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Increased IRS-2 content and activation of IGF-I pathway contribute to enhance -cell mass in fetuses from undernourished pregnant rats

Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Ciudad Universitaria, Madrid, Spain

Submitted 15 June 2006 ; accepted in final form 10 August 2006

We have previously shown that fetuses from undernourished (U) pregnant rats exhibited an increased -cell mass probably related to an enhanced IGF-I replicative response. Because IGF-I signaling pathways have been implicated in regulating -cell growth, we investigated in this study the IGF-I transduction system in U fetuses. To this end, an in vitro model of primary fetal islets was developed to characterize glucose/IGF-I-mediated signaling that specially influences -cell proliferation. We found that U fetal islets showed a greater replicative response to glucose and IGF-I than controls. Furthermore, insulin receptor substrate (IRS)-2 protein and its association with p85 were also increased. In the complete absence of IGF-I or stimulatory glucose, U islets presented an increased basal phosphorylation of downstream signals of the phosphatidylinositol 3-kinase (PI3K) pathway such as PKB, glycogen synthase kinase (GSK)3/, PKC, and mammalian target of rapamycin (mTOR). Similarly, phosphorylation of these proteins (except GSK3/) by glucose and IGF-I was augmented even though total protein content remained unchanged. Downstream of PKB, direct glucose activation of mTOR was increased as well. In contrast, ERK1/2 phosphorylation was unaffected by undernutrition, but ERK activation seemed to be required to induce a higher proliferative response in U islets. In conclusion, we have demonstrated that fetal U islets show increased IRS-2 content and an enhancement in both basal and glucose/IGF-I activations of the IRS-2/PI3K/PKB pathway. These molecular changes may be responsible for the greater glucose/IGF-I islet replication and contribute to the increased -cell mass found in these fetuses.

undernutrition; fetal islet; insulin-like growth factor I pathway; insulin receptor substrate-2