The actions of the structurally related
proglucagon-derived
peptides (PGDPs)-
glucagon,
glucagon-like peptide (GLP)-1 and GLP-2-are focused on complementary aspects of energy homeostasis.
Glucagon opposes
insulin action, regulates hepatic
glucose production, and is a primary hormonal defense against
hypoglycemia. Conversely, attenuation of
glucagon action markedly improves experimental diabetes, hence
glucagon antagonists may prove useful for the treatment of
type 2 diabetes.
GLP-1 controls
blood glucose through regulation of
glucose-dependent insulin secretion, inhibition of
glucagon secretion and gastric emptying, and reduction of food intake. GLP-1-receptor activation also augments
insulin biosynthesis, restores beta-cell sensitivity to
glucose, increases beta-cell proliferation, and reduces apoptosis, leading to expansion of the beta-cell mass. Administration of
GLP-1 is highly effective in reducing
blood glucose in subjects with
type 2 diabetes but native
GLP-1 is rapidly degraded by
dipeptidyl peptidase IV. A GLP-1-receptor agonist,
exendin 4, has recently been approved for the treatment of
type 2 diabetes in the US.
Dipeptidyl-peptidase-IV inhibitors, currently in phase III clinical trials, stabilize the postprandial levels of
GLP-1 and
gastric inhibitory polypeptide and lower
blood glucose in diabetic patients via inhibition of
glucagon secretion and enhancement of
glucose-stimulated insulin secretion. GLP-2 acts proximally to control energy intake by enhancing nutrient absorption and attenuating mucosal injury and is currently in phase III clinical trials for the treatment of
short bowel syndrome. Thus the modulation of
proglucagon-derived
peptides has therapeutic potential for the treatment of diabetes and
intestinal disease.