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.
Highlights
Metabolic diseases, which include insulin resistance (IR) and metabolic syndrome, are at the forefront of public health concern due to the global obesity epidemic [1, 2]
Examinations of the effect of insulin on TLR4 signaling in non-obese individuals, where circulating free fatty acids (FFAs) are not increased, are far less common
Results from the current study have shown decreased TLR4 protein expression in a cardiac crude membrane extract during conditions of prolonged (46 h) insulin infusion in healthy equine subjects
Summary
Metabolic diseases, which include insulin resistance (IR) and metabolic syndrome, are at the forefront of public health concern due to the global obesity epidemic [1, 2]. IR can persist for many years in human patients before pancreatic decompensation results in the development of diabetes. The disease is characterized by hyperinsulinemia and occurs in both humans and animals [4]. Considering that horses with IR exhibit similar features to metabolic diseases in other species, including humans and small animals, comparative metabolism studies in both small and large animals may aid in further elucidating the pathophysiology of metabolic dysfunction across species. The recent development of a prolonged, euglycemic, hyperinsulinemic clamp in healthy, adult, disease free horses that are not prone to cardiovascular disease or diabetes mellitus has resulted in an unprecedented opportunity to study the effect of prolonged hyperinsulinemia in this unique large animal model
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