Regulatory role of CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase) in insulin secretion by glucose in pancreatic β cells: Enhanced insulin secretion in CD38-expressing transgenic mice

Ichiro Kato, Shin Takasawa, Atsuya Akabane, Osamu Tanaka, Hiroshi Abe, Toshinari Takamura, Yu Suzuki, Koji Nata, Hideto Yonekura, Takashi Yoshimoto, Hiroshi Okamoto

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100 Citations (Scopus)

Abstract

Cyclic ADP-ribose (cADPR) serves as a second messenger for Ca2+ mobilization in insulin secretion, and CD38 has both ADP-ribosyl cyclase and cADPR hydrolase activities (Takasawa, S., Tohgo, A., Noguchi, N., Koguma, T., Nata, K., Sugimoto, T., Yonekura, H., and Okamoto, H. (1993) J. Biol. Chem. 268, 26052-26054). Here, we produced transgenic mice overexpressing human CD38 in pancreatic β cells. The enzymatic activity of CD38 in transgenic islets was greatly increased, and ATP efficiently inhibited the cADPR hydrolase activity. The Ca2+ mobilizing activity of cell extracts from transgenic islets incubated in high glucose was 3-fold higher than that of the control, suggesting that ATP produced by glucose metabolism increased cADPR accumulation in transgenic islets. Glucose- and ketoisocaproate-induced but not tolbutamide- nor KCl-induced insulin secretions from transgenic islets were 1.7-2.3-fold higher than that of control. In glucose-tolerance tests, the transgenic serum insulin level was higher than that of control. The present study provides the first evidence that CD38 has a regulatory role in insulin secretion by glucose in β cells, suggesting that the Ca2+ release from intracellular cADPR-sensitive Ca2+ stores as well as the Ca2+ influx from extracellular sources play important roles in insulin secretion.

Original languageEnglish
Pages (from-to)30045-30050
Number of pages6
JournalJournal of Biological Chemistry
Volume270
Issue number50
DOIs
Publication statusPublished - 1995 Dec 15

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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