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

• Published in: Diabetes (New York, N.Y.) Vol. 60; no. 2; pp. 669 - 679
• Main Authors: FIGLER, Robert A, GUOQUAN WANG, KIM, Jason K, LANOUE, Kathryn F, LINDEN, Joel, SRINIVASAN, Susseela, DAE YOUNG JUNG, ZHIYOU ZHANG, PANKOW, James S, RAVID, Katya, FREDHOLM, Bertil, HEDRICK, Catherine C, RICH, Stephen S
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-02-2011
• Subjects: Adenosine-5'-(N-ethylcarboxamide) - pharmacology; Animals; Biological and medical sciences; Biomarkers - metabolism; Blood Glucose - metabolism; C-Reactive Protein - metabolism; Cells, Cultured; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - physiopathology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Genetics; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Inflammation - genetics; Inflammation - metabolism; Inflammation - physiopathology; Insulin - metabolism; Insulin Resistance - physiology; Interleukin-6 - metabolism; Liver - drug effects; Liver - metabolism; Liver - physiopathology; Macrophages - drug effects; Macrophages - metabolism; Medical sciences; Medicin och hälsovetenskap; Mice; Mice, Transgenic; Polymorphism, Single Nucleotide; Receptor, Adenosine A2B - genetics; Receptor, Adenosine A2B - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Endocrinopathy; Human; Target tissue resistance; Vertebrata; Mammalia; Mouse; Animal; Diabetes mellitus; A2B adenosine receptor; Rodentia; Metabolic diseases; Insulin resistance
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db10-1070

To determine the mechanisms by which blockade of adenosine A(2B) receptors (A(2B)Rs) reduces insulin resistance.
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.
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.
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.