Department of Information Engineering, University of Padova, Padova, Italy.
Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
Comput Methods Programs Biomed. 2022 Oct;225:107104. doi: 10.1016/j.cmpb.2022.107104. Epub 2022 Sep 8.
The glucose clamp (GC) is an experimental technique for assessing several aspects of glucose metabolism. In these experiments, investigators face the non-trivial challenge of accurately adjusting the rate of intravenous glucose infusion to drive subjects' blood glucose (BG) concentration towards a desired plateau level. In this work we present Gluclas, an open-source software to support researchers in the modulation of glucose infusion rate (GIR) during GC experiments.
Gluclas uses a proportional-integrative-derivative controller to provide GIR suggestions based on BG measurements. The controller embeds an anti-wind-up scheme to account for actuator physical limits and suitable corrections of control action to accommodate for possible sampling jitter due to manual measurement and actuation. The software also provides a graphic user interface to increase its usability. A preliminary validation of the controller is performed for different clamp scenarios (hyperglycemic, euglycemic, hypoglycemic) on a simulator of glucose metabolism in healthy subjects, which also includes models of measurement error and sampling delay for increased realism. In silico trials are performed on 50 virtual subjects. We also report the results of the first in-vivo application of the software in three subjects undergoing a hypoglycemic clamp.
In silico, during the plateau period, the coefficient of variation (CV) is in median below 5% for every protocol, with 5% being considered the threshold for sufficient quality. In terms of median [5th percentile, 95th percentile], average BG level during the plateau period is 12.18 [11.58 - 12.53] mmol/l in the hyperglycemic clamp (target: 12.4 mmol/), 4.92 [4.51 - 5.14] mmol/l in the euglycemic clamp (target: 5.5 mmol/) and 2.38 [2.33 - 2.64] in the hypoglycemic clamp (target: 2.5 mmol/). Results in vivo are consistent with those obtained in silico during the plateau period: average BG levels are between 2.56 and 2.68 mmol/l (target: 2.5 mmol/l); CV is below 5% for all three experiments.
Gluclas offered satisfactory control for tested GC protocols. Although its safety and efficacy need to be further validated in vivo, this preliminary validation suggest that Gluclas offers a reliable and non-expensive solution for reducing investigator bias and improving the quality of GC experiments.
葡萄糖钳夹（GC）是一种评估葡萄糖代谢多个方面的实验技术。在这些实验中，研究人员面临着一个非平凡的挑战，即需要精确地调整静脉内葡萄糖输注率，以将受试者的血糖（BG）浓度驱动到期望的平台水平。在这项工作中，我们提出了 Gluclas，这是一种开源软件，用于支持研究人员在 GC 实验中调节葡萄糖输注率（GIR）。
Gcludas 使用比例积分微分控制器根据 BG 测量值提供 GIR 建议。该控制器嵌入了一个反积分饱和方案，以考虑执行器的物理限制，并对控制动作进行适当的修正，以适应由于手动测量和执行而可能导致的采样抖动。该软件还提供了一个图形用户界面，以提高其可用性。在健康受试者的葡萄糖代谢模拟器上，针对不同的钳夹情况（高血糖、正常血糖、低血糖）对控制器进行了初步验证，该模拟器还包括测量误差和采样延迟模型，以提高真实性。在 50 个虚拟受试者上进行了模拟试验。我们还报告了该软件在 3 名接受低血糖钳夹的受试者中的首次体内应用结果。
在模拟中，在平台期内，每个方案的变异系数（CV）中位数均低于 5%，5%被认为是足够质量的阈值。在平均 BG 水平方面，在高血糖钳夹期间，平台期的平均 BG 水平为 12.18 [11.58-12.53]mmol/l（目标：12.4mmol/l），在正常血糖钳夹期间为 4.92 [4.51-5.14]mmol/l（目标：5.5mmol/l），在低血糖钳夹期间为 2.38 [2.33-2.64]mmol/l（目标：2.5mmol/l）。在体内的结果与平台期的模拟结果一致：平均 BG 水平在 2.56 至 2.68mmol/l 之间（目标：2.5mmol/l）；所有三个实验的 CV 均低于 5%。
Gcludas 为测试的 GC 方案提供了令人满意的控制。尽管其安全性和有效性需要在体内进一步验证，但初步验证表明，Gcludas 为减少研究人员偏见和提高 GC 实验质量提供了一种可靠且经济实惠的解决方案。
