Activation of the A₁adenosine receptor increases insulin-stimulated glucose transport in isolated rat soleus muscle

Abstract

The A1 adenosine receptor (A1AR) has been suggested to participate in insulin- and contraction-stimulated glucose transport in skeletal muscle, but the qualitative and quantitative nature of the effect are controversial. We sought to determine if A1AR is expressed in rat soleus muscle and then characterize its role in glucose transport in this muscle. A1AR mRNA and protein expression were determined by RT-PCR and Western blotting, respectively. To examine the role of adenosine in 3-O-methylglucose transport, isolated muscles were exposed to adenosine deaminase and alpha,beta-methylene adenosine diphosphate to remove endogenous adenosine and were left unstimulated (basal) or stimulated with insulin. To assess the functional participation of A1AR in 3-O-methylglucose transport, muscles were incubated with A1-selective agonist and (or) antagonist in the absence of endogenous adenosine and with or without insulin. A1AR mRNA was expressed in soleus muscle and A1AR was present at the plasma membrane. Removal of endogenous adenosine reduced glucose transport in response to 100 microU/mL insulin (approximately 50%). The A1-selective agonist, N6-cyclopentyladenosine, increased submaximal (100 microU/mL) insulin-stimulated glucose transport in a dose-dependent manner (0.001-1.0 micromol/L). This stimulatory effect was inhibited by the A1-selective receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine in a concentration-dependent manner (0.001-1.0 micromol/L). However, neither activation nor inhibition of A1AR altered basal or maximal (10 mU/mL) insulin-stimulated glucose transport. Our results suggest that adenosine contributes approximately 50% to insulin-stimulated muscle glucose transport by activating the A1AR. This effect is limited to increasing insulin sensitivity, but not to either basal or maximal insulin-stimulated glucose uptake in rat soleus muscle.

Contribution of the Extracellular cAMP-Adenosine Pathway to Dual Coupling of β2-Adrenoceptors to Gsand GiProteins in Mouse Skeletal Muscle

“…In view of the expression of distinct adenosine receptors subtypes (A 1 , A 2A-2B , and A 3 ) coupled to G i /G s proteins in skeletal muscle (Ren and Stiles, 1994;Lynge and Hellsten, 2000;Reading and Barclay, 2001;Thong et al, 2007), the interstitial formation of adenosine via ecto-5Ј-PDE and ecto-5Ј-nucleotidase (Hellsten and Frandsen, 1997;Chiavegatti et al, 2008) may allow the autocrine regulation of skeletal muscle function. This is of special clinical importance because ␤ 2 -AR agonists, used for treatment of asthma or chronic obstructive pulmonary disease, transiently improve isometric and isotonic contractility of respiratory skeletal muscle, including the diaphragm (Van Der Heijden et al, 1998), which is compromised in patients with chronic obstructive pulmonary disease (Ottenheijm et al, 2007).…”

Adenosine deaminase-related genes: Molecular identification, tissue expression pattern and truncated alternative splice isoform in adult zebrafish (Danio rerio)

“…In CNS, adenosine acts as a neuromodulator, controlling the excitatory and inhibitory synapses (Fredholm et al, 2005). Evidence showed that adenosine contributes to insulin-stimulated muscle glucose transport by activating the A 1 receptor (Thong et al, 2007) and plays a role in muscle vasodilatation acting on extraluminal A 2A receptors (Marshall, 2007). Moreover, it mediates vasoconstriction of afferent arterioles through A 1 activation, increasing intracellular calcium concentration in mouse kidney (Hansen et al, 2007).…”

Adenosine signalling in diabetes mellitus—pathophysiology and therapeutic considerations

“…74 The effects of adenosine on insulinstimulated glucose transport in skeletal muscle are controversial, with reports of both inhibitory 75,76 and stimulatory effects (Figure 3). [77][78][79] Early studies using adenosine deaminase treatment of soleus and extensor digitorum longus muscle preparations showed an inhibitory effect of endogenous adenosine on insulin-induced glucose transport and utilization. 75,76 Subsequently, it was observed that the inhibitory action of adenosine on glucose transport into skeletal muscle was mediated via A 1 adenosine receptors (Figure 3).…”