GLUCOSE-DEPENDENT ALTERATIONS OF INTRACELLULAR FREE CALCIUM BY GLUCAGON-LIKE PEPTIDE-1((7-36AMIDE)) IN INDIVIDUAL OB/OB MOUSE BETA-CELLS

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-1(a)) 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-1(a) (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-1(a)] 10-100 pM), and the integral of the [Ca2+](i) signal is increased ([GLP-1(a)] greater than or equal to 1 pM). GLP-1(a) 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-1(a). Activation of the GLP-1(a) receptor, or application of cAMP alters pancreatic beta-cell [Ca2+](i) only when [glucose] is high.