Glucagon is a 30 amino acid peptide hormone that is produced exclusively in alpha-cells of
the pancreatic islets. Glucagon binds to a G-protein coupled receptor and activates
intracellular signaling by increasing the synthesis of cyclic AMP by adenylate cyclase. The
glucagon receptor is most prominently expressed by hepatocytes and the cardinal action of
glucagon is to stimulate hepatic glucose output by increasing glycogenolysis and
gluconeogenesis. A deep body of literature supports physiologic actions of glucagon to
maintain fasting blood glucose and counter-regulate hypoglycemia, and the current view of
glucose metabolism is that insulin and glucagon have opposing and mutually balancing effects
on glycemia. However, it has long been appreciated that glucagon actually stimulates insulin
secretion and islet β-cells express the glucagon receptor and respond to its activation by
increasing cAMP.
The most potent stimulus for glucagon release is hypoglycemia and both low glucose per sé, as
well as sympathetic nervous system activity are potent activators of the alpha-cell. However,
glucagon is also stimulated by elevations of circulating amino acids, including after protein
containing meals; this setting is one in which the release of glucagon during a period of
elevated glycemia could contribute to postprandial insulin secretion. In fact, we have
demonstrated that normal mice injected with glucagon while fasting (BG 75 mg/dl) have a
prompt rise in blood glucose, whereas mice given glucagon while feeding (BG 150 mg/dl)
increase insulin output 3 fold and have a decrease in glycemia. Moreover, in studies with
isolated mouse and human islets we have demonstrated that glucagon stimulates insulin release
by activating both the glucagon and GLP-1 receptors. This counter-intuitive observation has
been reported by several other groups as well as ours.
In the studies proposed herein we wish to extend our novel observations to humans. The
possibility that glucagon acts in the fed state to promote insulin secretion and glucose
disposal would change current views of physiology in both healthy and diabetic persons.
Moreover, since one of the more promising area of drug development is the creation of
peptides that activate multiple receptors (GLP-1 + glucagon, GLP-1 + GIP + glucagon) the
results of our studies have potential implications for therapeutics as well.
Phase:
Phase 1
Details
Lead Sponsor:
David D'Alessio, M.D.
Collaborator:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)