1 BETA-CELL FAILURE IN DIABETES AND PRESERVATION BY ...

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