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

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function particularly when glycemic control is not satisfactory (47). Unfortunately, studies
with antioxidant vitamins to date have not improved glycemic control. Additionally,
aminoguanidine has not been used in humans because of its side effect profile in many
organs.
Summary / Conclusions
Aminoguanidine acts as an antioxidant in vivo, in diabetic animal models,
preventing ROS formation and lipid peroxidation and oxidant-induced apoptosis and at
higher doses inhibits inducible nitric oxide synthase (iNOS) with reduction in nitric oxide,
which was shown to ultimately cause beta-cell apoptosis in cultured prediabetidc ZDF rat
islets. Aminoguanidine has not been used in humans because of its side effect profile in
many organs.
3. Thiazolidinediones (TZDs)
The TZDs are agonists of peroxisome proliferator –activated receptor gamma
(PPARγ), a nuclear receptor that regulates transcription of genes involved in lipid and
glucose metabolism. Although predominantly expressed in adipose tissue, PPARγ is
present in other insulin sensitive tissues, including the pancreatic islet cells (113). Fully
10% of genes transcribed in adipose tissue are differentially expressed with the use of a
PPARγ agonist, as well as 2% of all genes expressed in liver and 1% of those expressed in
skeletal muscle (114). In adipose tissue, stimulation of PPARγ increases adipocyte
differentiation, resulting in an increased number of small, insulin–sensitive adipocytes
(115). The development of these insulin-sensitive cells enhance glucose uptake, improving
glycemic control. Improved insulin sensitivity, reported for TZDs, both in monotherapy
and combination in DM2, has the potential to protect beta-cells, as they may reduce the
demand on the pancreas (ref. cit in 116). Lowering plasma glucose may reduce the risk of
glucotoxicity. In addtion, TZDs by increasing adipose-tissue mass, promote fatty acid
uptake and storage in adipose tissue thus reducing levels of circulating FFAs where this has
the potential to alleviate lipotoxicity. Hence, TZDs retain fat where it belongs, according to
the “fatty acid steal” hypothesis (115). Reductions in FFAs may be mediated by