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

the possible mechanisms responsible for decreased beta-cell number
and impaired beta-cell function and their multifactorial aetiology.

Hazard of invasive sampling and lack of suitable non-invasive
methods to evaluate beta-cell mass and beta-cell functions are strong
limitations for studies of the living pancreas in human. In such a
perspective, appropriate rodent models are essential tools for
identification of the mechanisms that increase the risk of abnormal
beta-cell mass/function and of T2D. Some answers to these major
questions are available from studies using the Goto-Kakizaki (GK)
rat model of T2D and they are reviewed in the present paper. The
GK rat is a non obese substrain of Wistar rat origin, developing T2D
early in life. Mild fasting hyperglycaemia and postprandial glucose
intolerance are primarily due to impaired beta-cell mass and function
on the background of a polygenic inheritance. In addition, secondary
defects in beta-cell function and insulin action may superimpose
(e.g., due to chronic hyperglycaemia [glucotoxicity]). Since the GK
rat can be regarded as one of the best available rodent strains for the
study of inherited T2D, it is extensively used in preclinical diabetes
research.

THE GOTO-KAKIZAKI WISTAR (GK) RAT MODEL OF
SPONTANEOUS TYPE 2 DIABETES

Most rodent models used for studies of the inheritance of T2D
(ob/ob mouse, db/db mouse, ZDF rat, OLEFT rat) show association
of hyperglycaemia and obesity with insulin resistance. However, in
the inbred GK (Goto-Kakizaki) rat line and more specifically in our
colony (GK/Par subline) maintained since 1989, all rats are nonobese,
nonketotic, and display mild fasting hyperglycaemia. The GK line
was established by repeated inbreeding from Wistar (W) rats selected
at the upper limit of normal distribution for glucose tolerance (12-
14) (Figure 1).

The adult GK/Par body weight is 10-30% lower than that of age and
sex-matched control animals. In male GK/Par rats, non-fasting plasma
glucose levels are typically 10-14 mM (6-8 mM in age-matched Wistar
outbred controls). In female GK rats, somewhat lower plasma glucose
concentrations are noted. Non-fasting plasma insulin levels in GK rats

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