Development of closed-loop intraperitoneal insulin infusion algorithm -for long-term application of an implantable artificial endocrine pancreas-

开发人工内分泌胰腺的最终目标是实现长期严格的血糖调节。为了建立人工内分泌胰腺的生理胰岛素输送途径，腹膜内胰岛素输注可能是重要的。为此，我们试图通过建立数学模型来分析胰岛素在腹膜腔内规则吸收的药代动力学过程，从而开发出闭环式的腹膜腔胰岛素输注算法。计算了该算法的参数，以尽可能接近地模拟腹腔注射胰岛素后的血浆胰岛素谱。为了评估该算法的适用性，我们应用该算法对糖尿病犬进行了2g/kg口服葡萄糖负荷或80kcal/kg餐负荷后的血糖控制试验。使用我们之前报道过的皮下注射胰岛素的算法，四氧嘧啶诱导的糖尿病狗表现出餐后高血糖和延迟性高胰岛素血症，f…口服葡萄糖负荷2-g/kg后，低血糖发生率更高。然而，使用腹膜腔胰岛素输注算法，血糖控制良好(餐后血糖在70min和240min分别为9.1±0.8 mm o l/L和3.8±0.3 m o l/L)，没有任何相关的迟发性高胰岛素血症或低血糖。80kcal/kg餐负荷后的血糖漂移也被控制在3.9mmoL/kg~10.1mmoL/L。此外，使用本研究中描述的IP算法，无论是仰卧位的口服葡萄糖负荷还是站立位的餐负荷，糖尿病犬都可以获得良好的血糖控制。我们的结果证实了体内胰岛素输注算法的可行性，该算法在血糖调节方面优于皮下胰岛素利普罗输注算法。综上所述，我们开发了针对AEP的IP算法，该算法是对血糖浓度的比例和导数作用的和。使用该算法运行的AEP，成功地调节了糖尿病犬在口服葡萄糖负荷和进食负荷时的血糖和胰岛素谱。这些数据表明，在人类糖尿病患者的治疗中，通过闭合循环注射胰岛素来控制血糖是可行的。我们的结果可能在不久的将来鼓励植入型AEP的发展，它可以为患者，特别是1型糖尿病患者提供最佳的血糖控制。较少

The ultimate goal of the development of an artificial endocrine pancreas is to achieve a long-term strict glycemic regulation. In order to establish the physiological insulin delivery route of the artificial endocrine pancreas, intraperitoneal insulin infusion may be important. For this purpose, we tried to develop closed-loop intraperitoneal insulin infusion algorithm by analyzing the pharmacokinetics of intraperitoneal regular insulin absorption using a mathematical model. The parameters for this algorithm were calculated to simulate the plasma insulin profile after intraperitoneal insulin injection as closely as possible. To evaluate the appropriateness of this algorithm, we tried glycemic control after 2-g/kg oral glucose load or 80-kcal/kg meal load in diabetic dogs by applying the algorithm. Using the subcutaneous insulin lispro infusion algorithm, which we have previously reported, alloxan-induced diabetic dogs exhibited postprandial hyperglycemia and delayed hyperinsulinemia, f … More ollowed by hypoglycemia after 2-g/kg oral glucose load. However, using the intraperitoneal insulin infusion algorithm, excellent glycemic control (postprandial blood glucose of 9.1 ± 0.8 mmol/l at 70 min and 3.8 ± 0.3 mmol/l at 240 min, respectively) could be achieved without any associated delayed hyperinsulinemia or hypoglycemia. Glycemic excursion after 80-kcal/kg meal load was also controlled from 3.9 to 10.1 mmol/l. In addition, using the IP algorithm described n this study, excellent glycemic control after either an oral glucose load in the supine position or a meal load in the standing position could be achieved in diabetic dogs. It was not necessary to change the insulin infusion parameters in response to a positional change of the dogs.Our results confirm the feasibility of the intraperitoneal insulin infusion algorithm in vivo and that this algorithm can be superior to the subcutaneous insulin lispro infusion algorithm in the regulation of blood glucose.In conclusion, we developed the IP algorithm, designed for the AEP, as the summation of proportional and derivative actions in response to blood glucose concentration. With the AEP operated by this algorithm, blood glucose and insulin profiles during oral glucose load and meal load were successfully regulated in diabetic dogs. These data suggest the feasibility of glycemic control with closed-loop intraperitoneal insulin infusion in the treatment of human diabetes patients. Our results might encourage the development of the implantable AEP in the near future, which could provide optimal glycemic control of patients, especially those with type 1 diabetes. Less