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BERNARD PORTHA AN. R. ACAD. NAC. FARM.

appropriate growth factors to these progenitor cells to obtain a full
beta-cell phenotype. GLP-1 could be one of the most promising
candidate for doing so.

GLP-1 is an incretin and is produced by the L-cells of the intestine
(review in 38). Since its discovery, GLP-1 has received much
attention as a possible new treatment for type 2 diabetes. GLP-1
stimulates insulin secretion and biosynthesis and inhibits glucagon
release and both these effects are glucose dependent and therefore
represent a very safe way of lowering increased blood glucose (38).
A key factor limiting the therapeutic potential of GLP-1 is, however,
its very short half-life in vivo (38). Therefore, GLP-1 analogs with
longer duration of in vivo actions have been studied. Exendin-4
(Ex-4; now marketed as an antidiabetic under the name exenatide),
a peptide isolated from the salivary secretions of Heloderma
suspectum is one of them (38). Ex-4 shows 53% amino acid identity
to GLP-1 and similar insulinotropic action compared to GLP-1 (38).
Lately, it was demonstrated that both GLP-1 and Ex-4 were able to
stimulate growth and proliferation of pancreatic beta-cells in vitro
and in vivo in adult rodents (38).

Taking advantage of the opportunity that the GK model is a
unique one to test the effect of any pharmacological agent suspected
to target the beta cell growth and function under conditions of
spontaneous T2D, we evaluated if a GLP-1 or Ex-4 treatment applied
during few days in pre-diabetic stage in GK rats would halt or
prevent the pathological progression.

Accordingly, we have raised the question of what is the impact of
GLP-1 or Ex-4 treatment, first in term of beta-cell mass enlargement
and long-term improvement of glucose homeostasis in the GK model.
To address this issue, we have investigated the capacity of GLP-1 or
Ex-4 treatment to promote beta-cell proliferation in GK rats during
the pre-diabetic stage and thereby to prevent the pathological
progression of the T2D when animals become adults. To this end,
GK rats were submitted to GLP-1 or Ex-4 injection from postnatal
day 2 to day 6 only, and their body weight and plasma glucose and
insulin levels were examined longitudinally from weaning to
adulthood (39). Their beta-cell mass and pancreatic functions were
tested on day 7 and later on, at 2 months. Both treatments enhanced,

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