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

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