HIGH INSULIN IMPAIRS PI-3 KINASE/AKT-MEDIATED INSULIN SIGNALING IN HUMAN ENDOTHELIAL CELLS: AN IN VITRO INDUCTION OF INSULIN RESISTANCE?

Insulin receptors (IRs) on endothelial cells may have a role in the regulation of transport of circulating insulin to its target tissues; however, how this impacts on insulin action in vivo is unclear. Using mice with endothelial-specific inactivation of the IR gene (EndoIRKO), we find that in response to systemic insulin stimulation, loss of endothelial IRs caused delayed onset of insulin signaling in skeletal muscle, brown fat, hypothalamus, hippocampus, and prefrontal cortex but not in liver or olfactory bulb. At the level of the brain, the delay of insulin signaling was associated with decreased levels of hypothalamic proopiomelanocortin, leading to increased food intake and obesity accompanied with hyperinsulinemia and hyperleptinemia. The loss of endothelial IRs also resulted in a delay in the acute hypoglycemic effect of systemic insulin administration and impaired glucose tolerance. In high-fat diet-treated mice, knockout of the endothelial IRs accelerated development of systemic insulin resistance but not food intake and obesity. Thus, IRs on endothelial cells have an important role in transendothelial insulin delivery in vivo which differentially regulates the kinetics of insulin signaling and insulin action in peripheral target tissues and different brain regions. Loss of this function predisposes animals to systemic insulin resistance, overeating, and obesity.

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Vascular repair utilising immobilised heparin conjugate for protection against early activation of inflammation and coagulation

Thrombosis and Haemostasis ◽

10.1160/th14-09-0724 ◽

2015 ◽

Vol 113 (06) ◽

pp. 1312-1322 ◽

Cited By ~ 18

Author(s):

Sofia Nordling ◽

Jaan Hong ◽

Karin Fromell ◽

Fredrik Edin ◽

Johan Brännström ◽

...

Keyword(s):

Endothelial Cells ◽

Thrombus Formation ◽

Innate Immune ◽

Human Endothelial Cells ◽

Coagulation Activation ◽

Ischaemia Reperfusion Injury ◽

Novel Approach ◽

One Step ◽

Chamber Model

SummaryIschaemia-reperfusion injury (IRI) poses a major challenge in many thrombotic conditions and in whole organ transplantation. Activation of the endothelial cells and shedding of the protective vascular glycocalyx during IRI increase the risk of innate immune activation, cell infiltration and severe thrombus formation, promoting damage to the tissue. Here, we present a novel one-step strategy to protect the vasculature by immobilisation of a unique multi-arm heparin conjugate to the endothelium. Applying a new in vitro blood endothelial cell chamber model, the heparin conjugate was found to bind not only to primary human endothelial cells but also directly to the collagen to which the cells adhered. Incubation of hypoxic endothelial cells with freshly drawn human blood in the blood chambers elicited coagulation activation reflected by thrombin anti-thrombin formation and binding of platelets and neutrophils. Immobilisation of the heparin conjugate to the hypoxic endothelial cells created a protective coating, leading to a significant reduction of the recruitment of blood cells and coagulation activation compared to untreated hypoxic endothelial cells. This novel approach of immobilising multi-arm heparin conjugates on the endothelial cells and collagen of the basement membrane ensures to protect the endothelium against IRI in thrombotic disorders and in transplantation.

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Centrifugal enhancement of Kaposi's sarcoma-associated virus infection of human endothelial cells in vitro

Journal of Virological Methods ◽

10.1016/j.jviromet.2008.07.026 ◽

2008 ◽

Vol 154 (1-2) ◽

pp. 160-166 ◽

Cited By ~ 24

Author(s):

Seung-Min Yoo ◽

Ae-Kyung Ahn ◽

Taegun Seo ◽

Hyo Bong Hong ◽

Myung-Ae Chung ◽

...

Keyword(s):

Endothelial Cells ◽

Virus Infection ◽

Kaposi's Sarcoma ◽

Kaposi’S Sarcoma ◽

Human Endothelial Cells

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Disruption of endothelial Pfkfb3 ameliorates diet-induced murine insulin resistance

Journal of Endocrinology ◽

10.1530/joe-20-0524 ◽

2021 ◽

Author(s):

Qiuhua Yang ◽

Jiean Xu ◽

Qian Ma ◽

Zhiping Liu ◽

Yaqi Zhou ◽

...

Keyword(s):

Insulin Resistance ◽

Endothelial Cells ◽

High Fat Diet ◽

Inflammatory Responses ◽

Critical Role ◽

Endothelial Inflammation ◽

Glucose Clearance ◽

Deficient Mice

Overnutrition-induced endothelial inflammation plays a crucial role in high fat diet (HFD)-induced insulin resistance in animals. Endothelial glycolysis plays a critical role in endothelial inflammation and proliferation, but its role in diet-induced endothelial inflammation and subsequent insulin resistance has not been elucidated. PFKFB3 is a critical glycolytic regulator, and its increased expression has been observed in adipose vascular endothelium of C57BL/6J mice fed with HFD in vivo, and in palmitate (PA)-treated primary human adipose microvascular endothelial cells (HAMECs) in vitro. We generated mice with Pfkfb3 deficiency selective for endothelial cells to examine the effect of endothelial Pfkfb3 in endothelial inflammation in metabolic organs and in the development of HFD-induced insulin resistance. EC Pfkfb3-deficient mice exhibited mitigated HFD-induced insulin resistance, including decreased body weight and fat mass, improved glucose clearance and insulin sensitivity, and alleviated adiposity and hepatic steatosis. Mechanistically, cultured PFKFB3 knockdown HAMECs showed decreased NF-κB activation induced by PA, and consequent suppressed adhesion molecule expression and monocyte adhesion. Taken together, these results demonstrate that increased endothelial PFKFB3 expression promotes diet-induced inflammatory responses and subsequent insulin resistance, suggesting that endothelial metabolic alteration plays an important role in the development of insulin resistance.

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