Rb. Stevens et al., INSULIN DOWN-REGULATES THE INDUCIBLE NITRIC-OXIDE SYNTHASE PATHWAY - NITRIC-OXIDE AS CAUSE AND EFFECT OF DIABETES, The Journal of immunology, 159(11), 1997, pp. 5329-5335
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.