Parkinson Joanna, Hamrén Bengt, Kjellsson Maria C, Skrtic Stanko
Cardiovascular & Metabolic Disease, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, 431 83, Sweden.
Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University, Sweden.
Br J Clin Pharmacol. 2016 Dec;82(6):1613-1624. doi: 10.1111/bcp.13069. Epub 2016 Aug 16.
The integrated glucose-insulin (IGI) model is a semi-mechanistic physiological model which can describe the glucose-insulin homeostasis system following various glucose challenge settings. The aim of the present work was to apply the model to a large and diverse population of metformin-only-treated type 2 diabetes mellitus (T2DM) patients and identify patient-specific covariates.
Data from four clinical studies were pooled, including glucose and insulin concentration-time profiles from T2DM patients on stable treatment with metformin alone following mixed-meal tolerance tests. The data were collected from a wide range of patients with respect to the duration of diabetes and level of glycaemic control.
The IGI model was expanded by four patient-specific covariates. The level of glycaemic control, represented by baseline glycosylated haemoglobin was identified as a significant covariate for steady-state glucose, insulin-dependent glucose clearance and the magnitude of the incretin effect, while baseline body mass index was a significant covariate for steady-state insulin levels. In addition, glucose dose was found to have an impact on glucose absorption rate. The developed model was used to simulate glucose and insulin profiles in different groups of T2DM patients, across a range of glycaemic control, and it was found accurately to characterize their response to the standard oral glucose challenge.
The IGI model was successfully applied to characterize differences between T2DM patients across a wide range of glycaemic control. The addition of patient-specific covariates in the IGI model might be valuable for the future development of antidiabetic treatment and for the design and simulation of clinical studies.
整合葡萄糖 - 胰岛素（IGI）模型是一种半机械生理模型，能够描述在各种葡萄糖激发设置下的葡萄糖 - 胰岛素稳态系统。本研究的目的是将该模型应用于大量且多样化的仅接受二甲双胍治疗的2型糖尿病（T2DM）患者群体，并确定患者特异性协变量。
汇总了四项临床研究的数据，包括T2DM患者在混合餐耐量试验后仅接受二甲双胍稳定治疗时的葡萄糖和胰岛素浓度 - 时间曲线。这些数据是从糖尿病病程和血糖控制水平各异的广泛患者中收集的。
IGI模型通过四个患者特异性协变量进行了扩展。以基线糖化血红蛋白表示的血糖控制水平被确定为稳态葡萄糖、胰岛素依赖性葡萄糖清除率和肠促胰岛素效应大小的显著协变量，而基线体重指数是稳态胰岛素水平的显著协变量。此外，发现葡萄糖剂量对葡萄糖吸收率有影响。所开发的模型用于模拟不同血糖控制水平的T2DM患者组的葡萄糖和胰岛素曲线，并且发现它能够准确地表征他们对标准口服葡萄糖激发的反应。
IGI模型成功应用于表征广泛血糖控制范围内T2DM患者之间的差异。在IGI模型中添加患者特异性协变量可能对抗糖尿病治疗的未来发展以及临床研究的设计和模拟具有重要价值。
