INSULIN DOWN-REGULATES THE INDUCIBLE NITRIC-OXIDE SYNTHASE PATHWAY - NITRIC-OXIDE AS CAUSE AND EFFECT OF DIABETES

Evidence in this paper indicates that insulin can down-regulate the in ducible nitric oxide synthase (iNOS) pathway in vivo. The iNOS pathway is up-regulated in diabetes-prone rats and mice and is associated wit h an autoimmune process. However, the results presented here indicate that macrophage nitric oxide (NO) production and iNOS mRNA expression are also elevated in rats or mice made diabetic by streptozotocin inje ction in which there is no primary autoimmune component. Insulin admin istration reduces NO production in autoimmune-prone and streptozotocin -induced diabetic rodents. Finally, insulin decreases macrophage NO pr oduction in normal hosts, These results indicate that the autoimmune p aradigm is inadequate to explain increased NO in diabetes. As a potent ial mechanism to explain insulin-mediated regulation of NO production, TGF-beta 1 may be involved because 1) macrophages from diabetic mice produce less TGF-beta 1 than macrophages from normal hosts; 2) the cir culating TGF-beta 1 level is lower in diabetic mice; and 3) insulin ad ministration increases circulating TGF-beta 1 in normal mice. Together , these results provide evidence that increased NO in diabetes is not only a cause but also an effect of beta-cell destruction and results i n part from a heretofore unrecognized immunomodulatory activity of ins ulin.