TY - JOUR

T1 - Regulation of integrin alpha 6A by lactogenic hormones in rat pancreatic beta-cells

T2 - Implications for the physiological adaptation to pregnancy

AU - Moldrup, Annette

AU - Lindberg, Martin Nerup

AU - Galsgaard, Elisabeth D.

AU - Henriksen, Ulrik

AU - Dalgaard, Louise T.

AU - Nielsen, Jens Hoiriis

PY - 2020

Y1 - 2020

N2 - Aim During pregnancy, the maternal beta-cell mass is increased in order to adapt to the physiological changes in insulin demand. Lactogenic hormones stimulate rodent beta-cell attachment and proliferation in vitro. The aim of this study was to identify adhesion molecules involved in expansion of the beta-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 alpha 6 beta 1. beta-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-alpha 6A, was upregulated 2.5-fold by PRL or GH. During pregnancy, a biphasic 3.4-4.5-fold increase of integrin-alpha 6A and B mRNA levels was detected. A disintegrin peptide (DP) reduced the hormone-stimulated mitotic activity in neonatal rat beta-cells from 2.9 +/- 0.4-fold to 1.3 +/- 0.3-fold. The hormone-induced expression of alpha 6 beta 1 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-alpha 6 in beta-cells is upregulated by lactogenic hormones and is required but not sufficient for the expansion of the beta-cell mass in pregnancy in the rat, which may have implications for the understanding and treatment of gestational diabetes mellitus.

AB - Aim During pregnancy, the maternal beta-cell mass is increased in order to adapt to the physiological changes in insulin demand. Lactogenic hormones stimulate rodent beta-cell attachment and proliferation in vitro. The aim of this study was to identify adhesion molecules involved in expansion of the beta-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 alpha 6 beta 1. beta-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-alpha 6A, was upregulated 2.5-fold by PRL or GH. During pregnancy, a biphasic 3.4-4.5-fold increase of integrin-alpha 6A and B mRNA levels was detected. A disintegrin peptide (DP) reduced the hormone-stimulated mitotic activity in neonatal rat beta-cells from 2.9 +/- 0.4-fold to 1.3 +/- 0.3-fold. The hormone-induced expression of alpha 6 beta 1 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-alpha 6 in beta-cells is upregulated by lactogenic hormones and is required but not sufficient for the expansion of the beta-cell mass in pregnancy in the rat, which may have implications for the understanding and treatment of gestational diabetes mellitus.

KW - integrins

KW - islets of Langerhans

KW - lactogenic hormones

KW - pregnancy

KW - Signal Transducer and Activator of Transcription 5 (STAT5)

KW - beta-cells

KW - GESTATIONAL DIABETES-MELLITUS

KW - GLYCOGEN-SYNTHASE KINASE

KW - GROWTH-HORMONE

KW - PROLACTIN RECEPTOR

KW - PROTEIN-KINASE

KW - ENDOCRINE PANCREAS

KW - INSULIN-SECRETION

KW - SIGNAL TRANSDUCER

KW - EXTRACELLULAR-MATRIX

KW - MOLECULAR-CLONING

U2 - 10.1111/apha.13454

DO - 10.1111/apha.13454

M3 - Journal article

C2 - 32056357

VL - 229

JO - Acta Physiologica

JF - Acta Physiologica

SN - 1748-1708

IS - 3

M1 - 13454

ER -