Links Between Insulin Resistance, Adenosine A2B Receptors, and Inflammatory Markers in Mice and Humans
- Robert A. Figler1,
- Guoquan Wang2,
- Susseela Srinivasan1,
- Dae Young Jung3,
- Zhiyou Zhang3,
- James S. Pankow4,
- Katya Ravid5,
- Bertil Fredholm6,
- Catherine C. Hedrick1,
- Stephen S. Rich7,
- Jason K. Kim3,
- Kathryn F. LaNoue5 and
- Joel Linden1
- 1Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia
- 2Adenosine Therapeutics Group of PGxHealth, Clinical Data Incorporated, Charlottesville, Virginia
- 3Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania
- 4Department of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota
- 5Department of Biochemistry, Boston University, Boston, Massachusetts
- 6Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
- 7Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia
- Corresponding author: Joel Linden, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db10-1070/-/DC1.
J.K.K. is currently affiliated with the Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
- Received July 28, 2010.
- Accepted October 26, 2010.
- © 2011 by the American Diabetes Association.
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