Insulinlike Growth Factor-Binding Protein-1 Improves Vascular Endothelial Repair in Male Mice in the Setting of Insulin Resistance

Insulin resistance is associated with impaired endothelial regeneration in response to mechanical injury. We recently demonstrated that insulinlike growth factor–binding protein-1 (IGFBP1) ameliorated insulin resistance and increased nitric oxide generation in the endothelium. In this study, we hypothesized that IGFBP1 would improve endothelial regeneration and restore endothelial reparative functions in the setting of insulin resistance. In male mice heterozygous for deletion of insulin receptors, endothelial regeneration after femoral artery wire injury was enhanced by transgenic expression of human IGFBP1 (hIGFBP1). This was not explained by altered abundance of circulating myeloid angiogenic cells. Incubation of human endothelial cells with hIGFBP1 increased integrin expression and enhanced their ability to adhere to and repopulate denuded human saphenous vein ex vivo. In vitro, induction of insulin resistance by tumor necrosis factor α (TNFα) significantly inhibited endothelial cell migration and proliferation. Coincubation with hIGFBP1 restored endothelial migratory and proliferative capacity. At the molecular level, hIGFBP1 induced phosphorylation of focal adhesion kinase, activated RhoA and modulated TNFα-induced actin fiber anisotropy. Collectively, the effects of hIGFBP1 on endothelial cell responses and acceleration of endothelial regeneration in mice indicate that manipulating IGFBP1 could be exploited as a putative strategy to improve endothelial repair in the setting of insulin resistance

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Altered placental development and intrauterine growth restriction in IGF binding protein-1 transgenic mice

IGF binding protein-1 (IGFBP-1) is a secretory product of decidualized endometrium and a major constituent of amniotic fluid. It is thought to modulate the actions of the IGFs on trophoblast cells and is therefore potentially important in regulating placental development and fetal growth. To investigate this hypothesis, we have studied the effects of decidual IGFBP-1 excess on fetoplacental growth in transgenic mice overexpressing human IGFBP-1. Endogenous fetal IGFBP-1 overexpression is associated with a transient impairment of fetal growth in midgestation. Maternal decidual IGFBP-1 excess is also associated with impaired fetal growth in midgestation independent of fetal genotype, indicating placental insufficiency. Our data also demonstrate that amniotic fluid IGFBP-1 is derived almost exclusively from maternal sources. Decidual IGFBP-1 overexpression has a marked effect on placental development. Placental morphology is abnormal in transgenic females due to altered trophoblast invasion and differentiation. These changes result in an increase in placental mass throughout pregnancy. This study provides the first compelling in vivo evidence that IGFBP-1 plays a role in placentation and suggests that IGFBP-1 has a pathological role in preeclampsia, a disorder characterized by shallow uterine invasion and altered placental development

Belgium: Transparent Entities: The Case of the French SCI under the Belgium-French Tax Treaty

peer reviewedThis book is a unique publication that gives a global overview of international tax disputes on double tax conventions, thereby filling a gap in the area of tax treaty case law. It covers the 41 most important tax treaty cases that were decided around the world in 2016. The systematic structure of each chapter allows for the easy and efficient study and comparison of the various methods adopted for applying and interpreting tax treaties in different cases. With the continuously increasing importance of tax treaties, Tax Treaty Case Law around the Globe 2017 is a valuable reference tool for anyone interested in tax treaty case law. This book is of interest to tax practitioners, multinational businesses, policymakers, tax administrators, judges and academics

Effect of Endothelium-Specific Insulin Resistance on Endothelial Function In Vivo

OBJECTIVE—Insulin resistance is an independent risk factor for the development of cardiovascular atherosclerosis. A key step in the development of atherosclerosis is endothelial dysfunction, manifest by a reduction in bioactivity of nitric oxide (NO). Insulin resistance is associated with endothelial dysfunction; however, the mechanistic relationship between these abnormalities and the role of impaired endothelial insulin signaling versus global insulin resistance remains unclear. RESEARCH DESIGN AND METHODS—To examine the effects of insulin resistance specific to the endothelium, we generated a transgenic mouse with endothelium-targeted overexpression of a dominant-negative mutant human insulin receptor (ESMIRO). This receptor has a mutation (Ala-Thr(1134)) in its tyrosine kinase domain that disrupts insulin signaling. Humans with the Thr(1134) mutation are insulin resistant. We performed metabolic and vascular characterization of this model. RESULTS—ESMIRO mice had preserved glucose homeostasis and were normotensive. They had significant endothelial dysfunction as evidenced by blunted aortic vasorelaxant responses to acetylcholine (ACh) and calcium ionophore. Furthermore, the vascular action of insulin was lost in ESMIRO mice, and insulin-induced endothelial NO synthase (eNOS) phosphorylation was blunted. Despite this phenotype, ESMIRO mice demonstrate similar levels of eNOS mRNA and protein expression to wild type. ACh-induced relaxation was normalized by the superoxide dismutase mimetic, Mn(III)tetrakis(1-methyl-4-pyridyl) porphyrin pentachloride. Endothelial cells of ESMIRO mice showed increased superoxide generation and increased mRNA expression of the NADPH oxidase isoforms Nox2 and Nox4. CONCLUSIONS—Selective endothelial insulin resistance is sufficient to induce a reduction in NO bioavailability and endothelial dysfunction that is secondary to increased generation of reactive oxygen species. This arises independent of a significant metabolic phenotype