Inhibition of Insulin Secretion by Anti-CD38 Autoantibodies in Diabetes

Cyclic ADP-ribose (cADPR) has been shown to be a mediator for intracellular Ca 2 1 mobilization for insulin secretion by glucose in pancreatic b cells, and CD38 shows both ADP-ribosyl cyclase to synthesize cADPR from NAD 1 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 # 0.05). Insulin secretion from pancreatic islets by glucose is significantly inhibited by the addition of the NIDDM sera with anti-CD38 antibodies ( P # 0.04–0.0001), and the inhibition of insulin secretion is abolished by the addition of recombinant CD38 ( P # 0.02). The increase of cADPR levels in pancreatic islets by glucose was also inhibited by the addition of the sera ( P # 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. ( J. Clin. Invest. 1998. 102:395–401.)