Links between Insulin resistance, adenosine A_2B receptors, and inflammatory markers in mice and humans

OBJECTIVE - To determine the mechanisms by which blockade of adenosine A_2B receptors (A_2BRs) reduces insulin resistance. RESEARCH DESIGN AND METHODS - We investigated the effects of deleting or blocking the A_2BR 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_2BR 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 _2BR 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_2BR deletion or blockade and minimally affected by deletion of A1Rs or A_2ARs. During hyperinsulinemic-euglycemic clamp of diabetic KKA^Y mice, A_2BR 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_2BR 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_2BRs that stimulate IL-6 and CRP production, insulin resistance, and the association between ADORA2B SNPs and inflammatory markers. We hypothesize that increased A_2BR signaling in diabetes increases insulin resistance in part by elevating proinflammatory mediators. Selective A_2BR blockers may be useful to treat insulin resistance.