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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44<br />
which GLP-1 modulates beta-cell-specific gene expression is unknown, but recent studies<br />
strongly suggest involvement of the homeodomain transcription factor PDX-1 .The<br />
capability of GLP-1 to regulate the expression of PDX-1, a major determinant in<br />
pancreatic organogenesis, has led investigators to propose that GLP-1 may be involved in<br />
the regulation of the mechanism(s) that governs endocrine phenotype specification during<br />
beta-cell differentiation and growth (187).<br />
Therapy with GLP-1 receptor (GLP-1R) agonists has also been associated with<br />
expansion of beta-cell mass via stimulation of beta-cell proliferation, promotion of islet cell<br />
neogenesis, and inhibition of beta-cell apoptosis (185, 190). Since GLP-1R is widely<br />
expressed and the observation that activation of GLP-1R signaling is coupled to stimulation<br />
of cell proliferation and enhanced cell survival it is viewed as a positive aspect of GLP-1<br />
action in the context of promoting expansion and survival of functioning beta-cells (182)<br />
and has generated great interest in the development of GLP-1R agonists for treatment of<br />
DM2. However, the proliferative and anti-apoptotic action of these agents may have<br />
theoretical consequences on tumor formation in either the endocrine or exocrine<br />
pancreas,considering that GLP-1R may also be expressed in the pancreatic ductal<br />
epithelium,a potential precursor site for the development of pancreatic cancer.Recently it<br />
was shown that although human pancreatic cancer cell lines may express a functional GLP-<br />
1R, activation of GLP-1R signaling by synthetic exendin-4 was not coupled to stimulation<br />
of cell proliferation or resistance to cell death in short-term studies (191). The levels and<br />
duration of exendin-4 exposure in the study in question were considerably different to<br />
levels of exposure to exendin-4, recently introduced in the treatment of DM2, that might be<br />
expected in human subjects.<br />
Furthermore, it was shown that human and non-human primate islet culture with<br />
excendin-4 and daily exendin-4 administration to transplant recipients (non-diabetic or<br />
diabetic NOD-SCID mice) increase both the survival and function of islets transplanted into<br />
the liver (192).<br />
In Table 2 are presented the animal data relative to the effects of GLP-1 and<br />
incretin mimetics (exendin-4 and liraglutide) on β-cells.