RESUMO
AIM: During pregnancy, the maternal ß-cell mass is increased in order to adapt to the physiological changes in insulin demand. Lactogenic hormones stimulate rodent ß-cell attachment and proliferation in vitro. The aim of this study was to identify adhesion molecules involved in expansion of the ß-cell mass during pregnancy in the rat. METHODS: Quantitative RT-PCR was used to evaluate the expression of several integrins and laminins in isolated neonatal rat islets in response to growth hormone (GH) and prolactin (PRL) treatment. Double-immunofluorescence staining of rat pancreas was used to localize the expression of integrin α6ß1. ß-cell proliferation was evaluated by incorporation of bromodeoxyuridine (BrdU). The role of STAT5 phosphorylation was tested by addition of STAT5 mutants. RESULTS: We found that the mRNA level of integrin-α6A, was upregulated 2.5-fold by PRL or GH. During pregnancy, a biphasic 3.4-4.5-fold increase of integrin-α6A and B mRNA levels was detected. A disintegrin peptide (DP) reduced the hormone-stimulated mitotic activity in neonatal rat ß-cells from 2.9 ± 0.4-fold to 1.3 ± 0.3-fold. The hormone-induced expression of α6ß1 integrin was shown to be mediated via STAT5 as a dominant negative (DN) mutant prevented and a constitutive active (CA) mutant augmented the hGH-stimulated expression. The DP was found to inhibit hGH-induced transactivation of the PRL receptor promoter 1A and reduce the hGH-induced phosphorylation of STAT5. CONCLUSION: These results show that integrin-α6 in ß-cells is upregulated by lactogenic hormones and is required but not sufficient for the expansion of the ß-cell mass in pregnancy in the rat, which may have implications for the understanding and treatment of gestational diabetes mellitus.
