ROLE OF CNS INSULIN AS A MODULATOR OF DIABETIC COMPLICATIONS

描述（改编自申请人的摘要）：糖尿病是 以绝对或相对胰岛素不足为特征。 这 缺乏启动一系列事件，导致主要的 糖尿病的典型特征：多食、多饮和多尿。 食欲、口渴和排尿的增加被归因于 对营养（葡萄糖）和水分损失的生理反应。 然而，在这方面， 最近的研究表明，中枢神经系统的剥夺以及 外周剥夺在介导一些 糖尿病的特征。 现在人们普遍认为， 胰岛素确实进入了大脑，大脑中有胰岛素， 受体。 事实上，将胰岛素注入脑室内 (IVC)已经被证明可以减少食欲和体重增加。 神经肽Y (NPY)已被证明在注入时强烈刺激食欲 正常动物的IVC。 此外，已经观察到，在许多情况下， 糖尿病模型下丘脑核团及胰岛素抑制NPY 合成. 因此，胰岛素可能介导其食欲抑制作用 通过调节中枢神经系统神经肽Y的浓度。 可以想象 外周胰岛素不足将导致CNS自主控制 机制，从而发挥重要作用， 慢性糖尿病的长期内脏行为并发症。 的 这些并发症中最重要的是心血管变化， 胃肠道紊乱和代谢改变，尤其是 葡萄糖和脂肪代谢。 在拟议的研究中，将尝试 研究正常人和糖尿病患者中枢胰岛素水平的变化 动物：1）心血管调节和性能，2）喂养 行为，3）胃肠分泌和运动，4）肝葡萄糖 产生，和5）白色脂肪组织中的脂蛋白脂酶活性。 外周激素、血浆代谢物、CNS神经肽和生物源性 在所有实验条件下定量胺水平。 还将尝试表征协调的CNS部位 这些反应。 最后，内脏内分泌反应模式介导 将检查延髓中的孤束核（NTS）， 与由喙部CNS调节位点介导的反应模式相比， 就像下丘脑。

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.