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

uptake to levels higher than those observed in control cells (Figure 7,
panel E). In addition, insulin or IGF-1 enhanced cell viability
in control cells. In the same way, IGF-1 induced cell viability in
beta cells lacking IR. Rec A but not Rec B cells, increased cell viability
in response to either insulin or IGF-1 (Figure 7, panel F). More
importantly, insulin or IGF-1 increased proliferation, as estimated
by thymidine incorporation, in control beta cells. However, beta
cells lacking IR did not respond to IGF-1. Finally, insulin and
IGF-1 induced proliferation in Rec A but not in Rec B cells (Figure 7,
panel G).

4. DISCUSSION

Insulin promotes both metabolism and growth in the liver.
Constitutive ablation of IR in liver resulted in both metabolic changes
and a reduction in liver size by about 50% (8). Likewise, mice in
which there is variable IR deletion (cellular mosaicism) exhibit
different degrees of growth retardation and metabolic abnormalities
depending on the extent of IR deletion (23). Those findings suggest
that insulin regulates growth independently of metabolism and
that the IR number is an important determinant of the insulin
action specificity. Using the approach to generate LIRKO mice in
an inducible manner, we were able to induce variable IR deletion
(liver mosaicism). As a result, iLIRKO induced progressive insulin
resistance and glucose intolerance without growth retardation. Under
our experimental conditions, the insulin-induced effect on growth
and metabolic regulation are mutually independent. Thus, while
the late IR deletion gave rise to irreversible insulin resistance and
progressive glucose intolerance for over one year, no liver damage
was observed.

Previous tissue specific knockout and tissue specific reconstitution
studies concluded that the progression of insulin resistance to
diabetes with fasting hyperglycemia requires defects in tissues other
than liver (7, 8). More importantly, acute IR deletion by the liver
although impaired insulin signaling did not induce insulin resistance
or hyperinsulinemia (24). Our results show that liver-specific
disruption of IR could produce impaired hepatic and extra hepatic

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