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ÓSCAR ESCRIBANO Y COLS. AN. R. ACAD. NAC. FARM.

expression in parallel to IR deletion in the liver. This resulted in a
persistent increase of plasma IGF-1, consistent with the fact that the
liver is the main source of circulating IGF-1 (28). Previous data
demonstrated that IGF-1R in the beta-cell is not crucial for islet
ß-cell mass growth, but participates in control of differentiated
function (29). In fact, we have found a relationship among beta-cell
hyperplasia, hyperinsulinemia and an increase of genes related to
beta-cell proliferation and differentiation in iLIRKO mice. Thus, IGF-
1 signaling might be involved in the induction of genes related to
glucose-stimulated insulin secretion among others. However, IGFBPs
regulates the IGF-1 systemic effect in a complex manner (30). More
importantly, iLIRKO mice induced IGFBP1 in parallel to IGF-1
depending on the level of IR deletion by the liver. These results are
entirely consistent with the insulin-mediated effect on the IGFBP1
gene expression by the liver cells (31). IGFBP1, which is mainly
produced by the liver in the adult mice, inhibits IGF-dependent
cellular growth in vivo (30, 32, 33). In addition, adult transgenic
mice showed glucose intolerance and fasting hyperglycemia and
hyperinsulinemia. However, the hyperinsulinemia observed in
IGFBP1 transgenic mice can not be attributable to insulin resistance
alone (34, 35). In fact, adult transgenic mice showed larger and more
numerous beta-cell islets and also an increased beta-cell proliferation
(36). Finally, iLIRKO mice showed an increase in the IR expression
in the pancreatic islets. More importantly, an increase in the
proportion of IR-A versus IR-B in the total percentage of IR was
observed in pancreatic islets from iLIRKO mice. On this regard, it
was previously reported that IGF-2 and also IGF-1 showed a high
affinity to IR-A (37). In addition, BrdU incorporation experiments
performed in pancreatic islets isolated from 6-month-old control and
iLIRKO mice revealed that the islets from iLIRKO mice were
significantly more sensitive to the IGF-1-induced proliferation.
Moreover, as assessed in mouse beta-cell lines, occurrence mostly of
IR-A in pancreatic islets from iLIRKO mice might imply firstly, an
increase in the rate of glucose uptake, a mitogenic signal in beta
cells independently of insulin (17) and secondly, an enhanced
proliferation in response to either insulin or IGF-1. Taking together,
IR-A, but not IR-B, confers a proliferative capability to beta-cells in
response to insulin or IGF-1 that may account for beta-cell
hyperplasia induced by liver insulin resistance in iLIRKO mice.

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