Diabetes has long been viewed as a bihormonal disorder, with glucagon excess, in the setting of insulin deficiency or insulin resistance, contributing significantly to the development of hyperglycemia. Accordingly strategies for reducing glucagon secretion (amylin, GLP-1), or inhibiting glucagon action, may be useful for the treatment of excess glucose production in patients with diabetes.
Shah and colleagues examined the importance of the ambient insulin concentration for development of glucagon-mediated hyperglycemia in human subjects following a prandial glucose load. The authors find that glucagon excess in the presence of relative insulin deficiency clearly contributes to impaired suppression of glucose production and hyperglycemia Impact of lack of suppression of glucagon on glucose tolerance in humans. Am J Physiol. 1999 Aug;277(2 Pt 1):E283-90.
Studies in patients with type 2 diabetes suggests that lack of glucagon suppression contributes to postprandial hyperglycemia in part via accelerated glycogenolysis. Analysis of blood glucose in the presence or absence of somatostatin-induced glucagon suppression during an OGTT revealed a significant increase in glucose in subjects with higher glucagon levels. See Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2000 Nov;85(11):4053-9
In this regard, development of structural and functional glucagon receptor antagonists represents a potential approach to decrease hepatic glucose production and lower blood glucose in patients with diabetes. The fungal bisanthroquinone skyrin, isolated from Talaromyces wortmannin, inhibits glucagon-stimulated cAMP formation and glucose output from rat and human hepatocytes. Skyrin does not appear to interfere with glucagon receptor binding in CHO cells or hepatocytes. Whether skyrin will also reduce blood glucose in normal or diabetic rodents in vivo remains unclear. See Effects of skyrin, a receptor-selective glucagon antagonist, in rat and human hepatocytes. Diabetes. 2000 Dec;49(12):2079-86
Complete elimination of signaling through the glucagon receptor in the mouse has now been reported. Remarkably, glucagon receptor knockout mice are viable, and do exhibit mild hypoglycemia and improved glucose tolerance with elevated levels of circulating glucagon. See Glycemic control in mice with targeted disruption of the glucagon receptor gene. Biochem Biophys Res Commun. 2002 Jan 18;290(2):839-43
Moreover, GLUR-/- mice exhibit a number of unexpected and striking phenotypes, including a significant increase in total pancreatic weight, marked islet α cell hyperplasia, extremely large elevations in circulating levels of circulating glucagon and GLP-1, and mild reproductive abnormalities. For a detailed overview of the phenotype, see Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1438-43
Gcgr-/- mice also exhibit resistance to diet-induced obesity, elevated levels of GLP-1, reduced gastric emptying, and resistance to streptozotocin-induced diabetes, as outlined in Glucagon receptor knockout mice are resistant to diet-induced obesity and streptozotocin-mediated beta cell loss and hyperglycaemia. Diabetologia. 2006 Nov 28; [Epub ahead of print]
Glucagon receptor antagonists and Type 2 Diabetes
The concept that antagonism of glucagon receptor action may be coupled to attenuation of experimental hyperglycemia has been examined for more than 2 decades, as clearly outlined in Hyperglycemia of diabetic rats decreased by a glucagon receptor antagonist. Science. 1982 Feb 26;215(4536):1115-6.
Just over twenty years later, a related proof of concept study for blocking glucagon action was carried out in db/db mice using antisense oligonucleotide administration to reduce glucagon receptor expression in the liver. This 3 week experiment demonstrated successful reduction of blood glucose, free fatty acids, and triglycerides, without the development of hypoglycemia, as outlined in Reduction in Glucagon Receptor Expression by an Antisense Oligonucleotide Ameliorates Diabetic Syndrome in db/db Mice. Diabetes. 2004 Feb;53(2):410-417
Immunoneutralization of endogenous glucagon action using acute or chronic administration of monoclonal antibody directed against glucagon produced acute and sustained reduction on plasma glucose, triglycerides, glucose tolerance, HbA1c, and hepatic glucose production in ob/ob mice as described in Immunoneutralization of Endogenous Glucagon Reduces Hepatic Glucose Output and Improves Long-Term Glycemic Control in Diabetic ob/ob Mice. Diabetes. 2006 Oct;55(10):2843-8
Similar studies in a variety of different rodent models have been reported using glucagon receptor antisense oligonucleotides (ASOs). Treatment of ob/ob and db/db mice, and ZDF rats, with twice weekly glucagon receptor ASOs produced striking and long lasting improvements in glycemia, together with reduced levels of triglycerides, and a decrease in plasma insulin. Consistent with findings in the Gcgr-/- mouse, rodents treated with Gcgr ASOs exhibited a-cell hyperplasia, markedly increased levels of circulating glucagon, and significantly (10-15-fold) increased levels of circulating GLP-1, together with increased levels of islet GLP-1. Hence, targeting the glucagon receptor and disrupting normal Gcgr signaling unmasks a compensatory increase in islet α cell activity accompanied by a shift towards islet GLP-1 production, with therapeutic benefits for the treatment of experimental diabetes. See Hepatic and glucagon-like peptide-1–mediated reversal of diabetes by glucagon receptor antisense oligonucleotide inhibitors J. Clin. Invest. 113:1571-1581 (2004).
A glucagon receptor antagonists which blocked glucagon action in experiments employing cell lines or primary cultures in vitro, or rodent studies in vivo as described in: Design and synthesis of glucagon partial agonists and antagonists. Biochemistry. 1986 Dec 16;25(25):8278-84 and Synthesis of two glucagon antagonists: receptor binding, adenylate cyclase, and effects on blood plasma glucose levels. J Med Chem. 1987 Aug;30(8):1409-15 and Biological activities of des-His1[Glu9]glucagon amide, a glucagon antagonist. Peptides. 1989 Nov-Dec;10(6):1171-7.
The majority of the initial antagonists were peptide-based, whereas more recent efforts have been directed at identification of non-peptide orally available agents, as exemplified in Discovery and structure-activity relationship of the first non-peptide competitive human glucagon receptor antagonists. J Med Chem. 1998 Dec 17;41(26):5150-7
Qureshi and colleagues identified a novel chemical series of glucagon antagonists by screening a chemical library for compounds that blocked binding to membranes isolated from CHO cells expressing the human Gcgr. A prototype antagonist was identified, N-[3-cyano-6-(1, 1-dimethylpropyl)-4, 5, 6, 7-tetrahydro-1-benzothien-2-yl]-2 -ethylbutanamide (Cpd 1), that blocked A novel glucagon receptor antagonist inhibits glucagon-mediated biological effects. Diabetes. 2004 Dec;53(12):3267-73
The concept that glucagon receptor antagonism may be a useful approach to therapy of diabetic patients was tested in preliminary human studies using the Bayer antagonist Bay 27-9955. This compound appeared safe and blocked exogenous glucagon action in short term human studies, however clinical development of this particular compound was not pursued. Effects of a novel glucagon receptor antagonist (Bay 27-9955) on glucagon-stimulated glucose production in humans. Diabetologia. 2001 Nov;44(11):2018-24
Nevertheless, there remains active pharmaceutical industry interest in developing ideal compounds that might block glucagon receptor action in diabetic subjects, as outlined in Glucagon receptor antagonists for the treatment of type II diabetes: current prospects. Curr Opin Investig Drugs. 2002 Nov;3(11):1617-23.