title: Hyperglycemia- and hyperinsulinemia-induced insulin resistance causes alterations in cellular bioenergetics and activation of inflammatory signaling in lymphatic muscle.
abstract: Insulin resistance is a well-known risk factor for obesity, metabolic syndrome (MetSyn) and associated cardiovascular diseases, but its mechanisms are undefined in the lymphatics. Mesenteric lymphatic vessels from MetSyn or LPS-injected rats exhibited impaired intrinsic contractile activity and associated inflammatory changes. Hence, we hypothesized that insulin resistance in lymphatic muscle cells (LMCs) affects cell bioenergetics and signaling pathways that consequently alter contractility. LMCs were treated with different concentrations of insulin or glucose or both at various time points to determine insulin resistance. Onset of insulin resistance significantly impaired glucose uptake, mitochondrial function, oxygen consumption rates, glycolysis, lactic acid, and ATP production in LMCs. Hyperglycemia and hyperinsulinemia also impaired the PI3K/Akt while enhancing the ERK/p38MAPK/JNK pathways in LMCs. Increased NF-κB nuclear translocation and macrophage chemoattractant protein-1 and VCAM-1 levels in insulin-resistant LMCs indicated activation of inflammatory mechanisms. In addition, increased phosphorylation of myosin light chain-20, a key regulator of lymphatic muscle contraction, was observed in insulin-resistant LMCs. Therefore, our data elucidate the mechanisms of insulin resistance in LMCs and provide the first evidence that hyperglycemia and hyperinsulinemia promote insulin resistance and impair lymphatic contractile status by reducing glucose uptake, altering cellular metabolic pathways, and activating inflammatory signaling cascades.-Lee, Y., Fluckey, J. D., Chakraborty, S., Muthuchamy, M. Hyperglycemia- and hyperinsulinemia-induced insulin resistance causes alterations in cellular bioenergetics and activation of inflammatory signaling in lymphatic muscle.
authors.affiliation: Department of Medical Physiology, Texas A&M Health Science Center College of Medicine, College Station, Texas, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Health and Kinesiology, Texas A&M University, College Station, Texas, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Fluckey
authors.affiliation: Department of Medical Physiology, Texas A&M Health Science Center College of Medicine, College Station, Texas, USA; schakraborty@medicine.tamhsc.edu.
authors.forename: Sanjukta
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: Department of Medical Physiology, Texas A&M Health Science Center College of Medicine, College Station, Texas, USA; marim@tamu.edu.
authors.forename: Mariappan
authors.initials: M
authors.lastname: Muthuchamy
mesh_terms: D000818:Animals; D001786:Blood Glucose; D004734:Energy Metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000139:chemically induced* / Q000378:metabolism; D006946:Hyperinsulinism / Q000139:chemically induced* / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D007328:Insulin / Q000009:adverse effects*; D007333:Insulin Resistance; D042601:Lymphatic Vessels / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009119:Muscle Contraction / Q000502:physiology*; D009130:Muscle, Smooth / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology
chemical_list: D001786:Blood Glucose; D007328:Insulin; D005947:Glucose
keywords: glycolysis; insulin signaling; lymphatic contractility; metabolism; signal transduction