Depolarizing concentrations of glucose produce characteristic alterations of intracellular free Ca2+ ([Ca2+]i) in pancreatic beta-cells. The effects of the proposed incretin, glucagon-like peptide-1(7-36amide) (GLP-1a) on [Ca2+]i were determined from Fura-2 fluorescence ratio imaging of cultured ob/ob mouse pancreatic beta-cells. In control cells, [Ca2+]i is low in 3 mM glucose; increasing [glucose] to 8-12 mM results in an initial dip in [Ca2+]i followed by slow oscillating increases in [Ca2+]i. GLP-1a (0.03-10,000 pM) does not alter [Ca2+]i in 3 mM glucose, but does change the response to elevated glucose (8-12 mM). The time integral of the initial dip is reduced ([GLP-1a] 10-100 pM), and the integral of the [Ca2+]i signal is increased ([GLP-1a] > or = 1 pM). GLP-1a increases the frequency of sustained, stable plateau responses to elevated glucose, and the frequency of large, rapid spikes of increased [Ca2+]i associated with either plateaus, or oscillations. Application of a cAMP analog mimics most of the actions of GLP-1a. Activation of the GLP-1a receptor, or application of cAMP alters pancreatic beta-cell [Ca2+]i only when [glucose] is high.