POLYMORPHONUCLEAR LEUKOCYTE FUNCTION IN DIABETES

糖尿病中的多形核白细胞功能

• 批准号: 3240508
• 负责人: CHRISTOPHER P NIELSON
• 金额: $ 6.89万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-08-01 至 1991-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3240508
• 关键词: aldehyde reductase; arachidonate; blood glucose; calcium; cellular respiration; cyclic AMP; diabetes mellitus; fluorescent dye /probe; gas chromatography mass spectrometry; glucose metabolism; high performance liquid chromatography; human subject; hypoglycemia; immunoregulation; insulin; membrane lipids; neutrophil; oxidoreductase inhibitor; phosphatidylinositols; protein kinase C; radioimmunoassay; stimulus /response; superoxides

The objective of this project is to determine how polymorphonuclear leukocyte (PMN) function is impaired in diabetes and whether the impairments in cell function are reversible. Although altered PMN function has been previously reported to occur in diabetes, the causes of cell dysfunction are not well understood. In addition, therapeutic interventions to improve PMN function are not established. Because infection is a major cause of morbidity in diabetic patients, the causes of impaired PMN function and means to improve cell function may of clinical importance. Glucose metabolism through the polyol pathway during periods of hyperglycemia may be associated with depletion of cellular myo- inositol. Myo-inositol is in an equilibrium with phosphatidyinositol, a phospholipid of critical importance in PMN stimulus-response coupling. It is therefore proposed that altered phosphatidylinositol metabolism is a cause of impaired PMN function in diabetes. Impaired PMN function caused by glucose metabolism through the polyol pathway may be of clinical importance because therapeutic interventions to prevent or reverse depletion of myo-inositol are available. Aldose-reductase inhibitors reduce glucose metabolism through the polyol pathway and myo-inositol supplementation restores cellular inositol concentrations. The proposed studies will characterize an in vitro model of impaired PMN function induced by elevated glucose concentrations. Using this model, the effects of insulin, aldose- reductase inhibitors and myo-inositol on PMN function will be evaluated. PMN from diabetic subjects will be then by studied to determine whether cell function may be improved following normalization of extracellular glucose, treatment with insulin, incubation with aldose-reductase inhibitors or exposure to myo- inositol. The results of these studies may be of value in both the care of diabetic subjects and development of new therapeutic interventions. Methods for rapidly evaluating stimulus-response coupling and PMN function in diabetic patients will be developed. The specific defects in PMN function which are induced by hyperglycemia will be characterized. Potential therapeutic interventions to improve PMN function will be evaluated. The proposed experiments are unique, the model of PMN function is novel but straightforward and the results are likely to be relevant to the care of diabetic patients.

该项目的目标是确定如何 中性粒细胞(PMN)功能受损 糖尿病和细胞功能损害是否 可逆的。尽管改变了PMN功能之前 据报道发生在糖尿病中，细胞功能障碍的原因是 不是很清楚。此外，治疗干预措施还包括 改善PMN功能没有建立。因为感染是一种 糖尿病患者发病的主要原因， 受损的PMN功能和改善细胞功能的方法可能 具有临床重要性。 糖代谢通过多元醇途径在一段时期 高血糖可能与细胞肌力衰竭有关。 肌醇。肌醇与磷脂酰肌醇处于平衡状态， 一种在中性粒细胞刺激反应中起关键作用的磷脂 耦合。因此，建议修改 磷脂酰肌醇代谢是中性粒细胞受损的原因之一 在糖尿病中起作用。葡萄糖引起的中性粒细胞功能受损 通过多元醇途径的代谢可能具有临床意义。 之所以重要，是因为采取治疗措施来预防或 肌醇的反向消耗是可用的。醛糖还原酶 抑制剂通过多元醇途径降低葡萄糖代谢 补充肌醇可恢复细胞肌醇 浓度。 拟议的研究将描述一种体外模型 高血糖引起的中性粒细胞功能受损 浓度。使用这个模型，胰岛素、醛糖- 还原酶抑制剂和肌醇对中性粒细胞功能的影响 已评估。然后对糖尿病患者的PMN进行研究，以 确定细胞功能是否可以在以下方面得到改善 细胞外葡萄糖正常化，胰岛素治疗， 与醛糖还原酶抑制剂孵育或暴露于肌肉- 肌醇。 这些研究的结果可能在这两个方面都有价值 糖尿病患者与新治疗方法的发展 干预措施。一种快速评价刺激反应的方法 糖尿病患者的偶联和中性粒细胞功能将得到发展。 中性粒细胞功能的特殊缺陷 高血糖将是其特征。潜在的治疗方法 将对改善PMN功能的干预措施进行评估。这个 提出的实验是独一无二的，PMN函数的模型是 新颖但直截了当，结果很可能是相关的 用于糖尿病患者的护理。