Links between insulin resistance, adenosine A2B receptors, and inflammatory markers in mice and humans.
Links between insulin resistance, adenosine A2B receptors, and inflammatory markers in mice and humans.
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作者：
Figler RA;Wang G;Srinivasan S;Jung DY;Zhang Z;Pankow JS;Ravid K;Fredholm B;Hedrick CC;Rich SS;Kim JK;LaNoue KF;Linden J
目的：探讨阻断腺苷A2B受体(A2BRs)减轻胰岛素抵抗的机制。我们通过葡萄糖耐量试验(GTTS)和高胰岛素-正常血糖钳夹试验研究了删除或阻断A2BR对2型糖尿病小鼠胰岛素敏感性的影响。检测糖尿病对人、小鼠巨噬细胞和小鼠内皮细胞A2BR转录和信号转导的影响。此外，还评估了包含A2BR基因的∼42kb中的标签单核苷酸多态(SNP)与糖尿病和炎症标志物的相关性。用非选择性腺苷受体激动剂5‘-N-乙基氨基腺苷(NECA)治疗小鼠，可增加空腹血糖，并减缓GTTS期间的糖代谢。这些反应被A2BR缺失或阻断所抑制，而A1R或A2AR缺失对这些反应的影响最小。在糖尿病KKAY小鼠的高胰岛素-正常血糖钳夹期间，A2BR拮抗剂增加了葡萄糖输注速率，减少了肝脏葡萄糖的产生，并增加了骨骼肌和棕色脂肪组织对葡萄糖的摄取。糖尿病引起血管内皮细胞和巨噬细胞A2BR基因表达增加四到六倍，并且由于蛋白激酶A和C的激活，导致NECA导致IL-6的产生增加。ADORA2B中连续5个标签SNP与IL-6和C反应蛋白(CRP)高度相关。糖尿病对炎症标志物的变化有非常显著的独立影响。当考虑到糖尿病状态时，几个ADORA2B SNP与炎症标志物之间的关联强度增加。糖尿病影响腺苷的产生和A2BRs的表达，从而刺激IL-6和CRP的产生，影响胰岛素抵抗，以及ADORA2B SNPs与炎症标志物的关联。我们假设，糖尿病中A2BR信号的增加部分是通过升高促炎介质来增加胰岛素抵抗的。选择性A2BR阻滞剂可能对治疗胰岛素抵抗有用。
To determine the mechanisms by which blockade of adenosine A2B receptors (A2BRs) reduces insulin resistance. 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. 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. 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.
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