BRAIN TRANSPORT & METABOLISM IN HYPOGLYCEMIA & DIABETES

脑燃料转运研究的临床意义 微血管代谢是双重的。 首先，低血糖是常见的， 有时胰岛素或磺脲类药物治疗的破坏性影响。 低血糖限制了糖尿病治疗。 争取欧盟阻挠 长期并发症可能会导致严重的低血糖， 功能障碍和损伤。 糖尿病和慢性低血糖都会改变大脑 燃料运输和微血管代谢以平行的方式进行。 糖尿病 降低脑微血管葡萄糖转运和代谢。 相反，在慢性低血糖大鼠中，两者均增加。 这项建议 研究这些交通变化的机制和后果， 新陈代谢. 其次，糖尿病增加中风风险和损害。 脑微血管代谢异常可能是脑缺血后 中风损伤 几个假设的基础上提出的工作。 第一，长期变化， 血浆葡萄糖和胰岛素水平特异性地改变脑转运 和微血管的燃料代谢。 第二，燃料代谢可能 影响葡萄糖转运，尽管代谢和转运可能只是 进行协调调节。 第三，一种独特的葡萄糖转运蛋白 存在于可能受糖尿病影响的脑实质中， 低血糖 最后，高耗氧率和干扰燃料 糖尿病脑微血管的代谢损害了它们对 缺血 为了评估这些假设，将使用以下内容进行研究 目标：1.确定血糖慢性变化的影响 和胰岛素浓度对脑微血管己糖转运的影响; 2.表征脑微血管和脑实质的己糖转运 体外实验性糖尿病和低血糖; 3.评估可能 调节葡萄糖转运的分子机制; 4.检查 脑微血管燃料代谢与己糖相互关系 糖尿病和低血糖症中的转运;以及5.确定是否 糖尿病引起的燃料代谢的变化损害了 脑微血管维持其能量状态（ATP和ATP/ADP比值） 当燃料被剥夺或在体外缺氧时。 这些研究将进一步 了解大脑己糖运输的调节， 微血管燃料代谢，以及改变它的分子机制。 它们也可能有助于解释为什么糖尿病会降低脑血管耐受性 局部缺血

The clinical significance of the proposed studies on brain fuel transport and microvascular metabolism is twofold. First, hypoglycemia is a common, sometimes devastating effect of insulin or sulfonylurea treatment. Hypoglycemia limits diabetes therapy. Striving for euglycemia to thwart long term complications may risk hypoglycemia severe enough to cause brain dysfunction and damage. Both diabetes and chronic hypoglycemia alter brain fuel transport and microvascular metabolism in a parallel manner. Diabetes decreases brain microvascular glucose transport and metabolism. Conversely, in rats with chronic hypoglycemia both increase. This proposal examines the mechanisms and consequences of these changes in transport and metabolism. Second, diabetes increases both stroke risk and damage. Abnormal brain microvascular metabolism could account for the increased stroke damage. Several hypotheses underlie the proposed work. First, chronic changes in both plasma glucose and insulin levels specifically modify brain transport and its microvascular fuel metabolism. Second, fuel metabolism probably influences glucose transport, although metabolism and transport may simply undergo coordinate regulation. Third, a unique glucose transport protein exists in brain parenchyma which may be affected by diabetes or hypoglycemia. Last, high rates of oxygen consumption and disturbed fuel metabolism in diabetic brain microvessels impair their tolerance to ischemia. To evaluate these hypotheses, studies will be performed with the following aims: 1. Determine the influence of chronic changes in the plasma glucose and insulin concentrations on brain microvascular hexose transport in vivo; 2. Characterize hexose transport by brain microvessels and parenchyma in vitro in experimental diabetes and hypoglycemia; 3. Evaluate possible molecular mechanisms whereby glucose transport is modulated; 4. Examine the interrelationship between brain microvascular fuel metabolism and hexose transport in diabetes and hypoglycemia; and 5. Determine whether the changes in fuel metabolism induced by diabetes impair the ability of the brain microvessels to maintain their energy status (ATP and ATP/ADP ratio) when fuel deprived or made anoxic in vitro. These studies will advance understanding of the regulation of brain hexose transport, its relation to microvascular fuel metabolism, and the molecular mechanisms altering it. They may also help explain why diabetes reduces cerebrovascular tolerance to ischemia.