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

Abstract Cyclic ADP-ribose(cADPR) serves as a second messenger for Ca2+ mobilization in insulin secretion, and CD38has both ADP-ribosylcyclase and cADPR hydrolaseactivities (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 transgenicmice overexpressing human CD38in pancreatic β cells. The enzymatic activity of CD38in transgenicislets was greatly increased, and ATP efficiently inhibited the cADPR hydrolaseactivity. The Ca2+ mobilizing activity of cell extracts from transgenicislets incubated in high glucose was 3-fold higher than that of the control, suggesting that ATP produced by glucose metabolism increased cADPR accumulation in transgenicislets. Glucose- and ketoisocaproate-induced but not tolbutamide- nor KCl-induced insulin secretions from transgenicislets were 1.7-2.3-fold higher than that of control. In glucose-tolerance tests, the transgenicserum insulin level was higher than that of control. The present study provides the first evidence that CD38has 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.