The decreased AR mediated response has been

The decreased βAR-mediated response has been attributed to different mechanisms, including an attenuation of PKA activation, an impaired generation of cyclic AMP, a reduced receptor density, and a less efficient coupling to adenylyl-cyclase [10]. However, currently there is no single molecular or cellular factor that can fully explain the decline in βAR function. Nonetheless, the etiology seems to be most likely associated with alterations in the ability of βAR to respond to agonists at the cellular level.
Adrenergic signaling and metabolism The adrenergic system is involved in regulating several metabolic pathways. Increased circulating catecholamines and activation of the different ARs present in the various organs produce important metabolic responses, including increased gluconeogenesis by the liver to provide substrate for the brain, increased lipolysis and elevated levels of fatty acids in plasma, and modulation of insulin secretion by pancreatic islets of Langerhans. Such responses are detrimental to the functioning of different organs (e.g. the heart). Metabolic modifications including insulin resistance, altered glucose and lipid metabolism, and mitochondrial dysfunction represent common features of many conditions involving adrenergic overdrive. Notably, these alterations are seen in a number of different pathological conditions and are generally highly correlated with the level of activation of the sympathetic system. Chronic βAR stimulation induces insulin resistance and in this context the β2AR has a key role in overall glucose homeostasis by modulating pancreatic islet hormone secretion as well as liver and muscle glucose homeostasis. Short- and long-term stimulation of the β2AR has been associated with the modulation of fatty BQ-123 and glucose metabolism [98]. Indeed, acute treatment with β2AR agonists of myocytes or skeletal muscle increases glucose uptake to levels comparable to those seen after insulin stimulation [99]. A potential mechanism for β2AR function in insulin resistance involves the activation of PI3K and its downstream signal pathway and in particular the phosphorylation and inactivation of TBC1D4 by AKT [100]. TBC1D4 inhibits the translocation to the plasma membrane of the glucose transporter type 4 (GLUT4) [100]. Moreover, TBC1D4 is also targeted by AMPK, which represents a pivotal mechanism in the regulation of insulin-independent glucose uptake [100], [101]. Strikingly, higher levels of AMPK phosphorylation and activity are seen in response to βAR stimulation [102], [103] as a result of changes in the AMP/ATP ratio or activation of upstream AMPK kinases [104]. Besides, in vivo studies show a greater efficiency of carvedilol, a non-selective βAR antagonist, in ameliorating myocardial insulin sensitivity and glucose extraction in an animal model of heart failure, compared to the selective β1AR antagonist metoprolol [105]. Chronic adrenergic stimulation, as seen during heart failure, would be detrimental by mechanisms involving mechanisms such as JNK, β-arrestins and GRKs [4], [106]. Insulin resistance highly correlates with adrenergic function [75], [107], [108], [109], [110], [111]. In both type 2 diabetes mellitus (T2DM) and heart failure circulating insulin levels are elevated, causing a persistent stimulation of insulin receptors [52], [112], [113], [114], [115], [116], [117]. Hyperactive insulin signaling can accelerate adverse left ventricular remodeling [72], [118]. Recently, insulin has been demonstrated to directly impair adrenergic pathways for contractile function via an insulin receptor/β2AR signaling complex [114]. In numerous conditions associated with insulin resistance, such as hypertension and T2DM, there are elevated GRK2 levels [97], [119]. In vitro experiments demonstrated that insulin increases GRK2 levels, causing GRK2–IRS1 association [97], [120]. On these bases, GRK2 inhibition has been proposed to be beneficial. Indeed, chronic treatment of spontaneously hypertensive rats with an inhibitor of GRK2 kinase activity ameliorates glucose homeostasis and decreases blood pressure [120].