INTERRELATIONSHIP OF CHANGES IN ISLET NICOTINE ADENINEDINUCLEOTIDE, INSULIN-SECRETION, AND CELL VIABILITY INDUCED BY INTERLEUKIN-1-BETA

Complete loss of pancreatic insulin function in insulin-dependent diab etes is thought to be due to an autoimmune cytokine-mediated destructi on of the beta-cell. The effects of several classes of agents on inter leukin-1 beta (IL-1 beta)-induced suppression of insulin secretion, be ta-cell NAD levels, and beta-cell viability were examined. After overn ight incubation of isolated rat islets with 15 U/ml IL-1 beta and 11 m M glucose, sequential hourly insulin secretory responses to the same g lucose concentration, 22 mM glucose, and 22 mM glucose plus forskolin were severely inhibited to 10-37% of the control value. Islet NAD leve ls were also sharply reduced to 43% of the control value after 24-h-ex posure to IL-1 beta, but not after 1 or 3 h, demonstrating the same ti me course as that for inhibition of insulin secretion. Exposure to IL- 1 beta also decreased islet cell viability measured as trypan blue exc lusion. Only 1 mM N-methyl arginine, an inhibitor of nitric oxide synt hase, completely protected all three parameters of beta-cell function from damage by IL-1 beta. Nicotinamide and thymidine prevented the IL- 1 beta-induced loss of cell viability and suppression of NAD, but had no effect on sustaining insulin secretion. Antioxidants, steroids, and several neuropeptides also did not prevent inhibition or restore the secretory response. Thus, the loss of the secretory response appears t o be more narrowly restricted to nitric oxide radical damage induced b y exposure to IL-1 beta.