BRAIN TRANSPORT & METABOLISM IN HYPOGLYCEMIA & DIABETES

脑燃料转运研究的临床意义 而微血管代谢是双重的。首先，低血糖是一种常见的， 有时胰岛素或磺脲类药物治疗会产生毁灭性的影响。 低血糖限制了糖尿病的治疗。为正常血糖而奋斗以挫败 长期并发症可能会导致严重的低血糖，从而导致脑部 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方式进行。糖尿病 减少脑微血管葡萄糖的运输和代谢。 相反，在慢性低血糖的大鼠中，两者都会增加。这项建议 研究这些运输和运输变化的机制和后果 新陈代谢。其次，糖尿病会增加中风的风险和损害。 脑微血管代谢异常可能是脑微血管代谢增加的原因 中风损伤。 有几个假设是这项拟议工作的基础。第一，长期的变化 血糖和胰岛素水平都可以特异性地改变大脑的运输 以及它的微血管燃料代谢。第二，燃料新陈代谢可能 影响葡萄糖的转运，尽管新陈代谢和转运可能只是 进行协调监管。第三，一种独特的葡萄糖运输蛋白 存在于脑实质中，可能受糖尿病或 低血糖症。最后，耗氧率高，燃料受干扰 糖尿病脑微血管代谢损害其耐受性 缺血症。 为了评估这些假设，将进行以下研究 目的：1.确定慢性血糖变化对血糖的影响 体内胰岛素浓度对脑微血管己糖转运的影响； 2.脑微血管和脑实质己糖转运的特征 实验性糖尿病和低血糖的体外实验；3.评估可能性 调控葡萄糖转运的分子机制；4.研究 脑微血管燃料代谢与己糖的相互关系 糖尿病和低血糖中的运输；以及5.确定 糖尿病引起的燃料代谢变化损害了 脑微血管维持能量状态(三磷酸腺苷和三磷酸腺苷/二磷酸腺苷比值) 当燃料缺乏或在体外造成缺氧时。这些研究将取得进展 对脑己糖转运调控的认识及其与 微血管燃料代谢以及改变它的分子机制。 这也可能有助于解释为什么糖尿病会降低脑血管耐受性。 到脑缺血。

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.