glucagon, glucagon-like peptide-1 (7-36)amide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). METHODS: Expression of the glucagon, GLP-1 and GIP receptors in human islets was investigated by northern blots and reverse transcription-polymerase chain reaction analysis. Functional activity of these receptors was assessed by the effects of peptides (agonists and antagonists) on glucose-induced insulin release. RESULTS: Human islet cells express transcripts encoding glucagon, GLP-1 and GIP receptors. Glucose (10 mmol/l) stimulated insulin release 4.5 +/- 0.6-fold over basal (2.5 mmol/l). This glucose effect was amplified by 10 nmol/l GLP-1, GIP or glucagon. It was reduced by 51 +/- 6% in the presence of 1 micromol/l of the glucagon-receptor antagonist des-His1-[Glu9]-glucagon-amide (n = 8; p < 0.05), indicating participation of endogenously released glucagon in the process of glucose-induced insulin release. The glucagon-receptor antagonist also suppressed the potentiation of glucose-induced insulin release by addition of 10 nmol/l glucagon. CONCLUSION/INTERPRETATION: These data suggest that human beta cells express functional glucagon receptors which can, similar to incretin hormone receptors, generate synergistic signals for glucose-induced insulin secretion.

Biological activities of des-His1[Glu9]glucagon amide, a glucagon antagonist.[Pubmed:2560175]

Peptides. 1989 Nov-Dec;10(6):1171-7.

Hyperglycemia in diabetes mellitus is generally associated with elevated levels of glucagon in the blood. A glucagon analog, des-His1[Glu9]glucagon amide, has been designed and synthesized and found to be an antagonist of glucagon in several systems. It has been a useful tool for investigating the mechanisms of glucagon action and for providing evidence that glucagon is a contributing factor in the pathogenesis of diabetes. The in vitro and in vivo activities of the antagonist are reported here. The analog bound 40% as well as glucagon to liver membranes, but did not stimulate the release of cyclic AMP even at 10(6) higher concentration. However, it did activate a second pathway, with the release of inositol phosphates. In addition, the analog enhanced the glucose-stimulated release of insulin from pancreatic islet cells. Of particular importance were the findings that the antagonist also showed only very low activity (less than 0.2%) in the in vivo glycogenolysis assay, and that at a ratio of 100:1 the analog almost completely blocked the hyperglycemic effects of added glucagon in normal rabbits. In addition, it reduced the hyperglycemia produced by endogenous glucagon in streptozotocin diabetic rats. Thus, we have an analog that possesses properties that are necessary for a glucagon antagonist to be potentially useful in the study and treatment of diabetes.