Reversal of dietary-induced insulin resistance in muscle of the rat by adenosine deaminase and an adenosine-receptor antagonist

Budohoski, L; Challiss, R. A. John; Cooney, Greg; McManus, Bronwyn; Newsholme, Eric A.

doi:10.1042/bj2240327

Cited by 26 publications

(10 citation statements)

References 22 publications

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“…Adenosine has been shown to modulate insulin actions and insulin sensitivity in muscle and adipose tissue (Budohoski et al, 1984;Rolband et al, 1990). In adipocytes, the increase in insulin sensitivity by adenosine was suggested to be mediated by A 1 receptors.…”

Section: Discussionmentioning

confidence: 99%

Antilipolytic Activity of a Novel Partial A₁Adenosine Receptor Agonist Devoid of Cardiovascular Effects: Comparison with Nicotinic Acid

Dhalla

Santikul²,

Smith³

et al. 2007

J Pharmacol Exp Ther

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Elevated lipolysis and circulating free fatty acid (FFA) levels have been linked to the pathogenesis of insulin resistance. A 1 adenosine receptor agonists are potent inhibitors of lipolysis. Several A 1 agonists have been tested as potential antilipolytic agents; however, their effect on the cardiovascular system remains a potential problem for development of these agents as drugs. In the present study, we report that CVT-3619, a novel partial A 1 receptor agonist, significantly reduces circulating FFA levels without any effect on heart rate and blood pressure in awake rats. Rats were implanted with indwelling arterial and venous cannulas to obtain serial blood samples, record arterial pressure, and administer drug. CVT-3619 decreased FFA levels in a dose-dependent manner at doses from 1 up to 10 mg/kg. The FFA-lowering effect was blocked by the A 1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine. Triglyceride (TG) levels were also significantly reduced by CVT-3619 treatment in the absence and presence of Triton. Tachyphylaxis of the antilipolytic effect of CVT-3619 (1 mg/kg i.v. bolus) was not observed with three consecutive treatments. An acute reduction of FFA by CVT-3619 was not followed by a rebound increase of FFA as seen with nicotinic acid. The potency of insulin to decrease lipolysis was increased 4-fold (p Ͻ 0.01) in the presence of CVT-3619 (0.5 mg/kg). In summary, CVT-3619 is an orally bioavailable A 1 agonist that lowers circulating FFA and TG levels by inhibiting lipolysis. CVT-3619 has antilipolytic effects at doses that do not elicit cardiovascular effects.

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Section: Discussionmentioning

confidence: 99%

Antilipolytic Activity of a Novel Partial A₁Adenosine Receptor Agonist Devoid of Cardiovascular Effects: Comparison with Nicotinic Acid

Dhalla

Santikul²,

Smith³

et al. 2007

J Pharmacol Exp Ther

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“…physical training, cold exposure), or decreasing (e.g. overnutrition) muscle sensitivity to insulin has been pre-viously postulated (Espinal, Dohm and Newsholme 1983;Budohoski, Challis, Lozeman, McManus and Newsholme 1984;Budohoski, Challis, Cooney, McManus and Newsholme 1984).…”

Section: Discussionmentioning

confidence: 99%

Reduced Insulin Sensitivity of Tenotomized Muscle: A Possible Role of Adenosine

Budohoski¹,

Kozłowski²,

Dubaniewicz³

et al. 1986

Horm Metab Res

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“…Challis and coworkers reported that adenosine receptor antagonists (Challis et al, 1984) or degradation of adenosine with adenosine deaminase (Budohoski et al, 1984) reverse insulin resistance in skeletal muscle isolated from diabetic animals. The orally active antagonist, adenosine receptor antagonist BW-1433, was found to persistently reverse insulin resistance in obese Zucker rats (Crist et al, 1998, 2001; Xu et al, 1998).…”

Section: Disease Relevance Of Adenosine To Immune Signalingmentioning

confidence: 99%

Regulation of Leukocyte Function by Adenosine Receptors

Linden

2011

Advances in Pharmacology

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The immune system responds to cues in the microenvironment to make acute and chronic adaptations in response to inflammation and injury. Locally produced purine nucleotides and adenosine provide receptor-mediated signaling to all bone-marrow derived cells of the immune system to modulate their responses. This review summarizes recent advances in our understanding of the effects of adenosine signaling through G protein-coupled adenosine receptors on cells of the immune system. Adenosine A2A receptors (A2ARs) have a generally suppressive effect on the activation of immune cells. Moreover, their transcription is strongly induced by signals that activate macrophages or dendritic cells through toll-like receptors, or T cells through T cell receptors. A2AR induction is responsible for producing a gradual dissipation of inflammatory responses. A2AR activation is particularly effective in limiting the activation of invariant NKT (iNKT) cells that play a central role in acute reperfusion injury. A2A agonists have clinical promise for the treatment of vaso-occlusive tissue injury. Blockade of A2A receptors may be useful to enhance immune-mediated killing of cancer cells. A2BR expression also is transcriptionally regulated by hypoxia, cytokines, and oxygen radicals. Acute A2BR activation attenuates the production of proinflammatory cytokines from macrophages, but sustained activation facilitates macrophage and dendritic cell remodeling and the production of acute phase proteins and angiogenic factors that may participate in evoking insulin resistance and tissue fibrosis. A2BR activation also influences macrophage and neutrophil function by influencing expression of the anti-inflammatory netrin receptor, UNC5B. The therapeutic significance of adenosine-mediated effects on the immune system is discussed.

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Reversal of dietary-induced insulin resistance in muscle of the rat by adenosine deaminase and an adenosine-receptor antagonist

Cited by 26 publications

References 22 publications

Antilipolytic Activity of a Novel Partial A₁Adenosine Receptor Agonist Devoid of Cardiovascular Effects: Comparison with Nicotinic Acid

Antilipolytic Activity of a Novel Partial A₁Adenosine Receptor Agonist Devoid of Cardiovascular Effects: Comparison with Nicotinic Acid

Reduced Insulin Sensitivity of Tenotomized Muscle: A Possible Role of Adenosine

Regulation of Leukocyte Function by Adenosine Receptors

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Reversal of dietary-induced insulin resistance in muscle of the rat by adenosine deaminase and an adenosine-receptor antagonist

Cited by 26 publications

References 22 publications

Antilipolytic Activity of a Novel Partial A1Adenosine Receptor Agonist Devoid of Cardiovascular Effects: Comparison with Nicotinic Acid

Antilipolytic Activity of a Novel Partial A1Adenosine Receptor Agonist Devoid of Cardiovascular Effects: Comparison with Nicotinic Acid

Reduced Insulin Sensitivity of Tenotomized Muscle: A Possible Role of Adenosine

Regulation of Leukocyte Function by Adenosine Receptors

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Antilipolytic Activity of a Novel Partial A₁Adenosine Receptor Agonist Devoid of Cardiovascular Effects: Comparison with Nicotinic Acid

Antilipolytic Activity of a Novel Partial A₁Adenosine Receptor Agonist Devoid of Cardiovascular Effects: Comparison with Nicotinic Acid