Maternal insulin therapy does not restore foetoplacental endothelial dysfunction in gestational diabetes mellitus.

Mario Subiabre, Luis Silva, Roberto Villalobos-Labra, Fernando Toledo, Mario Paublo, Marcia A López, Rocío Salsoso, Fabián Pardo, Andrea Leiva, Luis Sobrevia

Journal: Biochimica et biophysica acta. Molecular basis of disease 2018;1863(11):2987-2998

PMID: 28756217

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Abstract

Pregnant women diagnosed with gestational diabetes mellitus subjected to diet (GDMd) that do not reach normal glycaemia are passed to insulin therapy (GDMi). GDMd associates with increased human cationic amino acid transporter 1 (hCAT-1)-mediated transport of L-arginine and nitric oxide synthase (NOS) activity in foetoplacental vasculature, a phenomenon reversed by exogenous insulin. Whether insulin therapy results in reversal of the GDMd effect on the foetoplacental vasculature is unknown. We assayed whether insulin therapy normalizes GDMd-associated foetoplacental endothelial dysfunction. Primary cultures of human umbilical vein endothelial cells (HUVECs) from GDMi pregnancies were used to assay L-arginine transport kinetics, NOS activity, p44/42 and protein kinase B/Akt activation, and umbilical vein rings reactivity. HUVECs from GDMi or GDMd show increased hCAT-1 expression and maximal transport capacity, NOS activity, and eNOS, and p44/42, but not Akt activator phosphorylation. Dilation in response to insulin or calcitonin-gene related peptide was impaired in umbilical vein rings from GDMi and GDMd pregnancies. Incubation of HUVECs in vitro with insulin (1 nmol/L) restored hCAT-1 and eNOS expression and activity, and eNOS and p44/42 activator phosphorylation. Thus, maternal insulin therapy does not seem to reverse GDMd-associated alterations in human foetoplacental vasculature.

Address: Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile.; Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (UMCG), Groningen, 9700 RB, The Netherlands.; Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; Department of Basic Sciences, Faculty of Sciences, Universidad del Bío-Bío, Chillán 3780000, Chile.; Gynaecology and Obstetrics Service, Hospital San Juan de Dios, Santiago 8330024, Chile.; Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; Department of Physiology, Faculty of Pharmacy, Universidad de Sevilla, Seville E-41012, Spain.; Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; Metabolic Diseases Research Laboratory, Center of Research, Development and Innovation in Health - Aconcagua Valley, San Felipe Campus, School of Medicine, Faculty of Medicine, Universidad de Valparaíso, San Felipe 2172972, Chile.; Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; Department of Physiology, Faculty of Pharmacy, Universidad de Sevilla, Seville E-41012, Spain; University of Queensland, Centre for Clinical Research (UQCCR), Faculty of Medicine and Biomedical Sciences, University of Queensland, Herston, QLD 4029, Queensland, Australia. Electronic address: [email protected].

DOI: 10.1016/j.bbadis.2017.07.022

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https://linkinghub.elsevier.com/retrieve/pii/S0925...

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https://medlineplus.gov/diabetesmedicines.html

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https://scite.ai/reports/28756217

MeSH Terms: Adult, Cationic Amino Acid Transporter 1, Diabetes, Gestational, Endothelium, Vascular, Female, Gene Expression Regulation, Human Umbilical Vein Endothelial Cells, Humans, Insulin, Mitogen-Activated Protein Kinase 3, Nitric Oxide Synthase Type III, Phosphorylation, Placenta, Pregnancy, Proto-Oncogene Proteins c-akt