1 BETA-CELL FAILURE IN DIABETES AND PRESERVATION BY ...
1 BETA-CELL FAILURE IN DIABETES AND PRESERVATION BY ...
1 BETA-CELL FAILURE IN DIABETES AND PRESERVATION BY ...
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29<br />
in in vitro studies in rodent and human islets. If these findings translate to patients with<br />
DM2, at least some long-acting sulfonylureas may have adverse effects on beta-cells while<br />
short-acting ones will be preferred due to the fact that patients will be less exposed to<br />
proapoptotic stimuli during protracted treatment with these agents.<br />
C. Anti – apoptotic drugs<br />
1. Leptin<br />
As indicated earlier, leptin in ZDF rat islet protects the beta-cell from FFA-induced<br />
apoptosis (109). However, it induces beta-cell apoptosis in human islets by the mechanism<br />
previously discussed (70).<br />
2. Aminoguanidine<br />
Aminoguanidine acts as an antioxidant in vivo, in diabetic animal models,<br />
preventing reactive oxygen species (ROS) formation and lipid peroxidation in cells and<br />
tissues, while also preventing oxidant-induced apoptosis (110). Moreover, at higher doses<br />
this inhibits inducible nitric oxide synthase (iNOS) with reduction in nitric oxide which has<br />
been shown to mediate Il-1β-induced impairement of beta-cell function and ultimately<br />
cause beta-cell apoptosis as reported in cultured prediabetic ZDF islets (111, 59). Because<br />
ROS are known to increase intracellular advanced glycation end-products (AGEs) and anti-<br />
oxidants are known to inhibit AGEs formation (110) presumably the time required for<br />
formation of immunodetectable intracellular AGEs is much longer than the time-course for<br />
oxidant-induced apoptosis, suggesting that intracellular AGE formation does not play a<br />
causal role in this process of oxidant-induced apoptosis. Furthermore, diabetic models<br />
using aminoguanidine have also shown a reduction in diabetes related complications such<br />
as retinopathy, neuropathy and nephropathy. Specifically, reduction in retinal microvessel<br />
formation, albuminuria and the prevention or decrease in motor and sensory nerve<br />
conduction velocity have been reported (ref. cit in 112). In line with previously indicated<br />
considerations (47), the prescription of antioxidants as adjunct therapy in DM2 is warranted<br />
to determine whether this approach would prevent continued deterioration in beta-cell