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

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suppression of TNF-α expression, which has been demonstrated by in vitro studies,such as
those of Arner who has reported that rosiglitazone suppresses TNF-α to almost
undetectable levels in human pre-adipocytes (117). Thus, according to this author,TZDs
reduce the release of FFAs from the adipocytes by two mechanisms: increasing the insulin
sensitivity of the cell – and thereby improving the anti-lipolytic effect of insulin - and
reducing levels of TNF-α, known to suppress insulin’s anti-lipolytic properties by
inhibiting the insulin-signalling cascade (117).
While rosiglitazone seems to be a pure PPARγ agonist, the other TZD approved for
the medical therapy, is pioglitazone which seems to also act like a partial PPARα agonist
(118). In general, PPARα regulates genes involved in fatty acid uptake and oxidation (liver,
kidney, heart and skeletal muscle), inflammation and vascular function, whereas PPARγ, as
shown, regulates genes involved in fatty acid uptake and storage, inflammation and
glucose homeostasis (119).
a) Effect of TZDs on beta-cells.
1) Animal data:
In obese ZDF rats, the over-accumulation of fat in the pancreatic islets induce beta-
cell dysfunction, reflecting a mutation of the leptin receptor which blocks the normal
triglyceride –lowering action of leptin on islets, as discussed previously, leading to
lipotoxicity through exaggerated production of nitric oxide (111). In isolated islets from
obese ZDF rats, addition of troglitazone halved the triglyceride content, doubled insulin
secretion stimulated by arginine and produced a greater than 30-fold increase to that
stimulated by glucose (120). This is consistent with the ability of TZDs to prevent TNF-α-
induced inhibition of insulin signalling by islets. In the same animal model, rosiglitazone
treatment was shown to maintain beta-cell proliferation and to produce a 5-fold attenuation
in the net rise in beta-cell death, preventing the loss of beta-cell mass indicated previously
(87). Since excessive beta-cell apoptosis is associated with excessive accumulation of
intracellular triglycerides, as reported earlier (59), staining of islet cells for insulin in