The actions of glucagon and the glucagon-like peptides are transduced via interaction with a subset of G protein coupled receptors
The GLP-1 receptor was the first to be cloned, followed by the glucagon receptor, and more recently, the GLP-2 receptor. These receptors are linked to the adenylate cyclase-dependent pathway, and in some cases, stimulation of inositol trisphosphate and calcium influx.
Mice with a targeted mutation in the GLP-1 Receptor have been generated in the Drucker lab. Although mutations in the glucagon receptor have been reported to be more common in some patients with diabetes and hypertension, the clinical significance of these reports remain uncertain.
No linkage between the GLP-1 receptor and patients with diabetes, or the GLP-2 receptor and patients with intestinal disease, has been reported.
Intriguingly, a polymorphism in the human Glucagon receptor (GLU-R) gene, localized to human chromosome 17q25, has been identified that exhibits linkage, in some families and populations, to an increased risk of type 2 diabetes. Patients in France and Sardinia with a Gly40Ser mutation were reported to have an increased risk of developing type 2 diabetes. A missense mutation in the glucagon receptor gene is associated with non-insulin dependent diabetes mellitus. Nat Genet. 1995:299-304 However, the incidence of this polymorphism is higher in certain populations than others, and intriguingly, physiological characterization of mutant Gly40Ser GLU-R function demonstrates that carriers of the Gly40Ser mutation exhibited a significantly lower glucose response to glucagon compared to control Gly40 subjects. These findings predict that the Gly40Ser should be associated with reduced levels of blood glucose, rendering difficult the interpretation of the Gly40Ser association with type 2 diabetes in some populations. Although constitutively active glucagon receptors have been generated experimentally in vitro Mol Endocrinol 1998 12(1):78-86, similar mutations have not yet been identified in human subjects.
The GLP-2 receptor was isolated by Don Munroe and colleagues at NPS Allelix Biopharmaceuticals. The mechanism of GLP-2 action in the GI tract remains elusive. For an overview of the sites of GLP-2 receptor expression and GLP-2 receptor signaling, see the section on the GLP-2 Receptor.