DISORDER OF MET ENCEPHALIN LEVELS IN DIABETES

糖尿病患者甲硫氨酸脑啡肽水平紊乱

• 批准号: 5211668
• 负责人: MALAK G KOLTA
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5211668
• 关键词: adrenal medulla; blood glucose; brain metabolism; diabetes mellitus; diabetes mellitus therapy; dopamine; drug metabolism; enkephalins; high performance liquid chromatography; insulin; laboratory rat; medical complication; neurochemistry; pharmacokinetics; radioimmunoassay; receptor binding; spinal cord

Complications of diabetes Mellitus are numerous and manifested by a wide range of pathological conditions including abnormalities in the response to painful stimuli. The role of endogenous opioid peptides in mediation of antinociceptive effect in animal and human has been documented. We have found that streptozotocin (STZ)-induced diabetes in rats resulted in a significant increase in the hot plate latency test which developed gradually over 6-7 weeks period post induction of diabetes. this analgesic response was associated with several-folds increase of free Met-enkephalin (ME) in plasma and various brain regions. The object of these studies is to determine the neurochemical basis that regulate the level of the endogenous ME in diabetes. We hypothesize that the high level of free ME is a result of an abnormal activation of the releasing process of ME from the larger pool (precursor) and/or decrease in its turn over rate. To test this hypothesis, we will determine: (1) Whether the high level of free ME in plasma, spinal cord and brain regions in diabetes is due to enhanced ME release and/or decrease in its degradation, (2) if the high circulating level of glucose in diabetes plays a role in increasing the level of ME, (3) whether the increase in free ME level is modulated indirectly by another endogenous neurotransmitter (i.e., DA) as a result of diabetes, (4) if diabetes alters the kinetic of free ME and/or its immediate precursor (cryptic form), (5) whether controlling the diabetic state with chronic insulin administration prevents, ameliorates or reverse such alteration in the level, and distribution of ME similar to that of the non-diabetes control rat. In addition to testing this hypothesis, we also plan to determine the time course for the development of such changes after the induction of diabetes as well as the schedule of insulin treatment that correct such problems. These studies should provide insight into the factors that regulate the level of ME in diabetes and indirectly, the analgesic response as one of the pathophysiological condition associated with this disease. Should the diabetic state produce an alteration in the releasing and/or turnover rate of ME, these results might provide a rational basis for drug treatment or drug interaction involving the antinociceptive system of diabetic patients.

糖尿病的并发症很多，表现为广泛的 一系列病理状况，包括反应异常 疼痛的刺激。 内源性阿片肽在介导中的作用 在动物和人类中的抗伤害效应已经被记录。 我们 已经发现链脲佐菌素（STZ）诱导的大鼠糖尿病导致 在热板潜伏期测试中， 在诱导糖尿病后6-7周内逐渐增加。 这 镇痛反应与几倍增加的游离 血浆和各脑区的甲硫氨酸脑啡肽（ME）。 的对象 这些研究的目的是确定调节神经系统的神经化学基础， 糖尿病患者的内源性ME水平。 我们假设 游离ME的水平是释放的异常激活的结果。 从较大的游泳池（前体）和/或其减少ME的过程 周转率 为了验证这一假设，我们将确定：（1）是否 血浆、脊髓和脑区游离ME水平高， 糖尿病是由于ME释放增强和/或其代谢产物减少。 （2）如果糖尿病患者的高循环葡萄糖水平 在增加ME水平方面起作用;（3）增加ME是否 游离ME水平间接受另一种内源性 神经递质（即，DA）糖尿病的结果，（4）如果糖尿病 改变游离ME和/或其直接前体（隐蔽的）的动力学 （5）是否用慢性胰岛素控制糖尿病状态 给药预防、改善或逆转了在细胞内的这种改变。 ME水平和分布与非糖尿病对照组相似 大鼠 除了测试这一假设之外，我们还计划确定 这种变化的发展时间进程后，诱导 糖尿病以及胰岛素治疗的时间表，纠正这种 问题 这些研究应该提供深入了解的因素， 调节糖尿病患者的ME水平， 反应作为与此相关的病理生理条件之一 疾病 糖尿病状态是否会改变 释放和/或周转率，这些结果可能会提供一个 涉及药物治疗或药物相互作用的合理依据 糖尿病患者的镇痛系统。