Cyclic ADP-ribose and inositol 1,4,5-trisphosphate as alternate second messengers for intracellular Ca²⁺ mobilization in normal and diabetic β- cells

Intracellular Ca²⁺ mobilization occurs in a variety of cellular processes and is mediated by two major systems, the inositol 1,4,5- trisphosphate (IP₃) and cyclic ADP-ribose (cADPR) systems. cADPR has been proposed to be a second messenger for insulin secretion induced by glucose in pancreatic β-cells (Takasawa, S., Nata, K., Yonekura, H., and Okamoto, H. (1993) Science 259, 370373). Here we show that the cADPR signal system for insulin secretion is replaced by the IP₃ system in diabetic β-cells such as ob/ob mouse islets and RINm5F cells. We measured the cADPR content in these β-cells by radioimmunoassay and found that the increase of the cADPR content by glucose did not occur in ob/ob mouse islets and RINm5F cells, whereas the increased cADPR level by glucose was observed in normal rat and mouse islets. Microsomes of these diabetic β-cells released Ca²⁺ in response to IP₃ but not to cADPR. In the diabetic β-cells, CD38 (ADP-ribosyl cyclase/cADPR hydrolase) and type 2 ryanodine receptor mRNAs were scarcely detected and, in contrast, an increased expression of IP₃ receptor mRNAs was observed. The diabetic β-cells secreted insulin rather by carbamylcholine than by glucose.