ROLE OF A1 ADENOSINE RECEPTORS IN INSULIN RESISTANCE OF THE OBESE

拟议研究的长期目标是了解 肥胖者常见胰岛素抵抗的分子基础 高血压患者。肥胖症之间联系的本质 尽管对胰岛素抵抗进行了深入的调查，但目前尚不清楚 问题就在这里。这项提议的第一个具体目标是找出 无论A1腺苷拮抗剂，茶碱是否改善胰岛素 肥胖胰岛素抵抗个体的敏感性。第二个目标是 评估间质腺苷水平与肿瘤的相关性 瘦人和肥胖者的胰岛素抵抗。第三个目标是 评估体内可能的高水平腺苷的来源 肥胖糖尿病患者的细胞外空间。一个来源可能是 交感神经突触小泡，含有高水平的ATP，然后 在细胞外间隙分解为腺苷。要实现这些目标 AIMS，我们计划微透析肥胖者的肌肉，以前 减掉50磅以上的肥胖个人，瘦身控制 个人。到目前为止(1998年2月)，我们有微透析的肌肉 在四名瘦削(对照)个体中，三名男性和一名女性。至 实现特定目标1，通过微透析将葡萄糖吸收到肌肉中 在存在和不存在茶碱和茶碱的情况下测量了油管 在透析液中存在和不存在饱和胰岛素的情况下。在… 同时，为了达到特定的目标2，腺苷和去甲肾上腺素 已经测量了从肌肉中渗出的透析液的水平。至 实现特定目标3、患者进行了有节奏的手臂锻炼 随着协议的重复。手臂锻炼能激起共鸣 兴奋，从而增加去甲肾上腺素和三磷酸腺苷的释放。《三磷酸腺苷》 被间质中的酶转化为腺苷。腺苷和 然后去甲肾上腺素扩散到透析液中 用高效液相色谱技术测定。为了促进这些目标的实现， 我们设计了一种新的方案来测量胰岛素刺激的血糖 从微渗析探头摄取。该方案利用了 天然药物立体异构体--L葡萄糖的放射性可利用度 发生D-葡萄糖作为代谢物从体内消失的对照 探针，与新陈代谢无关。来自对照个体的数据 论证了这种方法在活体肌肉定量中的实用性 胰岛素依赖的葡萄糖摄取和表现出非常显著的 然而，茶碱刺激胰岛素依赖的葡萄糖，因此 到目前为止，间质腺苷并没有因为运动而增加 观察到的。

The long range goal of the proposed studies is to understand the molecular basis for insulin resistance frequently observed in obese hypertensive individuals. The nature of the connection between obesity and insulin resistance is unclear, despite intensive investigation of the problem. The first specific aim of this proposal is to find out whether an A1 Adenosine antagonist, theophilline improves insulin sensitivity in obese insulin-resistant individuals. A second aim is to evaluate the correlation between interstitial adenosine levels and insulin resistance in lean and obese individuals. The third aim is to evaluate the source of possible high levels of adenosine in the extracellular space of obese diabetic individuals. One source may be sympathetic synaptic vesicles that contain high levels of ATP that then break down to adenosine in the extracellular space. To accomplish these aims, we plan to microdialyze muscles of obese individuals, formerly obese individuals who have lost more than fifty pounds, and lean control individuals. Thus far (February 1998), we have microdialyzed muscles of four lean (control) individuals, three males and one female. To achieve specific aim 1, glucose uptake into muscle from microdialysis tubing has been measured in the presence and absence of theophilline and in the presence and absence of saturating insulin in the dialysate. At the same time, to achieve specific aim 2, adenosine and norepinepherine levels in dialysate emerging from the muscle have been measured. To achieve specific aim 3, patients have performed rhythmic arm exercise as the protocol is repeated. Arm exercise evokes sympathetic excitation, thereby increasing norepinephrine and ATP release. The ATP is converted to adenosine by enzymes in the interstitium. Adenosine and norepinephrine then diffuse into the dialysate fluid where they can be measured by HPLC techniques. To facilitate achievement of these aims, we have devised an innovated sheme to measure insulin stimulated glucose uptake from microdialysis probes. The scheme takes advantage of the availability of radiolabeled L-glucose, the stereoisomer of naturally occurring D-glucose as a control for metabolite disappearance from the probe, unrelated to metabolism. Data from control individuals demonstrate the utility of this method for quantitating in vivo muscle insulin dependent glucose uptake and demonstrate a very significant stimulation of insulin dependent glucose by theophilline, however, thus far no increase in interstitial adenosine with exercise has been observed.