Diabetes is a debilitating disease characterized by chronic
hyperglycemia and is often associated with
obesity. With diabetes and
obesity incidence on the rise, it is imperative to develop novel
therapeutics that will not only lower
blood glucose levels, but also combat the associated
obesity. The
G protein-coupled receptors (GPCRs) for
glucose-dependent insulinotropic
polypeptide (GIP),
glucagon-like peptide-1 (GLP-1) and
glucagon are emerging as targets to treat both
hyperglycemia and
obesity. GIP is rapidly released from intestinal K-cells following food intake and stimulates
glucose-dependent insulin secretion from β-cells and the storage of fat in adipocytes. Both
GIP receptor agonists and antagonists have been demonstrated to display therapeutic potential to treat diabetes and
obesity. Similar to GIP,
GLP-1 is released from intestinal L-cells following food intake and potentiates
glucose-dependent insulin secretion from β-cells. In addition,
GLP-1 reduces
glucagon levels, suppresses gastric emptying and reduces food intake. As such,
GLP-1 receptor agonists effectively lower
blood glucose levels and reduce weight. Finally,
glucagon is released from α-cells and raises
blood glucose levels during the fasting state by stimulating gluconeogenesis and glycogenolysis in the liver. Thus, molecules that antagonize the
glucagon receptor may be used to treat
hyperglycemia. Given the structural similarity of these
peptides and their receptors, molecules capable of agonizing or antagonizing combinations of these receptors have recently been suggested as even better
therapeutics. Here we review the biology of GIP,
GLP-1 and
glucagon and examine the various therapeutic strategies to activate and antagonize the receptors of these
peptides.