PHYSIOLOGY & THERAPEUTIC USE OF INSULIN PULSES

生理

• 批准号: 3238390
• 负责人: DAVID S WEIGLE
• 金额: $ 4.17万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1992-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3238390
• 关键词: glucagon; glucose; human therapy evaluation; hypoglycemia; hypoketonemic hypoglycemia; insulin; ketones; lipolysis; liver metabolism; physiology; streptozotocin; tissue /cell culture

Pulsatile secretion of the islet hormones at an interval of 10-14 minutes has now been demonstrated conclusively in several species including man. The proposed work will utilize insights gained from in vitro studies performed in our laboratory in an effort to comprehensively assess the impact of pulsatile insulin secretion in the whole animal. The long term objective is to devise better insulin treatment strategies for human diabetics based on studies of pulsatile insulin administration to nonhuman primates. Work will proceed in three sequential stages each of which addresses a separate specific aim. First, the importance of pulsatile insulin secretion in normal physiology will be assessed by comparing the effects of continuous portal insulin replacement with those of pulsatile portal replacement at the natural secretory interval. Responses studied will include hepatic glucose production, glucose clearance, ketogenesis, lipolysis, glucose counterregulation, and entrainment of glucagon secretion. Second, the consequences of varying the interval at which insulin pulses are administered peripherally will be examined. Previous in vitro work has suggested that differences in the frequency responsiveness of peripheral and hepatic tissues might be exploited to enhance the hepatic effects of peripherally- administered insulin. Finally, the efficacy of long term continuous and pulsatile insulin replacement in streptozotocin diabetic primates will be compared. The frequency of pulsatile insulin administration found in the second phase of this work to optimize hepatic responses will be used in these treatment trials. In future proposals the understanding gained in primates will be implemented with programmable hormone infusion technology to evaluate the efficacy of pulsatile insulin therapy of human diabetics.

胰岛激素以10-14的间隔脉冲式分泌 几分钟的时间里， 物种包括人类。拟议的工作将利用见解 从我们实验室进行的体外研究中获得， 努力全面评估脉冲胰岛素的影响 整个动物的分泌物。 长期目标是 为人类糖尿病患者设计更好的胰岛素治疗策略 基于对非人的脉冲式胰岛素给药的研究， 灵长类动物 工作将分三个连续阶段进行， 其针对单独的特定目标。 第一， 正常生理学中的脉冲式胰岛素分泌将通过 比较连续性门静脉胰岛素替代治疗 与自然条件下的搏动性门静脉置换术相比， 分泌间期 研究的缓解将包括肝葡萄糖 生产，葡萄糖清除，生酮，脂解，葡萄糖 胰高血糖素分泌的反调节和夹带。 第二，改变胰岛素注射时间间隔的后果， 将检查外周给予的脉冲。 先前 体外研究表明， 外周和肝组织的反应性可能是 用于增强外周- 注射胰岛素。 最后，长期疗效 链脲佐菌素持续和脉冲式胰岛素替代治疗 将比较糖尿病灵长类动物。 搏动频率 在这项工作的第二阶段发现的胰岛素给药， 这些治疗试验中将使用优化的肝脏反应。 在未来的提案中，在灵长类动物中获得的理解将是 采用可编程激素输注技术， 评价脉冲式胰岛素治疗人胰岛素抵抗的有效性 糖尿病人