Generation of Nicotinic Acid Adenine Dinucleotide Phosphate and Cyclic ADP-Ribose by Glucagon-Like Peptide-1 Evokes Ca2 Signal That Is Essential for Insulin Secretion in Mouse Pancreatic Islets

cellular Ca2 concentrations ([Ca2]i), resulting in insulin secre-tion from pancreatic -cells. The molecular mechanism(s) of the GLP-1–mediated regulation of [Ca2]i was investigated. RESEARCHDESIGNANDMETHODS—GLP-1–inducedchang-es in [Ca2]i were measured in -cells isolated from Cd38 / and Cd38/ mice. Calcium-mobilizing second messengers were identified by measuring levels of nicotinic acid adenine dinucle-otide phosphate (NAADP) and cyclic ADP-ribose (ADPR), using a cyclic enzymatic assay. To locate NAADP- and cyclic ADPR– producing enzyme(s), cellular organelles were separated using the sucrose gradient method. RESULTS—A GLP-1–induced [Ca2]i increase showed a coop-erative Ca2 signal, i.e., an initial [Ca2]i rise mediated by the action of NAADP that was produced in acidic organelles and