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

containing genes regulating fasting plasma glucose and insulin levels,
glucose tolerance, insulin secretion and adiposity in GK/Par rats.
The same conclusion was drawn by Galli et al. (35) using GK from
the Stockholm colony. This established the polygenic inheritance
of diabetes-related parameters in the GK rat. Both studies found
the strongest evidence of linkage between glucose tolerance and
markers spanning a region on rat chromosome 1, called Niddm1
locus. While it must be recognized that many of the glucose-
controlling locus variants reported (23, 35, 36) were associated in
fact with hyperinsulinaemia or enhanced insulin secretion, more
recent works using congenic technology have identified on the
Niddm1i locus a 3.5 cM region containing approximately ten genes,
as a major susceptibility locus for defective insulin secretion (37).
However, no QTL association with beta-cell mass or beta-cell size is
found in the GK/Par rat (Ktorza and Gauguier, unpublished data).
Therefore, the likehood that a genotype alteration contributes to the
low beta-cell mass phenotype in the GK/Par rat, is reduced. The
raised question to be answered now is the following: does epigenetic
perturbation of gene expression occur in the developing GK pancreas
and does it contribute to the alteration of early beta-cell growth? igf2
and igf1r genes are good candidates for such a perspective.

WHICH THERAPEUTIC FOR A DECREASED BETA-CELL
FUNCTIONAL MASS AS SEEN IN THE GK RAT? A ROLE

FOR GLP-1 RECEPTOR AGONISTS

Current therapy of T2D includes a modification of life style such
as diet and exercise and the use of a variety of pharmacological
agents that target increased insulin secretion, decreased hepatic
glucose production and increased insulin action. Despite these
approaches, a number of T2D patients may require exogenous
insulin. Facilitation of T2D treatment may be obtained through beta-
cell transplantation, or on more prospective basis, beta-cell mass
expansion after stimulation of beta-cell regeneration/neogenesis in
the diabetic patients. Indeed, the emerging understanding of beta-
cell growth in the adult, from precursor cells found in the pancreatic
ducts, hold the promise of developing new strategies for stimulating
beta-cell regeneration. Such approach may involve the delivery of

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