ROLE OF GLUCOSE, INSULIN, AND GLUCAGON IN CANCER ANOREXI

葡萄糖、胰岛素和胰高血糖素在癌症厌食症中的作用

• 批准号: 3173875
• 负责人: WILLIAM T CHANCE
• 金额: $ 8.09万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-12-01 至 1986-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3173875
• 关键词: anorexia; blood chemistry; blood glucose; brain metabolism; brain septal area; cachexia; cancer complication; dopamine; glucagon; high performance liquid chromatography; insulin; neurotransmitter metabolism; norepinephrine; nutrition aspect of cancer; nutrition related tag; serotonin

Anorexia is a major complicating factor of neoplastic disease that severely limits the use of available therapeutic options. Although many theories of cancer anorexia have been advanced, few investigations of the causes of the anorexia have been directed at the molecular biochemical level. Therefore we have little information concerning abnormalities in anorectic tumor-bearing (TB) subjects of systems that are thought to mediate hunger and satiety. In preliminary experiments levels of dopamine (DA) metabolites were significantly decreased in the brains of anorectic TB rats and increased in undernourished pair-fed control rats. Brain levels of DA metabolites were nearly doulbed when the anorexia was corrected by insulin injections. Blood levels of insulin were also significantly decreased early in the course of anorexia an concentrations of glucagon were increased during more severe anorexia. The net effect of these alterations in glucoregulatory hormones is to prevent hypoglycemia in the presence of increased glucose utilization. Since increased glucose usage rate is associated with satiety and glucose infusion decreases brain DA release, cancer anorexia may be partially caused by relative hyperglycemia reflected centrally as decreased turnover of DA. This hypothesis will be investigated in the proposed experiments by (1) assessing the effects of correcting cancer anorexia by insulin treatments on concentrations of amine neurotransmitters, precursors and metabolites in nine discrete brain regions; (2) assessing the effects of insulin treatments on blood levels of glucagon and cachexia; (3) examining the release of DA and norepinephrine (NE) in the hypothalamus, septal area, amygdala and corpus striatum of freely-behaving TB and control rats by push-pull perfusion of these brain areas and correlating these changes in catecholamines with plasma levels of glucose, insulin and glucagon; (4) assessing the effects of insulin administration on the release of DA and NE in these brain areas; (5) investigating the anti-anorectic effects of drugs that stimulate DA neurotransmission as possible candidates for pharmacological control of anorexia. These experiments are designed to comprehensively investigate the role of amine neurotransmitters in mediating cancer anorexia. An advantage of these studies is that ongoing peripheral events (changes in glucose) will be correlated with ongoing CNS neurochemical changes and the relationship of both peripheral and central biochemical changes to anorexia and feeding can be established in a freely-behaving animal.

厌食症是肿瘤疾病的主要复杂因素 限制使用可用的治疗选项。 虽然许多理论 癌症的厌食症已得到促进，很少对 厌食症已针对分子生化水平。 所以 我们几乎没有关于异常异常的信息 被认为介导饥饿的系统的肿瘤（TB）受试者 和饱腹感。 在初步实验中多巴胺的水平（DA） 厌食症大鼠的大脑中的代谢物显着降低 并增加了营养不良的配对对照大鼠。 da的大脑水平 通过胰岛素校正厌食症时，代谢产物几乎被淘汰 注射。 胰岛素的血液水平也显着降低 在厌食症的早期，胰高血糖素的浓度是 在更严重的厌食症期间增加。 这些改变的净效应 在糖调节激素中，是为了防止在存在的情况下 葡萄糖利用率增加。 由于增加的葡萄糖使用率是 与饱腹感和葡萄糖输注相关可降低脑da的释放， 癌症厌食症可能部分由反映的相对高血糖引起 DA的营业额减少。 这个假设将是 在提出的实验中调查了（1）评估的影响 通过胰岛素治疗对胺浓度纠正癌症厌食 九个离散大脑中的神经递质，前体和代谢物 地区； （2）评估胰岛素治疗对血液水平的影响 胰高血糖素和恶病质； （3）检查DA和去甲肾上腺素的释放 （NE）在下丘脑，间隔区域，杏仁核和语料库中 通过推动这些大脑的推动力灌注来自由地行为结核病和控制大鼠 区域并将儿茶酚胺中的这些变化与血浆水平相关联 葡萄糖，胰岛素和胰高血糖素； （4）评估胰岛素的影响 在这些大脑区域释放DA和NE； （5） 调查刺激DA的药物的抗动脉抗体作用 神经传递是对药理控制的可能候选者 厌食。 这些实验旨在全面研究 介导癌症厌食症的胺神经递质。 一个优势 这些研究是，持续的外围事件（葡萄糖的变化）将 与正在进行的中枢神经系统神经化学变化和关系相关 外围和中央生化变化的厌食和喂养 可以在自由行为的动物中建立。