title: Hyperinsulinemia Down-Regulates TLR4 Expression in the Mammalian Heart.
abstract: Toll-like receptors (TLR) are key regulators of innate immune and inflammatory responses and their activation is linked to impaired glucose metabolism during metabolic disease. Determination of whether TLR4 signaling can be activated in the heart by insulin may shed light on the pathogenesis of diabetic cardiomyopathy, a process that is often complicated by obesity and insulin resistance. The aim of the current study was to determine if supraphysiological insulin concentrations alter the expression of TLR4, markers of TLR4 signaling and glucose transporters (GLUTs) in the heart. Firstly, the effect of insulin on TLR4 protein expression was investigated in vitro in isolated rat cardiac myocytes. Secondly, protein expression of TLR4, the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) suppressor of cytokine signaling 3 (SOCS3) and GLUTs (1, 4, 8, 12) were examined in the equine ventricular myocardium following a prolonged, euglycemic, hyperinsulinemic clamp. Down-regulation of TLR4 protein content in rat cardiac myocytes was observed after incubation with a supraphysiologic concentration of insulin as well as in the equine myocardium after prolonged insulin infusion. Further, cardiac TLR4 expression was negatively correlated with serum insulin concentration. Markers of cardiac TLR4 signaling and GLUT expression were not affected by hyperinsulinemia and concomitant TLR4 down-regulation. Since TLRs are major determinants of the inflammatory response, our findings suggest that insulin infusion exerts an anti-inflammatory effect in the hearts of non-obese individuals. Understanding the regulation of cardiac TLR4 signaling during metabolic dysfunction will facilitate improved management of cardiac sequela to metabolic syndrome and diabetes.
authors.affiliation: Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University , Stillwater, OK , USA.
authors.forename: Melody A
authors.initials: MA
authors.lastname: de Laat
authors.affiliation: Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University , Stillwater, OK , USA.
authors.forename: Kaylynn J
authors.initials: KJ
authors.lastname: Gruntmeir
authors.affiliation: Australian Equine Laminitis Research Unit, School of Veterinary Science, The University of Queensland , Gatton, QLD , Australia.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Pollitt
authors.affiliation: Institute of Ageing and Chronic Disease, Faculty of Health and Life Sciences, University of Liverpool , Neston , UK.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: McGowan
authors.affiliation: Earth, Environmental and Biological Sciences, Queensland University of Technology , Brisbane, QLD , Australia.
authors.forename: Martin N
authors.initials: MN
authors.lastname: Sillence
authors.affiliation: Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University , Stillwater, OK , USA.
authors.forename: Véronique A
authors.initials: VA
authors.lastname: Lacombe
keywords: clamp technique; cytokine; insulin; myocardium; toll-like receptor
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