The UVA/PADOVA Type 1 Diabetes Simulator

Abstract

Recent studies have provided new insights into nonlinearities of insulin action in the hypoglycemic range and into glucagon kinetics as it relates to response to hypoglycemia. Based on these data, we developed a new version of the UVA/PADOVA Type 1 Diabetes Simulator, which was submitted to FDA in 2013 (S2013). The model of glucose kinetics in hypoglycemia has been improved, implementing the notion that insulin-dependent utilization increases nonlinearly when glucose decreases below a certain threshold. In addition, glucagon kinetics and secretion and action models have been incorporated into the simulator: glucagon kinetics is a single compartment; glucagon secretion is controlled by plasma insulin, plasma glucose below a certain threshold, and glucose rate of change; and plasma glucagon stimulates with some delay endogenous glucose production. A refined statistical strategy for virtual patient generation has been adopted as well. Finally, new rules for determining insulin to carbs ratio (CR) and correction factor (CF) of the virtual patients have been implemented to better comply with clinical definitions. S2013 shows a better performance in describing hypoglycemic events. In addition, the new virtual subjects span well the real type 1 diabetes mellitus population as demonstrated by good agreement between real and simulated distribution of patient-specific parameters, such as CR and CF. S2013 provides a more reliable framework for in silico trials, for testing glucose sensors and insulin augmented pump prediction methods, and for closed-loop single/dual hormone controller design, testing, and validation.

Cross-Validation of a Glucose-Insulin-Glucagon Pharmacodynamics Model for Simulation Using Data From Patients With Type 1 Diabetes

“…The ability of insulin to suppress the glycogenolytic response to glucagon at high insulin concentration is not reflected in previously published models of glucose-glucagon dynamics [18][19][20]. A comparative study found that a multiplicative relationship was needed to describe insulin's inhibitory effect and glucagon's stimulating effect on glycogenolysis with insulin overriding the effect of glucagon at high concentrations of both hormones [21].…”

Insulin kinetics and the Neonatal Intensive Care Insulin–Nutrition–Glucose (NICING) model

“…[3][4][5][6]), or Type 1 Diabetes cohorts (e.g. [7]). These models tend to be less complex, as metabolic measurements are minimised in clinical or outpatient settings due to clinical and patient factors such as cost, availability, or comfort.…”

Development and in silico validation of the PID-algorithm for the artificial pancreas with intraperitoneal insulin delivery

“…Первый доклинический этап тестирования эффективности и безопасности работы управляющего алгоритма принято проводить в условиях программной симуляции. Исследователи из университетов Вирджинии (США) и Падуи (Италия) разработали метаболический симулятор UVA/Padova для облегчения разработки алго-ритмов ИПЖ и их виртуального тестирования (в условиях in silico), которое по одобрению Food and Drug Administration (FDA, США) может заменить этап доклинического те-стирования с участием лабораторных животных [18][19][20].…”