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VOL. 76 (1), 23-44, 2010 BETA-CELL HYPERPLASIA INDUCED BY HEPATIC INSULIN...

insulin signaling and that the severity of this resistance depends on the
level of IR deletion; iLIRKO mice suffer early insulin resistance, as a
primary defect, directly related to the ablation of IR, but also have
impaired insulin signaling in extra hepatic tissues. Thus, iLIRKO mice
induce late insulin resistance, as a secondary effect. Given the fact that
IR expression in those tissues was not affected, this effect may be
likely due to IR desensitisation due to prolonged hyperinsulinemia.
Our results demonstrate that a primary defect in the liver triggers a
secondary insulin resistance in extra hepatic tissues. Accordingly, the
progression to diabetes only requires defects in the liver as observed
in iLIRKO mice.

Insulin resistance is associated with hyperinsulinemia and leads
to beta-cell hyperplasia. Thus, early IR deletion by the liver in
constitutive LIRKO induced beta-cell hyperplasia (8). However,
in mice in which was created muscle-specific insulin resistance
by conditional inactivation of the IR (MIRKO mice, 11), no islet
hyperplasia was found in response to the isolated muscle insulin
resistance. More importantly, insulin levels are elevated in most states
of insulin resistance, including the LIRKO mouse, but are not elevated
in MIRKO mouse. Our results with iLIRKO demonstrate a direct
relationship between the level of IR deletion by the liver and the fold-
increase of plasma insulin levels and also beta-cell mass. Finally,
constitutive LIRKO developed hypersecretion of insulin for more than
one year. However, in iLIRKO mice compensatory hyperinsulinemia
in 1 year-old mice was much lower than in 6 month-old mice. Thus,
a failure in the beta cells insulin secretion seems to occur, given the
fact of the inhibition of the insulin clearance by the liver, the major
site of insulin degradation in an IR-dependent manner (25). More
importantly, iLIRKO suggests that owing to severe insulin resistance
and prolonged hypersecretion of insulin, the beta cells ultimately
undergo a failure in insulin secretion.

Previous evidence demonstrated that insulin signaling is essential
for beta-cell growth (10, 26). Just recently, IR double null allele in
the liver and in the beta cells failed to induce beta-cell hyperplasia
in response to severe insulin resistance. In fact, the persistence of
robust hyperplasia in six month-old hypoglycemic LIRKO mice
supports the concept of a glucose-independent circulating islet
growth factor (27). In this context, iLIRKO mice induced IGF-1

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