CARDIOVASCULAR AND RENAL DYSFUNCTION IN EARLY DIABETES

描述：高血压和高血压之间有明显的联系 IDDM的发病率和死亡率增加。本修订版中的研究 该提案将检验血糖控制不佳的核心假设 早发性糖尿病改变了血压和钠尿的关系 通过增加肾素血管紧张素的活性来增加动脉压 系统。这些研究将在一种独特的IDDM模式下进行，即 长期仪器和监测的老鼠，这将使立即 评价血糖控制与心血管疾病的关系 和肾功能在肾损伤发生之前。在此模式中，24小时 每天静脉注射。胰岛素输注在移除后立即开始。 内源性胰岛素通过链脲佐菌素(STZ)给药并调节 以个体大鼠为基础来维持任何所需的糖尿病水平或 血糖控制。然后可以研究对诱导IDDM的反应 与STZ的潜在间接影响无关。中心假说 这一提议将通过以下方式进行检验：一、检验假设 早发性糖尿病患者的血糖控制可提高平均动脉压。 2.检验IDDM血糖控制不佳会增加血液的假说 血管紧张素II介导的压力钠尿症的压力变化 通过：A.量化肾脏钠处理、液体平衡和 心输出量，与引起的血压升高有关 由IDDM患者的血糖控制不良所致。B.确定压力是否 IDDM患者钠尿改变，压力钠尿的作用是什么？ 参与调节心血管和肾功能的相关变化。 C.量化高血糖本身的重要性，独立于 循环中的胰岛素丢失，在调节肾功能和 全身血流动力学。D.检验增加血管紧张素的假设 II调节血压的升高。三、检验假设 血糖控制程度的波动将导致更早的发病 和/或通过血管紧张素更迅速地增加蛋白尿的严重程度 II-调节的血压变化，通过：A.确定 反复发作的高血糖，在一段时间内， 平均血糖控制是适度的，将导致比例变化 动脉压和蛋白尿的发病早于如果 血糖适度控制保持稳定。B.测试 长期将血浆血管紧张素II夹在控制水平的假说 会减弱发作性高血糖加速血糖升高的作用 蛋白尿的发生。C.确定是否增加了 每日动脉压，24小时平均没有增加 动脉压，会加速白蛋白尿的发展 糖尿病患者病情稳定，代谢控制不佳。

DESCRIPTION: There is a clear association between hypertension and increased morbidity and mortality in IDDM. The studies in this revised proposal will test the central hypothesis that poor glycemic control in early-onset diabetes shifts the pressure natriuresis relationship and increases arterial pressure by increasing activity of the renin angiotensin system. The studies will be conducted in a unique model of IDDM, in chronically instrumented and monitored rats, that will enable immediate assessment of the relationship between glycemic control and cardiovascular and renal function before renal damage has occurred. In this model, 24-hour per day i.v. insulin infusion is begun immediately following the removal of endogenous insulin by streptozotocin (STZ) administration and is adjusted on an individual rat basis to maintain any desired level of diabetes or glycemic control. The response to induction of IDDM then can be studied independently of potential indirect effects of STZ. The central hypothesis of this proposal will be tested by: I. Testing the hypothesis that poor glycemic control in early-onset diabetes increases mean arterial pressure. II. Testing the hypothesis that poor glycemic control in IDDM raises blood pressure through an angiotensin II-mediated shift in pressure natriuresis by: A. quantifying the changes in renal sodium handling, fluid balance, and cardiac output, that are associated with the rise in blood pressure induced by onset of poor glycemic control in IDDM. B. determining if pressure natriuresis is shifted in IDDM and what is the role of pressure natriuresis in mediating the associated changes in cardiovascular and renal function. C. quantifying the importance of hyperglycemia per se, independent of the loss of circulating insulin, in mediating the changes in renal function and systemic hemodynamics. D. testing the hypothesis that increased angiotensin II mediates the rise in blood pressure. III. Testing the hypothesis that oscillations in the degree of glycemic control will lead to earlier onset and/or a more rapid increase in severity of albuminuria through angiotensin II-mediated variation in blood pressure, by: A. determining whether repeated episodes of hyperglycemia, during a period in which the overall average glycemic control is moderate, will cause proportionate variation in arterial pressure and earlier onset of albuminuria than if that level of moderate glycemic control was maintained steadily. B. testing the hypothesis that chronically clamping plasma angiotensin II at control levels will attenuate the effect of episodic hyperglycemia to accelerate the development of albuminuria. C. determining whether increased variability in daily arterial pressure, without an increase in the 24-hour-averaged arterial pressure, will accelerate the development of albuminuria in diabetes with steadily-maintained, poor metabolic control.