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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45<br />
Table 2. Effects of incretin (GLP-1) and incretin mimetics (exendin-4<br />
and liraglutide) on β-cells: animal studies<br />
2) In vitro data in human β-cells<br />
Farilla et al. (195) found that GLP-1 delayed the morphological changes that<br />
occurred in human islets in culture, indicated by a longer-lasting preservation of their 3-<br />
dimensional structure, along with maintenance of the non-cellular membrane that surrounds<br />
healthy human islets. GLP-1 promoted a time-dependent increase in the expression of the<br />
anti-apoptotic protein bcl-2 and a down-regulation of the intracellular levels of the active<br />
form of caspase-3. A similar effect was observed at the mRNA level for bcl-2 and caspase-<br />
3. It was also shown that by improving cell viability the AA were able to show a significant<br />
amelioration of islet cell function. Indeed, GLP-1–treated human islets contained more<br />
insulin and were capable of greater glucose-dependent insulin secretion. However, because<br />
of the short-term nature of the experiment (the islets were cultured up to 5 days) an increase<br />
in the size or number of islets was not observed in response to GLP-1.<br />
Furthermore, it was demonstrated by Buteau et al. (196) that GLP-1 prevented<br />
glucose- and palmitate-induced apoptosis, singly or combined, in overnight cultured human<br />
islet cells isolated from healthy organ donors, between 50 and 65 years old. The anti-<br />
apoptotic action was mediated via activation of the PI-3K/PKB (phosphatidylinositol –3<br />
kinase/protein kinase B) signalling pathway, enhanced downstream target nuclear factor-<br />
κB(NF-κB) DNA binding activity and possibly stimulating the expression of IAP-2 and<br />
Bcl-2, two anti-apoptotic genes under the control of NF-κB. The same anti-apoptotic<br />
mechanism was observed earlier by Hu et al. in cultured mouse insulinoma cell line (184)<br />
and, as stated above, in human islets (195). Inhibition of NF-κB abolished the prevention of<br />
glucolipotoxicity by GLP-1. The anti-apoptotic action of GLP-1 and incretin mimetics, in<br />
addition to their increting effect, are of great interest as therapeutic agents in the treatment<br />
of DM2, particularly in the presence of glucolipotoxicity which is an important factor for<br />
beta-cell decompensation in the development of obesity-associated DM2 (196). It would<br />
be interesting to mention that GLP-1 induced beta-cell proliferation has not yet been<br />
reported in human islets, only in rodent.