Regulation of integrin α6A by lactogenic hormones in rat pancreatic β‐cells: Implications for the physiological adaptation to pregnancy

Abstract

Aim During pregnancy, the maternal β‐cell mass is increased in order to adapt to the physiological changes in insulin demand. Lactogenic hormones stimulate rodent β‐cell attachment and proliferation in vitro. The aim of this study was to identify adhesion molecules involved in expansion of the β‐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 α6β1. β‐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 β‐cells from 2.9 ± 0.4‐fold to 1.3 ± 0.3‐fold. The hormone‐induced expression of α6β1 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 β‐cells is upregulated by lactogenic hormones and is required but not sufficient for the expansion of the β‐cell mass in pregnancy in the rat, which may have implications for the understanding and treatment of gestational diabetes mellitus.

Possible mechanisms involved in improved beta cell function in pregnant women with type 1 diabetes

“…We have identified a number of peptides in serum from healthy pregnant women that may be involved in the increase in beta cell mass [ 23 ]. Recently we found that certain integrins are involved in the beta cell adaptation to pregnancy in the rat [ 24 ].…”

Pregnancy

“…7 Recent results from physiological research which suggest therapeutic perspectives for perinatal complications include, for example, an inhibition of prolyl hydroxylase to treat anaemia of prematurity 8 or brain-sparing physiological responses in perinatal asphyxia. 9 Interestingly, Moldrup et al 10 could recently show how lactogenic hormones upregulate integrin-α6 in pancreatic β-cells, aiding expansion of the β-cell mass in pregnancy, which may be impaired in gestational diabetes mellitus. Although done in a rodent model, the authors describe a novel pregnancy-relevant relation between lactogenic hormones, integrins and the extracellular matrix.…”

“…Interestingly, Moldrup et al 10 could recently show how lactogenic hormones upregulate integrin‐α6 in pancreatic β‐cells, aiding expansion of the β‐cell mass in pregnancy, which may be impaired in gestational diabetes mellitus. Although done in a rodent model, the authors describe a novel pregnancy‐relevant relation between lactogenic hormones, integrins and the extracellular matrix.…”

Growth

“…Hypersecretion of growth hormone (GH) and its mediator insulin‐like growth factor‐1 (IGF‐I) has been shown to improve, via an increase in nerve cell growth and differentiation, neurocognitive function 3,4 . Interestingly, GH is also critical for ß‐cell mass regulation 5 . It has been well known that thyroid hormone (TH) is vital for both embryonic development and adult brain function, the details of its regulating NSC biology at all stages are currently being elucidated 6 .…”