*3.3.3 The role of nitric oxide and inducible NO-synthase in the destruction of b-cells*

The study of the biological significance of nitric oxide (NO) was a significant breakthrough in understanding the mechanisms of destruction of pancreatic b-cells. Nitric oxide is a relatively unstable free radical with a half-life of several seconds [57]. Takamura et al. found that in b-cells of transgenic mice that develop type 1 diabetes mellitus, an increased expression of induced NO synthase is determined, which confirms the role of excessive nitric oxide formation and the development of T1DM in these animals without signs of insulitis [46]. Nitric oxide produced by activated macrophages functions as a specific effector molecule, but can also be involved in the destruction of b-cells [5]. Corbett and Daniel showed that the expression of inducible NO-synthase in macrophages and the formation of nitric oxide by them practically does not affect the function of the pancreatic islets. At the same time, the expression of inducible NO synthase directly in b-cells and the formation of NO here completely inhibit insulin secretion [58]. Thus, the main damaging value is attached to nitric oxide, which is formed directly in the b-cell. Eizirik and Mandrup-Poulsen showed that b-cells of human pancreatic islets are more resistant to the damaging action of various alkylating compounds (alloxan, streptozotocin), cytokines, oxygen free radicals and nitric oxide compared to rat pancreatic islets [59]. Induction of NO synthase in human pancreatic islets is observed several days after simultaneous exposure to IL-1b, TNF-a and IFN-g. Darville and Eizirik showed that in human pancreatic islets the expression of induced NO synthase occurs with the obligatory participation of IL-1b and IFN-g [60]. The transcription factors c-fos (protooncogene), JNK, and the nuclear factor NF-kB are involved in the regulation of induced NO-synthase mRNA expression. In vitro experiments have shown that the expression of NO synthase, which is activated by cytokines and various endotoxins, is inhibited by dexamethasone and insulin, which may be important in the prevention of type 1 diabetes [57].

The synthesis of nitric oxide in b-cells induced by pro-inflammatory cytokines can lead to their death by apoptosis, which is preceded by the appearance of many biological signs of the apoptotic process, including internucleosomal DNA fragmentation [11].
