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

  1. Byung-Ju Kim, MS1,
  2. Kwang-Hyun Park, PhD1,
  3. Chang-Yeol Yim, MD, PhD2,
  4. Shin Takasawa, MD, PhD3,
  5. Hiroshi Okamoto, MD, PhD3,
  6. Mie-Jae Im, PhD1 and
  7. Uh-Hyun Kim, MD, PhD (uhkim{at},,4
  1. 1Department of Biochemistry
  2. 2Department of Internal Medicine, and
  3. 4Institute of Cardiovascular Research, Chonbuk National University Medical School, Jeonju, 561-182, Republic of Korea
  4. 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.


      • Received April 2, 2007.
      • Accepted January 2, 2008.