title: Increased IRS-2 content and activation of IGF-I pathway contribute to enhance beta-cell mass in fetuses from undernourished pregnant rats.
abstract: We have previously shown that fetuses from undernourished (U) pregnant rats exhibited an increased beta-cell mass probably related to an enhanced IGF-I replicative response. Because IGF-I signaling pathways have been implicated in regulating beta-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 beta-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)3alpha/beta, PKCzeta, and mammalian target of rapamycin (mTOR). Similarly, phosphorylation of these proteins (except GSK3alpha/beta) 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 beta-cell mass found in these fetuses.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense, Ciudad Universitaria, 28040 Madrid, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Fernández
authors.forename: M Angeles
authors.initials: MA
authors.lastname: Martín
authors.forename: Susana
authors.initials: S
authors.lastname: Fajardo
authors.forename: Fernando
authors.initials: F
authors.lastname: Escrivá
authors.forename: Carmen
authors.initials: C
authors.lastname: Alvarez
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005333:Fetus / Q000166:cytology*; D005947:Glucose / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D044342:Malnutrition / Q000196:embryology / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011247:Pregnancy; D011270:Pregnancy, Animal; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526299:Irs2 protein, rat; D010750:Phosphoproteins; D007334:Insulin-Like Growth Factor I; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D005947:Glucose