OBJECTIVE

cAMP is a critical messenger for insulin and glucagon secretion from pancreatic β- and α-cells, respectively. Dispersed β-cells show cAMP oscillations, but the signaling kinetics in cells within intact islets of Langerhans is unknown.

RESEARCH DESIGN AND METHODS

The subplasma-membrane cAMP concentration (cAMP) was recorded in α- and β-cells in the mantle of intact mouse pancreatic islets using total internal reflection microscopy and a fluorescent translocation biosensor. Cell identification was based on the opposite effects of adrenaline on cAMP in α- and β-cells.

RESULTS

In islets exposed to 3 mmol/L glucose, cAMP was low and stable. Glucagon and glucagon-like peptide-1(7-36)-amide (GLP-1) induced dose-dependent elevation of cAMP, often with oscillations synchronized among β-cells. Whereas glucagon also induced cAMP oscillations in most α-cells, <20% of the α-cells responded to GLP-1. Elevation of the glucose concentration to 11-30 mmol/L in the absence of hormones induced slow cAMP oscillations in both α- and β-cells. These cAMP oscillations were coordinated with those of the cytoplasmic Ca(2+) concentration (Ca(2+)) in the β-cells but not caused by the changes in Ca(2+). The transmembrane adenylyl cyclase (AC) inhibitor 2'5'-dideoxyadenosine suppressed the glucose- and hormone-induced cAMP elevations, whereas the preferential inhibitors of soluble AC, KH7, and 1,3,5(10)-estratrien-2,3,17-β-triol perturbed cell metabolism and lacked effect, respectively.

CONCLUSIONS

Oscillatory cAMP signaling in secretagogue-stimulated β-cells is maintained within intact islets and depends on transmembrane AC activity. The discovery of glucose- and glucagon-induced cAMP oscillations in α-cells indicates the involvement of cAMP in the regulation of pulsatile glucagon secretion.