B. Fredholm

Bastard

Bild

Bottini

Budohoski

C. C. Hedrick

Castoldi

Challis

Crist

D. Y. Jung

Feve

G. Wang

Gokulakrishnan

Harada

J. K. Kim

J. Linden

J. S. Pankow

Johansson

K. F. LaNoue

K. Ravid

Kahn

Kolachala

Kong

Lalli

Linden

Olsson

R. A. Figler

S. S. Rich

S. Srinivasan

Sakowicz-Burkiewicz

Salazar-Martinez

Shryock

Stevens

Tacke

Tang

van Dieren

Wallenius

Yamauchi

Yang

Young

Z. Zhang

English

PubMed


                  OBJECTIVE
                  To determine the mechanisms by which blockade of adenosine A2B receptors (A2BRs) reduces insulin resistance.
               
               
                  RESEARCH DESIGN AND METHODS
                  We investigated the effects of deleting or blocking the A2BR on insulin sensitivity using glucose tolerance tests (GTTs) and hyperinsulinemic-euglycemic clamps in mouse models of type 2 diabetes. The effects of diabetes on A2BR transcription and signaling were measured in human and mouse macrophages and mouse endothelial cells. In addition, tag single nucleotide polymorphisms (SNPs) in ∼42 kb encompassing the A2BR gene, ADORA2B, were evaluated for associations with markers of diabetes and inflammation.
               
               
                  RESULTS
                  Treatment of mice with the nonselective adenosine receptor agonist 5′-N-ethylcarboxamidoadensoine (NECA) increased fasting blood glucose and slowed glucose disposal during GTTs. These responses were inhibited by A2BR deletion or blockade and minimally affected by deletion of A1Rs or A2ARs. During hyperinsulinemic-euglycemic clamp of diabetic KKAY mice, A2BR antagonism increased glucose infusion rate, reduced hepatic glucose production, and increased glucose uptake into skeletal muscle and brown adipose tissue. Diabetes caused a four- to sixfold increase in A2BR mRNA in endothelial cells and macrophages and resulted in enhanced interleukin (IL)-6 production in response to NECA due to activation of protein kinases A and C. Five consecutive tag SNPs in ADORA2B were highly correlated with IL-6 and C-reactive protein (CRP). Diabetes had a highly significant independent effect on variation in inflammatory markers. The strength of associations between several ADORA2B SNPs and inflammatory markers was increased when accounting for diabetes status.
               
               
                  CONCLUSIONS
                  Diabetes affects the production of adenosine and the expression of A2BRs that stimulate IL-6 and CRP production, insulin resistance, and the association between ADORA2B SNPs and inflammatory markers. We hypothesize that increased A2BR signaling in diabetes increases insulin resistance in part by elevating proinflammatory mediators. Selective A2BR blockers may be useful to treat insulin resistance.
               </jats:sec

Robert A. Figler

Guoquan Wang

Susseela Srinivasan

Dae Young Jung

Zhiyou Zhang

James S. Pankow

Katya Ravid

Bertil Fredholm

Catherine C. Hedrick

Stephen S. Rich

Jason K. Kim

Kathryn F. LaNoue

Joel Linden

Crossref

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2-Alkynyl-8-aryl-9-methyladenines as novel adenosine receptor antagonists: their synthesis and structureactivity relationships toward hepatic glucose production induced via agonism of the A(2B) receptor.

2-Alkynyl-8-aryladenines possessing an amide moiety: their synthesis and structure-activity relationships of effects on hepatic glucose production induced via agonism of the A(2B) adenosine receptor. Bioorg Med Chem

A subpopulation of macrophages inﬁltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways.

A1 adenosine receptor antagonism improves glucose tolerance in Zucker rats.

A1 receptor deﬁciency causes increased insulin and glucagon secretion in mice.

A2A-adenosine receptor reserve for coronary vasodilation. Circulation

Adenosine A(2B) receptor knock-out mice display an improved metabolic phenotype (Abstract). Diabetologia

Adenosine deaminase and adenosine receptor polymorphisms in aspirin-intolerant asthma. Respir Med

Adenosine deaminase and body mass index in non-insulin-dependent diabetes mellitus. Metabolism

Adenosine receptors in regulation of dendritic cell differentiation and function.

Adipokines: molecular links between obesity and atheroslcerosis.

Anilide derivatives of an 8-phenylxanthine carboxylic congener are highly potent and selective antagonists at human A(2B) adenosine receptors.

Association between serum values of C-reactive protein and cytokine production in whole blood of patients with type 2 diabetes.

Binding of C/EBPbeta to the C-reactive protein (CRP) promoter in Hep3B cells is associated with transcription of CRP mRNA.

Blockade of adenosine A2B receptors ameliorates murine colitis.

Characterization of human A (2B) adenosine receptors: radioligand binding, western blotting, and coupling to G(q) in human embryonic kidney 293 cells and HMC-1 mast cells. Mol Pharmacol

Coffee and caffeine ameliorate hyperglycemia, fatty liver, and inﬂammatory adipocytokine expression in spontaneously diabetic KK-Ay mice.

Coffee and tea consumption and risk of type 2 diabetes.

Coffee consumption and risk for type 2 diabetes mellitus.

Colgan SP. HIF-dependent induction of adenosine A2B receptor in hypoxia.

Cytokine and cytokine-like inﬂammation markers, endothelial dysfunction, and imbalanced coagulation in development of diabetes and its complications.

Deletion of the adenosine A1 receptor gene does not alter neuronal damage following ischaemia in vivo or in vitro.

Diabetes-induced decrease of adenosine kinase expression impairs the proliferation potential of diabetic rat T lymphocytes.

Dual role of interleukin-6 in regulating insulin sensitivity in murine skeletal muscle.

Effect of A2B adenosine receptor gene ablation on adenosine-dependent regulation of proinﬂammatory cytokines.

Effects of adenosine receptor antagonism on protein tyrosine phosphatase in rat skeletal muscle.

Effects of an adenosine-receptor antagonist on insulin-resistance in soleus muscle from obese Zucker rats.

Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss.

Gestational diabetes and the adenosine/L-arginine/ nitric oxide (ALANO) pathway in human umbilical vein endothelium.

Human adenosine 2B receptor: SNP discovery and evaluation of expression in patients with cystic ﬁbrosis.

Ijzerman AP. Structure-afﬁnity relationships of adenosine A2B receptor ligands. Med Res Rev

Interleukin-6-deﬁcient mice develop mature-onset obesity.

M2-like remodeling phenotypes of CD11c+ adipose tissue macrophages during high-fat diet–induced obesity in mice.

Migratory fate and differentiation of blood monocyte subsets.

Multi-Ethnic Study of Atherosclerosis: objectives and design.

New insights into the regulation of inﬂammation by adenosine.

Obesity is a major determinant of the association of C-reactive protein levels and the metabolic syndrome in type 2 diabetes.

Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1. Diabetes

Protection from ischemic liver injury by activation of A2A adenosine receptors during reperfusion: inhibition of chemokine induction.

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

Statin modulates insulin signaling and insulin resistance in liver and muscle of rats fed a high-fat diet.

Subclinical inﬂammation/oxidation as revealed by altered gene expression proﬁles in subjects with impaired glucose tolerance and type 2 diabetes patients.

The A2B adenosine receptor protects against inﬂammation and excessive vascular adhesion.

The fate of monocytes in atherosclerosis.

The role of interleukins in insulin resistance and type 2 diabetes mellitus.

Tissue-speciﬁc effects of in vivo adenosine receptor blockade on glucose uptake in Zucker rats.

TNF-alpha upregulates adenosine 2b (A2b) receptor expression and signaling in intestinal epithelial cells: a basis for A2bR overexpression in colitis. Cell Mol Life Sci

Upregulation of ecto-59-nucleotidase by rosuvastatin increases the vasodilator response to ischemia. Hypertension

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Links Between Insulin Resistance, Adenosine A2B Receptors, and Inflammatory Markers in Mice and Humans

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