As β₃‐adrenoceptors were first demonstrated to be expressed in adipose tissue they have received much attention for their metabolic effects in obesity and diabetes. After the existence of this subtype had been suggested to be present in the heart, studies focused on its role in cardiac function. While the presence and functional role of β₃‐adrenoceptors in the heart has not uniformly been detected, there is a broad consensus that they become up‐regulated in pathological conditions associated with increased sympathetic activity such as heart failure and diabetes. When detected, the β₃‐adrenceptor has been demonstrated to mediate negative inotropic effects in an inhibitory G protein‐dependent manner through the NO–cGMP–PKG signalling pathway. Whether these negative inotropic effects provide protection from the adverse effects induced by overstimulation of β₁/β₂‐adrenoceptors or in themselves are potentially harmful is controversial, but ongoing clinical studies in patients with congestive heart failure are testing the hypothesis that β₃‐adrenceptor agonism has a beneficial effect.Linked Articles: This article is part of a themed section on Adrenoceptors—New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc

Diabetes is a chronic, endocrine disorder that effects millions of people worldwide. Cardiovascular complications are the major cause of diabetes-related morbidity and mortality. Cardiac β₁- and β₂-adrenoceptor (AR) stimulation mediates positive inotropy and chronotropy, whereas β₃-AR mediates negative inotropic effect. Changes in β-AR responsiveness are thought to be an important factor that contributes to the diabetic cardiac dysfunction. Diabetes related changes in β-AR expression, signaling, and β-AR mediated cardiac function have been studied by several investigators for many years. In the present review, we have screened PubMed database to obtain relevant articles on this topic. Our search has ended up with wide range of different findings about the effect of diabetes on β-AR mediated changes both in molecular and functional level. Considering these inconsistent findings, the effect of diabetes on cardiac β-AR still remains to be clarified.

The first sodium-glucose cotransporter-2 inhibitor (SGLT2I), canagliflozin, was approved by the U.S. Food and Drug Administration for the treatment of type 2 diabetes in 2013. Since then, other members of this drug class (such as dapagliflozin, empagliflozin, and ertugliflozin) have become widely used. Unlike classical antidiabetic agents, these drugs do not interfere with insulin secretion or action, but instead promote renal glucose excretion. Since their approval, many preclinical and clinical studies have been conducted to investigate the diverse effects of SGLT2Is. While originally introduced as antidiabetic agents, the SGLT2Is are now recognized as pillars in the treatment of heart failure and chronic kidney disease, in patients with or without diabetes. The beneficial cardiac effects of this class have been attributed to several mechanisms. Among these, SGLT2Is inhibit fibrosis, hypertrophy, apoptosis, inflammation, and oxidative stress. They regulate mitochondrial function and ion transport, and stimulate autophagy through several underlying mechanisms. This review details the potential effects of SGLT2Is on cardiac cells.

β3-Adrenoceptor-mediated responses in diabetic rat heart