ROLE OF CNS INSULIN AS A MODULATOR OF DIABETIC COMPLICATIONS

描述(改编自申请者摘要)：糖尿病 以绝对或相对的胰岛素不足为特征。这 缺乏启动了一系列事件，导致重大 糖尿病的特征：多食、多饮和多尿。 食欲、口渴和尿量的增加被归因于 对营养(葡萄糖)和水分流失的生理反应。然而， 最近的研究表明，中枢神经系统的剥夺以及 外周剥夺在调节某些基因表达方面具有重要意义 糖尿病的特点。现在人们普遍认为 胰岛素确实可以进入大脑，而大脑中有胰岛素 感受器。事实上，将胰岛素注入脑室 (IVC)已被证明可以降低食欲和体重增加。神经肽Y (NPY)已被证明在输液时能强烈刺激食欲 进入正常动物的下腔静脉。 此外，还观察到NPY在一些情况下有所增加 糖尿病模型下丘脑核团与胰岛素抑制神经肽Y的关系 综合。因此，胰岛素可能参与其抑制食欲的作用。 通过其对CNS NPY浓度的调节。可以想象， 外周胰岛素不足将导致中枢自主神经控制 机制，从而在第二次和第二次和 慢性糖尿病中发现的长期内脏行为并发症。这个 这些并发症中最重要的是心血管变化， 胃肠紊乱和代谢改变，尤其是 葡萄糖和脂肪代谢。在拟议的研究中，将尝试 探讨正常人和糖尿病患者中枢神经系统胰岛素状态的影响 动物：1)心血管调节和表现，2)进食 行为，3)胃肠道分泌和运动，4)肝脏葡萄糖 5)白色脂肪组织中脂蛋白脂酶活性。 外周激素、血浆代谢物、中枢神经系统神经肽和生物源 在所有的实验条件下，胺的水平都将被量化。 还将尝试确定协调的CNS站点的特征 在这些回应中。最后，内脏内分泌反应模式由 将对延髓中的孤束核(NTS)进行检查和 与顶端CNS调控位点介导的反应模式相比， 作为下丘脑。

DESCRIPTION (Adapted from the Applicant's Abstract): Diabetes is characterized by an absolute or relative insulin insufficiency. This deficiency sets in motion a sequence of events that leads to the major characteristic features of diabetes: polyphagia, polydipsia, and polyuria. The increased appetite, thirst and urine production have been attributed to the physiologic response to nutrient (glucose) and water loss. However, more recent studies have demonstrated that CNS deprivation as well as peripheral deprivation is significant in mediating the expression of some of the characteristics of diabetes. It is now generally accepted that insulin does gain access to the brain and that the brain has insulin receptors. Indeed the infusion of insulin into the intracerebroventricles (IVC) has been shown to decrease appetite and weight gain. Neuropeptide Y (NPY) has been demonstrated to strongly stimulate appetite when infused into IVC of normal animals. Additionally, it has been observed that NPY is increased in a number of hypothalamic nuclei in diabetes models and that insulin inhibits NPY synthesis. Thus, insulin may mediate its appetite suppressive effect through its regulation of CNS NPY concentration. It is conceivable that peripheral insulin insufficiency will result in CNS autonomic control mechanisms and thereby play a consequential role in the secondary and long-term viscerobehavioral complications found in chronic diabetes. The most significant of these complications are cardiovascular changes, gastrointestinal disturbances, and metabolic alterations, especially of glucose and fat metabolism. In the proposed study, attempts will be made to investigate the effect of the CNS insulin status in normal and diabetic animals on: 1) cardiovascular regulation and performance, 2) feeding behavior, 3) gastrointestinal secretion and motility, 4) hepatic glucose production, and 5) lipoprotein lipase activity in white adipose tissue. Peripheral hormones, plasma metabolites, and CNS neuropeptide and biogenic amine levels will be quantitated in all of the experimental conditions. Attempts will also be made to characterize the CNS site of the coordination of these responses. Lastly, visceroendocrine response patterns mediated by the nucleus of the solitary tract (NTS) in the medulla will be examined and compared to response patterns mediated by rostral CNS regulatory sites such as the hypothalamus.