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

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