Glucagon and the
glucagon-like peptides are derived from a common
proglucagon precursor, and regulate energy homeostasis through interaction with a family of distinct
G protein coupled receptors. Three
proglucagon-derived
peptides,
glucagon,
GLP-1, and GLP-2, play important roles in energy intake, absorption, and disposal, as elucidated through studies utilizing
peptide antagonists and receptor knockout mice. The essential role of
glucagon in the control of hepatic
glucose production, taken together with data from studies employing
glucagon antagonists,
glucagon receptor antisense oligonucleotides, and
glucagon receptor knockout mice, suggest that reducing
glucagon action may be a useful strategy for the treatment of
type 2 diabetes.
GLP-1 secreted from gut endocrine cells controls
glucose homeostasis through
glucose-dependent enhancement of beta-cell function and reduction of
glucagon secretion and gastric emptying.
GLP-1 administration is also associated with reduction of food intake, prevention of
weight gain, and expansion of beta-cell mass through stimulation of beta-cell proliferation, and prevention of apoptosis. GLP-1R agonists, as well as
enzyme inhibitors that prevent
GLP-1 degradation, are in late stage clinical trials for the treatment of
type 2 diabetes.
Exenatide (Exendin-4) has been approved for the treatment of
type 2 diabetes in the United States in April 2005. GLP-2 promotes energy absorption, inhibits gastric acid secretion and gut motility, and preserves mucosal epithelial integrity through enhancement of crypt cell proliferation and reduction of epithelial apoptosis. A GLP-2R agonist is being evaluated in clinical trials for the treatment of
inflammatory bowel disease and
short bowel syndrome. Taken together, the separate receptors for
glucagon,
GLP-1, and GLP-2 represent important targets for developing novel therapeutic agents for the treatment of disorders of energy homeostasis.