Impaired Glucose Tolerance in the Absence of Adenosine A1 Receptor Signaling
Impaired Glucose Tolerance in the Absence of Adenosine A1 Receptor Signaling
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DOI：
10.2337/db11-0058
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发表时间：
2011-10-01
期刊：
影响因子：
7.7
通讯作者：
Schnermann, Jurgen B.
中科院分区：
文献类型：
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作者：
Faulhaber-Walter, Robert;Jou, William;Schnermann, Jurgen B.
腺苷（ADO）在葡萄糖稳态调节中的作用尚不清楚。在目前的研究中，我们使用A1-ADO受体（A1 AR）缺陷的小鼠来研究葡萄糖homeostasis.RESEARCH设计和方法的作用ADO/A1 AR信号断奶后，A1 AR（-/-）和野生型小鼠接受标准饮食（12千卡%的脂肪）或高脂肪饮食（HFD; 45千卡%的脂肪）。在8周龄小鼠中进行体重、空腹血糖、血浆胰岛素和腹膜内葡萄糖耐量试验，并在随后观察12-20周后再次进行。通过磁共振成像和附睾脂肪垫重量来量化身体成分。通过高胰岛素-正葡萄糖钳夹研究葡萄糖代谢。为了描述病理生理学机制，测量了脂肪因子和Akt磷酸化。由于脂肪量增加，因此，AITS-A1 AR（-/-）小鼠比野生型小鼠显著重。A1 AR（-/-）小鼠断奶后空腹血糖和胰岛素显著升高，并在成年期保持较高水平。腹膜内葡萄糖激发显示A1 AR（-/-）小鼠的葡萄糖清除明显较慢。HFD增强了A1 AR（-/-）小鼠的这种表型，并揭示了功能失调的胰岛素分泌机制。断奶后不久，A1 AR（-/-）小鼠的胰岛素敏感性显著受损。钳夹研究检测到A1 AR（-/-）小鼠的净葡萄糖摄取显著减少，肌肉和白色脂肪组织的葡萄糖摄取减少。影响没有引发瘦素缺乏症，但涉及Akt磷酸化减少。结论-ADO/A1 AR信号转导有助于重要的胰岛素控制的葡萄糖稳态和胰岛素敏感性在C57 BL/6小鼠，并参与脂肪组织的代谢调节。糖尿病60：2578-2587，2011
OBJECTIVE-The role of adenosine (ADO) in the regulation of glucose homeostasis is not clear. In the current study, we used A1-ADO receptor (A1AR)-deficient mice to investigate the role of ADO/A1AR signaling for glucose homeostasis.RESEARCH DESIGN AND METHODS-After weaning, A1AR(-/-) and wild-type mice received either a standard diet (12 kcal% fat) or high-fat diet (HFD; 45 kcal% fat). Body weight, fasting plasma glucose, plasma insulin, and intraperitoneal glucose tolerance tests were performed in 8-week-old mice and again after 12-20 weeks of subsequent observation. Body composition was quantified by magnetic resonance imaging and epididymal fat-pad weights. Glucose metabolism was investigated by hyperinsulinemic-euglycemic clamp studies. To describe pathophysiological mechanisms, adipokines and Akt phosphorylation were measured.RESULTS-A1AR(-/-) mice were significantly heavier than wild-type mice because of an increased fat mass. Fasting plasma glucose and insulin were significantly higher in A1AR(-/-) mice after weaning and remained higher in adulthood. An intraperitoneal glucose challenge disclosed a significantly slower glucose clearance in A1AR(-/-) mice. An HFD enhanced this phenotype in A1AR(-/-) mice and unmasked a dysfunctional insulin secretory mechanism. Insulin sensitivity was significantly impaired in A1AR(-/-) mice on the standard diet shortly after weaning. Clamp studies detected a significant decrease of net glucose uptake in A1AR(-/-) mice and a reduced glucose uptake in muscle and white adipose tissue. Effects were not triggered by leptin deficiency but involved a decreased Akt phosphorylation.CONCLUSIONS-ADO/A1AR signaling contributes importantly to insulin-controlled glucose homeostasis and insulin sensitivity in C57BL/6 mice and is involved in the metabolic regulation of adipose tissue. Diabetes 60:2578-2587, 2011