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VOL. 73 (3), 763-784, 2007 FROM PATHOGENESIS TO THERAPEUTIC OF TYPE 2...

on day 7, pancreatic insulin contents and total beta-cell mass by
stimulating beta-cell neogenesis and beta-cell regeneration. Follow
up of biological characteristics from day 7 to adult age (2 months)
showed that both treatment exerted long-term favorable influence
on beta-cell mass and glycaemic control at adult age (Figure 5). As
compared to untreated GK rats, 2-month-old GLP-1 or Ex-4 treated
GK rats exhibited significantly decreased basal plasma glucose. Their
glucose-stimulated insulin secretion, in vivo after intravenous glucose
load or in vitro using isolated perfused pancreas, were improved.
Moreover, plasma glucose disappearance rate was increased in both
treated GK groups compared to untreated GK group (39). These
findings in the GK model indicate that a GLP-1 or Ex-4 treatment
limited to the pre-diabetic period, delays the installation and limits
the severity of T2D.

We have also raised the question of what is the acute impact of
GLP-1 in term of beta-cell secretory function in the GK model. To
that aim, we have determined the effect of an acute GLP-1 exposure
on GK islets. We first found that GLP-1 was able to restore the
glucose competence of the GK beta-cell with a clear return of
the biphasic pattern of insulin release (Figure 6). Then, we have
demonstrated that this is by a mechanism which mainly reflects an
enhanced efficacy of Ca2+ on exocytosis (in the absence of Ca2+
elevation) and directly relates to an enhanced production of cAMP
and overexpression of AC1, 2, and 3 isoforms and Gsa in the GK
beta-cells. Such a sensitization to GLP-1 allows acute normalization
of the defective glucose responsiveness of the GK beta-cell (40).

According to our preclinical studies in the GK model, the GLP-
1 receptor agonists therefore represent a class of compound with
unique property due to their beta-cell replenishing effect in
spontaneously diabetic rodents. They may prove invaluable agent
not only for treatment of yet installed human T2D but also for its
prevention.

In conclusion, the defective beta-cell mass and function in the
GK/Par model reflects the complex interactions of three pathogenic
players: i) several independent loci containing genes responsible
for some diabetic traits (but not decreased beta-cell mass); (ii)
gestational metabolic impairment inducing a programming of

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