Insulin and β Adrenergic Receptor Signaling: Crosstalk in Heart

Abstract

Recent advances show that insulin may affect β adrenergic receptor (βAR) signaling in heart, to modulate cardiac function in clinically relevant states such as diabetes and heart failure. Conversely, activation of βAR regulates cardiac glucose uptake and promotes insulin resistance in HF. We discussed recent characterization on the interaction between cardiac insulin receptor and βAR in myocardium, in which insulin stimulation cross talk with cardiac βAR via insulin receptor substrate-dependent and G protein receptor kinase 2-mediated phosphorylation of β2AR. The insulin-induced phosphorylation promotes β2AR coupling to Gi and expression of phosphodiesterase 4, which inhibit cardiac adrenergic signaling and compromise cardiac contractile function. These progresses might support new approaches for effectively prevention or treatment of obesity-or diabetes-related heart failure.

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“…The mechanisms of adrenoceptor activation, its downstream targets, its signal specificity versus bias and receptor dynamics have been extensively studied for understanding the role of adrenergic system in cardiovascular pathophysiology (Lohse, 2015). Also, the cross talk between adrenergic signaling and that by other receptor viz., insulin, EGF and TGFβ play a critical role in cardiovascular function (Saha et al, 2012;Heger et al, 2016;Fu et al, 2017;Mohan et al, 2017). Signaling by these receptors in heart involve a plethora of kinases, phosphatases, second messengers and gene regulatory proteins.…”

New Insights in Cardiac β-Adrenergic Signaling During Heart Failure and Aging

“…It has also been reported that the prevalence of diabetes is augmented in patients with HF and hyperglycemia/hyperinsulinemia can strongly contribute to the impairment of cardiac function as well as worsen prognosis ( Dei Cas et al, 2015 ; Jia et al, 2016 ; Komici et al, 2018 ). Furthermore, an insulin-resistant state (insulin resistance in both cardiac and peripheral tissues) seems to occur as a consequence of increased circulating CAs, in HF patients ( Paolisso et al, 1991 ; Shimizu et al, 2012 ; Fu et al, 2017 ). In this regard, it is not surprising that both HF and diabetic patients show SNS overactivity ( Lymperopoulos et al, 2013 ; Han et al, 2016 ).…”

“…In this regard, it is not surprising that both HF and diabetic patients show SNS overactivity ( Lymperopoulos et al, 2013 ; Han et al, 2016 ). The insulin receptor (Ins-R) and β-AR cross talk, share similar down-stream signaling components, such as G αi , β-arrestins and GRK2, and counter-regulate each other ( Song et al, 2001 ; Morisco et al, 2005 ; Cipolletta et al, 2009 ; Garcia-Guerra et al, 2010 ; Mangmool et al, 2016 ; Fu et al, 2017 ). This strict interaction was further clarified when a direct interaction in a membrane complex was found between Ins-R and β 2 -AR ( Mandić et al, 2014 ).…”

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“…Insulin receptor substrates have multiple functions, including enzyme binding activity, insulin binding activity, and binding activity of insulin receptor substrates [46]. There are few studies on the involvement of Insr in Ab regulation.…”