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.
The Unger lab has carried out a series of studies demonstrating that in murine models of near complete beta cell destruction, animals do not develop hyperglycemia if Gcgr signaling is blocked or genetically interrupted. These observations are consistent with classic studies in humans with type 1 diabetes demonstrating that glucagon (suppressed by somatostatin infusion)is required for the development of hyperglycemia in human subjects with T1D, reviewed in Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover J Clin Invest. 2012 Jan;122(1):4-12. Wang and colleagues used a glucagon-immunoneutralizing antibody to prevent hyperglycemia and normalize A1c in insulin-deficient mice with type 1 diabetes Glucagon receptor antibody completely suppresses type 1 diabetes phenotype without insulin by disrupting a novel diabetogenic pathway Proc Natl Acad Sci U S A. 2015 Feb 9. pii: 201424934
Indeed there are now many experimental studies, nicely summarized in review articles, demonstrating prevention or marked attenuation of experimental diabetes in animals models of diabetes treated with glucagon receptior antagonists, or in the context of genetic deletion of the Gcgr.
Glucagon is the key factor in the development of diabetes Diabetologia 2016 Apr 26 in press
However, other studies have shown that fulminant diabetes will still develop in mice that lack insulin despite absence of Gcgr signaling. SeeAcute disruption of glucagon secretion or action does not improve glucose tolerance in an insulin-deficient mouse model of diabetes Diabetologia 2016 Feb;59(2):363-70and Blockade of glucagon signaling prevents or reverses diabetes onset only if residual β-cells persistElife.2016Apr 19;5. pii: e13828 and Glucagon receptor gene deletion in insulin knockout mice modestly reduces blood glucose and ketones but does not promote survival doi:10.1016/j.molmet.2016.05.014
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 inReduction 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
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):8278-84and Synthesis of two glucagon antagonists: receptor binding, adenylate cyclase, and effects on blood plasma glucose levels. J Med Chem. 1987 Aug;30(8):1409-15and 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.
