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 intracel lular Ca2+ mobilization for insulin secretion by glucose in pancreatic beta cells, and CD38 shows both ADP-ribosyl cyclase to synthesize cAD PR from NAD(+) and cADPR hydrolase to hydrolyze cADPR to ADP-ribose. W e show here that 13.8% of Japanese non-insulin-dependent diabetes (NID DM) patients examined have autoantibodies against CD38 and that the se ra containing anti-CD38 autoantibodies inhibit the ADP-ribosyl cyclase activity of CD38 (P less than or equal to 0.05), Insulin secretion fr om pancreatic islets by glucose is significantly inhibited by the addi tion 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). T he increase of cADPR levels in pancreatic islets by glucose was also i nhibited by the addition of the sera (P less than or equal to 0.05). T hese results strongly suggest that the presence of anti-CD38 autoantib odies in NIDDM patients can be one of the major causes of impaired glu cose-induced insulin secretion in NIDDM.