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This Article Full Text Full Text (PDF) All Versions of this Article: 292/1/E187    most recent 00283.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Fernández, E. Articles by Álvarez, C. Search for Related Content PubMed PubMed Citation Articles by Fernández, E. Articles by Álvarez, C.

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