title: Links between insulin resistance, adenosine A2B receptors, and inflammatory markers in mice and humans.
abstract: OBJECTIVE
  To determine the mechanisms by which blockade of adenosine A(2B) receptors (A(2B)Rs) reduces insulin resistance.
  
  
  METHODS
  We investigated the effects of deleting or blocking the A(2B)R on insulin sensitivity using glucose tolerance tests (GTTs) and hyperinsulinemic-euglycemic clamps in mouse models of type 2 diabetes. The effects of diabetes on A(2B)R 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 A(2B)R 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 A(2B)R deletion or blockade and minimally affected by deletion of A(1)Rs or A(2A)Rs. During hyperinsulinemic-euglycemic clamp of diabetic KKA(Y) mice, A(2B)R 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 A(2B)R 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 A(2B)Rs that stimulate IL-6 and CRP production, insulin resistance, and the association between ADORA2B SNPs and inflammatory markers. We hypothesize that increased A(2B)R signaling in diabetes increases insulin resistance in part by elevating proinflammatory mediators. Selective A(2B)R blockers may be useful to treat insulin resistance.
authors.affiliation: Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Figler
authors.forename: Guoquan
authors.initials: G
authors.lastname: Wang
authors.forename: Susseela
authors.initials: S
authors.lastname: Srinivasan
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Jung
authors.forename: Zhiyou
authors.initials: Z
authors.lastname: Zhang
authors.forename: James S
authors.initials: JS
authors.lastname: Pankow
authors.forename: Katya
authors.initials: K
authors.lastname: Ravid
authors.forename: Bertil
authors.initials: B
authors.lastname: Fredholm
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Hedrick
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.forename: Kathryn F
authors.initials: KF
authors.lastname: LaNoue
authors.forename: Joel
authors.initials: J
authors.lastname: Linden
mesh_terms: D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020641:Polymorphism, Single Nucleotide; D043704:Receptor, Adenosine A2B / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D007328:Insulin; D015850:Interleukin-6; D043704:Receptor, Adenosine A2B; D019830:Adenosine-5'-(N-ethylcarboxamide); D002097:C-Reactive Protein