ReviewAdenosine receptors and diabetes: Focus on the A2B adenosine receptor subtype
Graphical abstract
Introduction
Diabetes mellitus is a metabolic disease increasing worldwide and resulting in both morbidity and mortality [1]. In 2011 the number of people with diabetes in the world reached 366 million and it is expected to rise to 552 million by 2030 [2]. Potential causes for this rapid growth in the diabetic population include aging, urbanization, and increasing prevalence of obesity and physical inactivity [2]. It is mainly caused by the more frequent development of cardiovascular diseases and its complications are of major clinical and socioeconomic impact. Investigating possible treatment strategies need to be pursued with high priority.
Diabetes mellitus encompasses a group of metabolic disorders that affect the ability to regulate blood glucose levels and can be classified into two main groups, type 1 and type 2.
Previously known as juvenile-onset diabetes, type 1 diabetes is thought to derive from T-cell-mediated autoimmune destruction of insulin-producing β-cells and is believed to have a genetic component [3]. As a result, pancreatic β-cell mass and function deteriorate and patients become dependent on exogenous insulin [4].
Type 2 diabetes is characterized by insulin resistance in peripheral tissues and is sometimes associated with β-cell dysfunction; both features resulting from prolonged exposure to elevated blood glucose levels [5], [6]. Type 2 diabetes is usually a later onset disease; it is often associated with obesity and a low-grade inflammation of adipose tissue and auto-inflammation in islets. Afterwards an altered adipokines profiles may in part contribute to an induction of hepatic and skeletal muscle insulin resistance [7], [8]. Recent findings underline that the regulation of the body's β-cell mass is important in diabetes. Therefore endogenous pathways that increase the β-cell mass may have great interest to develop better treatments for this pathology. Such treatments could be used for both type I and type II diabetes because both of these diseases are characterized by a reduction in β-cell mass despite the differences in their pathogenesis [9].
Altered insulin-regulated glucose transport and metabolism characterize diabetes mellitus also in liver, skeletal muscle and adipose tissue. As a consequence glucose, free fatty acids and pro-inflammatory cytokines increase thus leading to a variety of diseases affecting different organ and tissues like heart, central nervous system, kidney, urogenital and gastrointestinal systems, skin and skeletal muscle [8].
In diabetes mellitus, an altered and defective cellular metabolism leads to dysregulated intracellular nucleotide levels. The nucleoside adenosine produced by the hydrolysis of adenine nucleotides (ATP, ADP and AMP) has important regulatory roles on glucose homeostasis and lipid metabolism [1], [10], [11], [12]. Consistent with its anti-inflammatory and immunosuppressive effects, adenosine receptors (ARs) have been found to be implicated in different aspects of glucose regulation. In particular, we will drive our attention on purinergic signaling related to diabetes through A2BARs modulation.
Section snippets
Adenosine
Adenosine is an ubiquitous homeostatic regulator produced in the extracellular space by hydrolysis of ATP through apyrase (CD39) and 5′-nucleotidase (CD73) [13], [14]. Dephosphorylation of extracellular AMP represents the limiting step for adenosine formation. Its extracellular concentration is controlled by re-uptake processes triggered by specific transporters. It is evaluated that the levels of adenosine in the interstitial fluid are in the range 20–200 nM [15], [16]. Adenosine concentrations
Adenosine receptor subtypes
Adenosine exerts its effects by enrolling a family of four G-protein coupled receptors (GPCRs) defined A1, A2A, A2B and A3. These receptors differ in their affinity for adenosine, in the type of G proteins that they recruit and finally in the downstream signaling pathways that are activated in the target cells [16], [37], [38].
In particular A1AR and A3AR stimulation decreases cyclic AMP (cAMP) concentration and raises intracellular Ca2+ levels by a pathway involving phospholipase C activation; A
A1 adenosine receptor
The involvement of A1AR activation in lipolysis suppression, decrease of the plasma free fatty acid level, improvement of insulin sensitivity and glucose homeostasis is well recognized for many years [1], [24], [42], [43], [44]. Its activation in adipocytes reduces AC activity and cAMP content and causes inhibition of lipolysis. Importantly, signaling through A1AR contributes to avoid a diabetogenic phenotype of insulin-resistance and grow fat [45], [46], [47], [48]. However, in general full A1
A3 adenosine receptor
As for the A3AR subtype few data till now have been reported on its function in diabetes. It has been shown that diabetes results in an increase in A3AR mRNA and protein levels in liver, heart, in cardiac myocytes and kidney cortex [53], [54], [55]. Recently, vascular A3AR overexpression has been found under diabetic conditions [56]. Indeed a role of A3AR in glucose metabolism has been related to its affinity for inosine, that derives by the deamination of adenosine during anaerobic or stress
A2A adenosine receptor
The role of A2AAR in glucose and lipid regulation has not been as well clarified as that of the A1AR subtype. Studies have shown that exogenous adenosine signaling through A2AAR increases gluconeogenesis and glucose release [23], [62], [63]. In primary cultured rat hepatocytes gluconeogenesis and glycogenolysis stimulation were found to be related to A2AAR activation and cAMP production [62], [63]. Accordingly, in fetal sheep A2AAR rises glucose and lactate levels due to an increase of
A2B adenosine receptor
In the past the pathophysiological role of the A2BAR has not been of high interest due to the requirement of high concentrations of adenosine in order to activate this subtype [77]. However the finding of the high expression of this receptor under inflammation, stress or injury [51], [78], [36], brought to a renewed interest in its biological relevance. In particular, attention in the pathophysiological role of A2BAR subtype in diabetes emerged by literature data.
The first evidence of an
Enzymes generating adenosine
CD39 and CD73 are well known enzymes working together to produce adenosine from ATP, that have also important effects in the immune response and in diabetes [102].
In CD39KO mice with type 1 diabetes an impaired glucose tolerance secondary, at least in part, to hepatic insulin resistance was found [103]. Accordingly, CD39 overexpression conferred protection against MLDS-induced diabetes because this overexpression prevented islet T cell infiltration and inflammatory gene expression after MLDS
Nucleoside transporters and adenosine kinase
A role for endogenous regulators of adenosine levels like equilibrative and concentrative nucleoside transporters (ENT and CNT) and adenosine kinase (AK), in diabetes has been identified [110], [111]. A reduction of extracellular adenosine concentrations occurs following its reuptake and phosphorylation by nucleoside transporters and AK, respectively [112].
The influence of elevated glucose level on adenosine transport and expression of nucleoside transporters was studied in several cell types
Conclusions
The GPCR ARs have attracted considerable attention due to their potential as targets in novel drug development [120], [121]. In recent years, we have learned much about the role of adenosine in mediating dysfunctional signaling pathways in metabolic diseases such as diabetes and confirmed its efficacy in pre-clinical models. All four ARs are expressed on islet cells, and they are involved in the regulation of islet hormone secretion and have the potential of being candidates as drug targets for
Conflict of interest
The authors declare that there is no conflict of interest regarding the publication of this paper.
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2021, Biochemical PharmacologyCitation Excerpt :Similar to A2AAR, the A2BAR is also highly expressed in BAT. A2BAR activation was found to reduce adipocyte inflammation, as well as insulin resistance and islet destruction [76]. However, some beneficial results were also observed with A2BAR antagonists in a diabetic mouse strain [76].
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2019, Pharmacology and TherapeuticsCitation Excerpt :The expanding knowledge of A2BAR pharmacology and the continued efforts to uncover subtype selective ligands has repositioned the A2BAR as a target with great biological importance. Alongside fibrosis, IRI, cancer and inflammation, the A2BAR is currently being investigated for the treatment of diabetes (Figler et al., 2011; Merighi et al., 2015), pulmonary hypertension (Bessa-Gonçalves, Bragança, Martins-Dias, Correia-de-Sá, & Fontes-Sousa, 2018; Mertens et al., 2018), sickle cell anaemia (Paz et al., 2017; Zhang et al., 2011), and bone diseases (Daniele et al., 2017; Trincavelli et al., 2014). An A2BAR antagonist has completed Phase I clinical trials for investigation in the prophylaxis and treatment of asthma (Kalla & Zablocki, 2009) and a dual A2AAR/A2BAR antagonist is currently entering Phase I clinical trial for patients with advanced malignancies (Vijayan, Young, Teng, & Smyth, 2017).