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

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Zeender et al. (127) were able to protect cultured human islets using pioglitazone
(and sodium salicilate) against apoptosis and impaired function induced by IL-1β and high
glucose by blocking nuclear factor κB (NFκB) activation.
Lin et al. (128) noting the association of DM2 with increased β-cell apoptosis and
the presence of islets amyloid derived from IAPP,showed that IAPP induces apoptosis in
cultured human pancreatic islets and that the addition of rosiglitazone to the incubation
prevented the IAPP-induced apoptosis.
3) Mechanism of action of TZDs on the beta-cell
Indirect effects by amelioration of insulin sensitivity
TZDs consistently lower fasting and postprandial glucose concentrations in clinical
studies as well as plasma FFAs in type 2 diabetics, with a reduction of gluco- and
lipotoxicity. Furthermore, as mentioned above, TZDs may directly protect the beta-cell
from lipotoxic insult (125). Besides, insulin concentrations also decrease in the majority of
trials, mirroring a decreased secretory demand on beta cells. Such changes indicate that
TZDs act as insulin sensitizers, which has been confirmed by direct measurements in in
vivo studies in humans. While the insulin-sensitizing effect of TZDs is well established,less
is known about their influence on insulin secretion. It now appears that TZDs normalize the
asynchronous insulin secretion that characterizes beta-cell failure. In a placebo-controlled
study in patients DM2, 13 weeks` treatment with rosiglitazone was shown to increase the
ability of an oscillatory glucose infusion to program high-frequency pulsatile insulin
secretion,despite the absence of any direct action on beta-cell secretory capacity.It was
postulated that the improvement in beta-cell function could be related to a reduction in
glucotoxicity due to the improved glycemic control and/or improved insulin sensitivity seen
with TZDs (129). This could suggest an increased ability of the beta-cell to sense and
respond to glucose changes within the physiological range after TZD treatment.
Direct effects via PPARγ activation in pancreatic islets
As a class effect, TZDs consistently improve basal beta-cell function,as measured
by the HOMA model, and as observed during TZD monotherapy and combination therapy