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

Byung Ju Kim, Kwang Hyun Park, Chang Yeol Yim, Shin Takasawa, Hiroshi Okamoto, Mie Jae Im, Uh Hyun Kim

Research output: Contribution to journalArticlepeer-review

93 Citations (Scopus)

Abstract

OBJECTIVE-Glucagon-like peptide-1 (GLP-1) increases intracellular Ca 2+ concentrations ([Ca2+]i), resulting in insulin secretion from pancreatic p-cells. The molecular mechanism(s) of the GLP-1-mediated regulation of [Ca2+]i was investigated. RESEARCHDESIGN AND METHODS-GLP-1-induced (changes in [Ca2+] i were measured in β-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 cooperative Ca2+ signal, i.e., an initial [Ca 2+]i rise mediated by the action of NAADP that was produced in acidic organelles and a subsequent long-lasting increase of [Ca 2+]i by the action of cyclic ADPR that was produced in plasma membranes and secretory granules. GLP-1 sequentially stimulated production of NAADP and cyclic ADPR in the organelles through protein kinase A and cAMP-regulated guanine nucleotide exchange factor II. Furthermore, the results showed that NAADP production from acidic organelles governed overall Ca2+ signals, including insulin secretion by GLP-1, and that in addition to CD38, enzymes capable of synthesizing NAADP and/or cyclic ADPR were present in β-cells. These observations were supported by the study with Cd38-/- β-cells, demonstrating production of NAADP, cyclic ADPR, and Ca2+ signal with normal insulin secretion stimulated by GLP-1. CONCLUSIONS-Our findings demonstrate that the GLP-1-mediated Ca2+ signal for insulin secretion in pancreatic β-cells is a cooperative action of NAADP and cyclic ADPR spatiotempo-rally formed by multiple enzymes.

Original languageEnglish
Pages (from-to)868-878
Number of pages11
JournalDiabetes
Volume57
Issue number4
DOIs
Publication statusPublished - 2008 Apr

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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