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

Cyclic ADP-ribose (cADPR) serves as a second messenger for Ca2+ mobili zation in insulin secretion, and CD38 has both ADP-ribosyl cyclase and cADPR hydrolase activities (Takasawa, S., Tohgo, A., Noguchi, N., Kog uma, T., Nata, R., Sugimoto, T., Yonekura, H., and Okamoto, H. (1993) J. Biol. Chem. 268, 26052-26054). Here, we produced transgenic mice ov erexpressing human CD38 in pancreatic beta cells. The enzymatic activi ty of CD38 in transgenic islets was greatly increased, and ATP efficie ntly inhibited the cADPR hydrolase activity. The Ca2+ mobilizing activ ity of cell extracts from transgenic islets incubated in high glucose was 3-fold higher than that of the control, suggesting that ATP produc ed by glucose metabolism increased cADPR accumulation in transgenic is lets. Glucose- and ketoisocaproate-induced but not tolbutamide- nor KC l-induced insulin secretions from transgenic islets were 1.7-2.3-foId higher than that of control. In glucose-tolerance tests, the transgeni c serum insulin level was higher than that of control. The present stu dy provides the first evidence that CD38 has a regulatory role in insu lin secretion by glucose in beta cells, suggesting that the Ca2+ relea se from intracellular cADPR-sensitive Ca2+ stores as well as the Ca2influx from extracellular sources play important roles in insulin secr etion.