PHYSIOLOGY & THERAPEUTIC USE OF INSULIN PULSES

胰岛激素以10~14次为间隔的搏动性分泌 会议纪要现在已经确凿地证明在几个 包括人类在内的物种。拟议的工作将利用洞察力 从我们实验室进行的体外研究中获得 努力全面评估脉动胰岛素的影响 整个动物体内的分泌物。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 基于对非人类脉冲式胰岛素注射的研究 灵长类动物。工作将分三个连续阶段进行，每个阶段 它解决了一个单独的具体目标。首先，要强调 正常生理中的脉动性胰岛素分泌将通过以下方式进行评估 门脉胰岛素持续替代治疗的疗效比较 与脉冲式门静脉置换术相比 分泌间歇。研究的反应将包括肝脏葡萄糖 生产、葡萄糖清除、酮类生成、脂肪分解、葡萄糖 反调节和夹带胰升糖素分泌。 第二，改变胰岛素使用时间间隔的后果 将检查外周给药的脉冲。上一首 体外研究表明，频率上的差异 外周和肝组织的反应性可能是 被用来增强外周的肝脏效应- 注射胰岛素。最后，长期的疗效。 链脲佐菌素的持续性和搏动性胰岛素替代治疗 患糖尿病的灵长类动物将被比较。脉搏波的频率 在这项工作的第二阶段发现给予胰岛素治疗 优化肝脏反应将用于这些治疗试验。 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实施 脉冲式胰岛素治疗人体的疗效评价 糖尿病患者。

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.