Insulin resistance disrupts cell integrity, mitochondrial function, and inflammatory signaling in lymphatic endothelium

Lee, Yang; Chakraborty, Sanjukta; Meininger, Cynthia J.; Muthuchamy, Mariappan

doi:10.1111/micc.12492

Cited by 22 publications

(21 citation statements)

References 112 publications

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“…Aberrant glucose homeostasis causes chronic hyperglycemia, which results in oxidative stress (aberrant mitochondrial function and nitric oxide synthase (NOS) phosphorylation). Increased oxidative stress results in an inflammatory response by activating microglia and reactive astrocytes, which in turn result in cellular damage (Bhatti et al, 2017;Lee et al, 2018;Ormazabal et al, 2018).…”

Section: How Does Insulin Resistance Affect Vascular Integrity and Enmentioning

confidence: 99%

Neurodegenerative Diseases – Is Metabolic Deficiency the Root Cause?

et al. 2020

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Neurodegenerative diseases, including Alzheimer, Parkinson, Huntington, and amyotrophic lateral sclerosis, are a prominent class of neurological diseases currently without a cure. They are characterized by an inexorable loss of a specific type of neurons. The selective vulnerability of specific neuronal clusters (typically a subcortical cluster) in the early stages, followed by the spread of the disease to higher cortical areas, is a typical pattern of disease progression. Neurodegenerative diseases share a range of molecular and cellular pathologies, including protein aggregation, mitochondrial dysfunction, glutamate toxicity, calcium load, proteolytic stress, oxidative stress, neuroinflammation, and aging, which contribute to neuronal death. Efforts to treat these diseases are often limited by the fact that they tend to address any one of the above pathological changes while ignoring others. Lack of clarity regarding a possible root cause that underlies all the above pathologies poses a significant challenge. In search of an integrative theory for neurodegenerative pathology, we hypothesize that metabolic deficiency in certain vulnerable neuronal clusters is the common underlying thread that links many dimensions of the disease. The current review aims to present an outline of such an integrative theory. We present a new perspective of neurodegenerative diseases as metabolic disorders at molecular, cellular, and systems levels. This helps to understand a common underlying mechanism of the many facets of the disease and may lead to more promising disease-modifying therapeutic interventions. Here, we briefly discuss the selective metabolic vulnerability of specific neuronal clusters and also the involvement of glia and vascular dysfunctions. Any failure in satisfaction of the metabolic demand by the neurons triggers a chain of events that precipitate various manifestations of neurodegenerative pathology.

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Section: How Does Insulin Resistance Affect Vascular Integrity and Enmentioning

confidence: 99%

Neurodegenerative Diseases – Is Metabolic Deficiency the Root Cause?

et al. 2020

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“…Other studies analyzing gene expression pathways in LECs isolated from patients with diabetes have shown that proinflammatory, pro-lymphangiogenic, and lipid-shuttling gene expression pathways are increased in diabetes, while genes related to immune defense, apoptosis mediation, and small-compound transporters are downregulated (Haemmerle et al, 2013). Using cultured LECs, Lee et al showed that prolonged hyperglycemia induced insulin resistance and these LECs showed disruption of adherent junction proteins, indicating negative effects of hyperglycemia on LECs (Lee et al, 2018). Using lymphatic muscle cells (LMCs), the same group found that hyperglycemia strongly inhibits LMC contractile function by alteration of cellular bioenergetics and activation of inflammatory signaling in lymphatic muscle.…”

Section: Lymphatic Function and Diabetesmentioning

confidence: 99%

Regulation of Lymphatic Function in Obesity

et al. 2020

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The lymphatic system has many functions, including macromolecules transport, fat absorption, regulation and modulation of adaptive immune responses, clearance of inflammatory cytokines, and cholesterol metabolism. Thus, it is evident that lymphatic function can play a key role in the regulation of a wide array of biologic phenomenon, and that physiologic changes that alter lymphatic function may have profound pathologic effects. Recent studies have shown that obesity can markedly impair lymphatic function. Obesity-induced pathologic changes in the lymphatic system result, at least in part, from the accumulation of inflammatory cells around lymphatic vessel leading to impaired lymphatic collecting vessel pumping capacity, leaky initial and collecting lymphatics, alterations in lymphatic endothelial cell (LEC) gene expression, and degradation of junctional proteins. These changes are important since impaired lymphatic function in obesity may contribute to the pathology of obesity in other organ systems in a feedforward manner by increasing low-grade tissue inflammation and the accumulation of inflammatory cytokines. More importantly, recent studies have suggested that interventions that inhibit inflammatory responses, either pharmacologically or by lifestyle modifications such as aerobic exercise and weight loss, improve lymphatic function and metabolic parameters in obese mice. The purpose of this review is to summarize the pathologic effects of obesity on the lymphatic system, the cellular mechanisms that regulate these responses, the effects of impaired lymphatic function on metabolic syndrome in obesity, and the interventions that may improve lymphatic function in obesity.

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“…One study showed that LECs derived from human dermal tissue (HDLECs) express much higher levels of INSR than that of adipose tissue microvascular ECs; an insulin level as low as 2.5 nM can induce AKT phosphorylation in HDLEC (Jaldin-Fincati et al, 2018), although circulating insulin concentrations in healthy individuals may still well-below the 2.5 nM range, which are around 100 pmol/L (Ford et al, 2006), whether similar responses can be induced at physiological conditions are unknown. Insulin-induced downstream signaling appears to be required for normal lymphatic vascular structure and function (Lee et al, 2018). Diminished LEC insulin signaling decreases eNOS phosphorylation and NO production, reduces mitochondria oxygen consumption, which alters LEC metabolism, and causes increased expression of proinflammatory molecules (Lee et al, 2018); these results suggest that physiological insulin signaling is essential for normal functioning of LECs.…”

Section: Lymphatic Endothelial Cell Insulin Resistancementioning

confidence: 99%

“…Insulin-induced downstream signaling appears to be required for normal lymphatic vascular structure and function (Lee et al, 2018). Diminished LEC insulin signaling decreases eNOS phosphorylation and NO production, reduces mitochondria oxygen consumption, which alters LEC metabolism, and causes increased expression of proinflammatory molecules (Lee et al, 2018); these results suggest that physiological insulin signaling is essential for normal functioning of LECs. Supporting the role of insulin signaling in lymphatic function, blockade of IRS1 suppresses lymphangiogenesis (Hos et al, 2011).…”

Section: Lymphatic Endothelial Cell Insulin Resistancementioning

confidence: 99%

The Lymphatic System in Obesity, Insulin Resistance, and Cardiovascular Diseases

et al. 2019

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Obesity, insulin resistance, dyslipidemia, and hypertension are fundamental clinical manifestations of the metabolic syndrome. Studies over the last few decades have implicated chronic inflammation and microvascular remodeling in the development of obesity and insulin resistance. Newer observations, however, suggest that dysregulation of the lymphatic system underlies the development of the metabolic syndrome. This review summarizes recent advances in the field, discussing how lymphatic abnormality promotes obesity and insulin resistance, and, conversely, how the metabolic syndrome impairs lymphatic function. We also discuss lymphatic biology in metabolically dysregulated diseases, including type 2 diabetes, atherosclerosis, and myocardial infarction.

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Insulin resistance disrupts cell integrity, mitochondrial function, and inflammatory signaling in lymphatic endothelium

Abstract: Our data provide the first evidence that insulin resistance disrupts endothelial barrier integrity, decreases eNOS phosphorylation and mitochondrial function, and activates inflammation in LECs.

Cited by 22 publications

References 112 publications

Neurodegenerative Diseases – Is Metabolic Deficiency the Root Cause?

Neurodegenerative Diseases – Is Metabolic Deficiency the Root Cause?

Regulation of Lymphatic Function in Obesity

The Lymphatic System in Obesity, Insulin Resistance, and Cardiovascular Diseases

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