Potentiation of
glucose-induced insulin secretion by intestinal factors has been described for many years. Today, two major
peptides with potent insulinotropic action have been recognized: gastric inhibitory
peptide and truncated forms of
glucagon-like peptide I, GLP-I(7-37) or the related GLP-I(7-36)amide. These
hormones have specific beta-cell receptors that are coupled to production of cAMP and activation of
cAMP-dependent protein kinase. Elevation in intracellular cAMP levels is required to mediate the glucoincretin effect of these
hormones: the potentiation of insulin secretion in the presence of stimulatory concentrations of
glucose. In addition, circulating glucoincretins maintain basal levels of cAMP, which are necessary to keep beta-cells in a
glucose-competent state. Interactions between glucoincretin signaling and
glucose-induced insulin secretion may result from the phosphorylation of key elements of the
glucose signaling pathway by
cAMP-dependent protein kinase. These include the
ATP-dependent K+ channel, the Ca++ channel, or elements of the secretory machinery itself. In
NIDDM, the glucoincretin effect is reduced. However, basal or stimulated gastric inhibitory
peptide and
glucagon-like peptide I levels are normal or even elevated, suggesting that signals induced by these
hormones on the beta-cells are probably altered. At pharmacological doses, infusion of
glucagon-like peptide I but not gastric inhibitory
peptide, can ameliorate postprandial
insulin secretory response in
NIDDM patients. Agonists of the
glucagon-like peptide I receptor have been proposed as new therapeutic agents in
NIDDM.