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Diabetes Publish Ahead of Print published online ahead of print January 9, 2008
DOI: 10.2337/db07-0443
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Original Research

Generation of NAADP and cADPR by Glucagon-Like Peptide-1 Evokes Ca2+ Signal That Is Essential for Insulin Secretion in Mouse Pancreatic Islets

Byung-Ju Kim, MS1, Kwang-Hyun Park, PhD1, Chang-Yeol Yim, MD, PhD2, Shin Takasawa, MD, PhD3, Hiroshi Okamoto, MD, PhD3, Mie-Jae Im, PhD1, and Uh-Hyun Kim, MD, PhD1,,4

1Department of Biochemistry
2Department of Internal Medicine, and
4Institute of Cardiovascular Research, Chonbuk National University Medical School, Jeonju, 561-182, Republic of Korea
3Department of Advanced Biological Sciences for Regeneration, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan

Objective: Glucagon-like peptide-1 (GLP-1) increases intracellular Ca2+ concentration ([Ca2+]i) that results in insulin secretion from pancreatic β cells. The molecular mechanism(s) of the GLP-1-mediated regulation of [Ca2+]i was investigated.

Research Design 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 dinucleotide phosphate (NAADP) and cyclic ADP-ribose (cADPR) using cyclic enzymatic assay. To locate NAADP and cADPR producing enzyme(s), cellular organelles were separated using sucrose gradient method.

Results: GLP-1-induced [Ca2+]i increase showed a cooperative Ca2+ signal, that is, an initial [Ca2+]i rise mediated by the action of NAADP which was produced in acidic-organelles, and a subsequent long-lasting increase of [Ca2+]i by the action of cADPR which was produced in plasma membranes and secretory granules. GLP-1 sequentially stimulated production of NAADP and cADPR in the organelles through PKA and Epac. 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 cADPR were present in β cells. These observations were supported by the study with Cd38-/- β cells, demonstrating production of NAADP, cADPR and Ca2+ signal with normal insulin secretion stimulated by GLP-1.

Conclusion: Our findings demonstrate that GLP-1-mediated Ca2+ signal for insulin secretion in pancreatic β cells is a cooperative action of NAADP and cADPR spatiotemporally formed by multiple enzymes.

Correspondence: uhkim{at}chonbuk.ac.kr


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