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- Title
Links Between Insulin Resistance, Adenosine A<sub>2B</sub> Receptors, and Inflammatory Markers in Mice and Humans.
- Authors
Figler, Robert A.; Wang, Guoquan; Srinivasan, Susseela; Dae Young Jung; Zhiyou Zhang; Pankow, James S.; Ravid, Katya; Fredholm, Bertil; Hedrick, Catherine C.; Rich, Stephen S.; Kim, Jason K.; LaNoue, Kathryn F.; Linden, Joel
- Abstract
OBJECTIVE--To determine the mechanisms by which blockade of adenosine A2BB 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, AD0RA2B, 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 AD0RA2B 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 AD0RA2B 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 AD0RA2B 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.
- Subjects
ADENOSINES; INSULIN resistance; GLUCOSE tolerance tests; LABORATORY mice; TYPE 2 diabetes; GENETIC transcription; CELLULAR signal transduction; GENETIC polymorphisms
- Publication
Diabetes, 2011, Vol 60, Issue 2, p669
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db10-1070