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

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with DM2 (81, 180, 170). Its sub-acute effect is enhancing insulin biosynthesis and
stimulation of insulin gene transcription and increasing expression of mRNA for glucose
transporter-2 and glucokinase, as shown in in-vitro studies in rodent models. The chronic
GLP-1 action is stimulation of beta-cell proliferation and induction of islet neogenesis from
precursor ductal cells which is associated with an expansion of beta-cell mass. Finally, an
inhibitory effect of GLP-1 was found in beta-cell apoptosis.These effects were observed in
rodent models of diabetes as well as in cultured beta-cells (37, 182, 183, 184). Similar
findings were obtained using the GLP-1 receptor agonist exendin-4 in rats rendered diabetic
by partial pancreatectomy (185). In Wistar rats, the age-dependent decline in beta-cell
function and the subsequent impairment of glucose tolerance were reversed by GLP-1
administration (186). It should be mentioned that the antiapoptotic effect of GLP-1 is
independent from its glucose-lowering activity, as demonstrated by in vitro experiments in
which GLP-1 was capable of inhibiting H2O2-dependent apoptosis in cultured mouse
insulinoma cell lines. GLP-1 reduced DNA fragmentation and improved cell survival (184).
In vivo studies have demonstrated that GLP-1 and exendin-4 may improve glucose
tolerance in animal diabetic models as well as in diabetic subjects (ref. cit in 187). These
beneficial effects were maintained long after the termination of GLP-1 or exendin-4
infusion. This finding indicates that GLP-1 induces long-term changes that cannot be due
simply to the modulation of preformed insulin secretion, but must involve more substantial
modifications in the functional activity of beta cells. Recent findings from in vivo studies
have shown that the beneficial long-lasting effects of GLP-1 can be partly attributed to
changes in beta-cell mass due to beta-cell growth and differentiation (182). However, the
ability to stimulate beta cell neogenesis was not associated with the promotion of
proliferative lesions in a 2-year rodent safety study (188).
Figure 3 :GLP-1 stimulates beta-cell regeneration and mass in animal models
The GLP-1-dependent regulation of glucose homeostasis appears to be based upon
biological mechanisms far more complex than the simple modulation of insulin secretion.
Indeed, GLP-1 also affects the expression of insulin and other beta-cell-specific genes
whose products are involved in the regulation of glucose utilization. The mechanism by