Autoantibodies against CD38 (ADP ribosyl cyclase cyclic ADP ribose hydrolase) that impair glucose-induced insulin secretion in noninsulin-dependent diabetes patients

Cyclic ADP-ribose (cADPR) has been shown to be a mediator for intracellular Ca2+ mobilization for insulin secretion by glucose in pancreatic beta cells, and CD38 shows both ADP-ribosyl cyclase to synthesize cADPR from NAD(+) and cADPR hydrolase to hydrolyze cADPR to ADP-ribose. We show here that 13.8% of Japanese non-insulin-dependent diabetes (NIDDM) patients examined have autoantibodies against CD38 and that the sera containing anti-CD38 autoantibodies inhibit the ADP-ribosyl cyclase activity of CD38 (P less than or equal to 0.05), Insulin secretion from pancreatic islets by glucose is significantly inhibited by the addition of the NIDDM sera with anti-CD38 antibodies (P less than or equal to 0.04-0.0001), and the inhibition of insulin secretion is abolished by the addition of recombinant CD38 (P less than or equal to 0.02). The increase of cADPR levels in pancreatic islets by glucose was also inhibited by the addition of the sera (P less than or equal to 0.05). These results strongly suggest that the presence of anti-CD38 autoantibodies in NIDDM patients can be one of the major causes of impaired glucose-induced insulin secretion in NIDDM.