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GLUCOSIM: Educational Software for Virtual Experiments with Patients with Type 1 Diabetes
Baris U. Agar, Meriyan Eren, and Ali Cinar
Department of Chemical and Environmental Engineering Illinois Institute of Technology Chicago, IL 60616 USA email@example.com Abstract-GLUCOSIM is an educational software package that simulates blood glucose and insulin dynamics in healthy individuals and patients with type 1 diabetes. It is being used to assist biomedical and chemical engineering students in visualizing the dynamic variations in blood glucose concentration in response to external variations such as food consumption and insulin administration. A nutritional database has been integrated to GLUCOSIM to provide meal inputs to the simulation. The simulator has been improved by the modification of mathematical models, and it has been adapted to include currently available commercial insulin brands. I. INTRODUCTION Type 1 or insulin-dependent diabetes mellitus (IDDM) is a disease characterized by insufficient secretion of insulin from -cells of pancreas, which results in elevated blood glucose levels. Modeling glucose-insulin interaction in human body requires an understanding of the physiological and metabolic processes that influence the variations observed over time in blood glucose concentration. A software package, GLUCOSIM has been developed to simulate blood glucose and insulin dynamics in healthy individuals and patients with type 1 diabetes for educational purposes. GLUCOSIM is being used to assist biomedical and chemical engineering students in visualizing the dynamic variations in blood glucose and insulin concentrations in response to external perturbations such as food consumption and insulin administration. It also provides an environment for students to perform virtual experiments with food choices, insulin injections and insulin infusion by automated pumps. Virtual experiments become useful especially when the experiments are either too expensive or too dangerous to carry out in real life. II. MODEL Several compartmental models have been developed to describe the dynamics of insulin and glucose levels in blood [1, 2]. GLUCOSIM utilizes the compartmental model developed by Puckett  as a starting point. Equations have been added and model parameters have been modified to simulate healthy individuals (insulin secretion) and effects
0-7803-8740-6/05/$20.00 ©2005 IEEE. 845
of various types of insulin currently available in the market. The body has been divided into several physiologic compartments
Fig. 1. Pharmacokinetic diagram of glucose
(tissues/organs) as illustrated in Fig. 1, and a mathematical model is developed by writing mass balance equations around each compartment for glucose and insulin. Mass balance for glucose around a specific tissue/organ can be formulated as:
1 (Qin , g Gin Vg rproduction
Qout , g Gout rutilization )
where V, Q, and G represent the effective volume, effective flow rate and blood glucose concentration respectively, subscripts “in” and “out” indicate inflow and outflow and subscript g indicates glucose. The rate of utilization and/or production of glucose within the compartment is denoted by
Authorized licensed use limited to: Wayne State University. Downloaded on May 17,2010 at 01:27:49 UTC from IEEE Xplore. Restrictions apply.
198/glucosim. Insulin Administration with Feedback Controlled Pumps The use of insulin infusion pumps is becoming an appealing therapy method for type 1 diabetes. and “Patient with Type 1 Diabetes”. A. 4] have been integrated to the detailed mathematical model to simulate glucose-insulin dynamics in a healthy individual. III. In addition. “Healthy Person”. It is assumed that flow through each compartment is constant (Qin. carbohydrate intake. A detailed mathematical model is constructed based on mass balances for the coupled glucose and insulin models.2010 at 01:27:49 UTC from IEEE Xplore. In addition. Insulin type and dose: The simulator has recently been modified to include various insulin types currently available in the market. Here. The software is available in several platforms. In the patient mode. The rate of change of glucose concentration in circulating blood (B) can be expressed as: using multiple daily insulin injections. A similar pharmacokinetic diagram is utilized to formulate the mass balance equations for insulin. and the subscripts “in” and “out” for G in (1) are replaced by the symbols of the previous and succeeding compartments. Two different submodels for pancreatic insulin release [3.47. GLUCOSIM provides the users with three options to perform virtual experiments: “Oral Glucose Tolerance Test” (OGTT). and a set of simultaneous ordinary differential equations is obtained.g = Qg. 2. Simulation window 1. Body weight Duration of exercise: The exercise option. A web-based version of GLUCOSIM is available at http://216. A simplified mathematical model is also derived by assuming quasi-steady state in each compartment and this results in two differential equations representing glucose and insulin concentrations in blood. 2 shows the GUI of the MATLAB version of GLUCOSIM. and duration of exercise on glucose and insulin dynamics in patients with type 1 diabetes. the user can select between insulin injections (open-loop control) and automatic feedback control pumps (closed-loop control) as means of insulin administration. The mathematical model is currently being modified to incorporate more detailed descriptions of utilization and production rates of glucose and insulin .). a nutritional database to determine the carbohydrate content of a meal is embedded in the software. 2.139. Downloaded on May 17. which is designed for moderate exercise is currently available for type 1 diabetic patients. timing of meal and insulin injections. B. Insulin Injection Therapy Multiple daily insulin injections is one of the conventional therapy methods for type 1 diabetes. The mathematical model and a graphical user interface (GUI) were initially developed in MATLAB platform . 4. GLUCOSIM can simulate a typical type 1 diabetic person 846 Fig. a model modification for patients with type 1 diabetes performing moderate exercise is incorporated.r. The current Authorized licensed use limited to: Wayne State University. Time of meal and insulin injection: The user can enter any value for the time of a meal or an insulin injection within the duration of simulation. . 6. Restrictions apply. liver glucose production rate. 5.g = Qout. SIMULATOR GLUCOSIM is a software for the simulation of plasma insulin and glucose dynamics in healthy individuals and patients with type 1 diabetes. insulin dosage. Carbohydrate content of the meal: A nutritional database is provided to determine the carbohydrate content of a specific meal. total glucose uptake etc. 3. Fig. the user has the flexibility in assigning different values to the input variables such as: dG B dt 1 [Q H (G B VB Q NS (G N S QL GL G H ) Q K (G K GB ) GB ) (2) G B ) Q PR (G PR Q PN (Q HA QGT )G B ]. and a stand alone version has been developed for Windows-based PCs. Duration of simulation The inputs listed above are relevant for investigating the effects of body weight. The output of the simulation displays the time course of several variables of the system such as: glucose and insulin concentrations in blood.
C. The program is capable of transferring carbohydrate content values from food tables to GLUCOSIM where they are used as inputs to the simulation. As expected. the meal time.2010 at 01:27:49 UTC from IEEE Xplore. In these projects the main objective of the students was to maintain the glucose level within the normoglycemic range (80-120 mg/dl) by balancing the food intake. IV. Downloaded on May 17. This way. For this purpose. a nutritional database with a user friendly GUI is provided on the web incorporated with GLUCOSIM. Nutritional Database One of the inputs to the simulator is the carbohydrate content of a meal. 847 Fig. exercise and timing. GLUCOSIM provides a virtual experimental environment for students to reason the combined or isolated effects of diet. Restrictions apply. the user has an option to switch to GLUCOSIM by choosing one of the simulator modes. and can select any food item from the food database. After creating the food table. The user can enter the type of the meal (breakfast. the simulator provides virtual environment for closed-loop control of plasma glucose concentration of patients with type 1 diabetes. The table shows the nutritional content (e. The dotted (red) line illustrates the injection rate and glucose concentration response using a PID controller. where students can tune the controllers by modifying the controller parameters and can examine the effect of different insulin infusion routes.g.4). 3 shows the variations the MPC. carbohydrate. which may not be readily available for the user. fat. followed by small adjustment in the infusion rate as the glucose concentration stays inside the desired range. and the dash-dotted (blue) line Authorized licensed use limited to: Wayne State University. The control algorithms employed by GLUCOSIM are proportional-integral-derivative (PID). EDUCATIONAL ACTIVITIES GLUCOSIM can be used to investigate glucose-insulin dynamics in human body for educational purposes.In addition. insulin and exercise on blood glucose levels. As an educational tool. IMC and MPC control systems. It provides a smart spreadsheet that determines the carbohydrate content of a specific meal and assigns it as an input to GLUCOSIM. internal model control (IMC) and model predictive control (MPC). The user can also create an account on the server where he/she can store various meals for later use. This type of studies can lead to the improvement of their reasoning skills. The user has the ability to devise several control strategies by varying controller parameters or restructuring the controllers by modifying control equations that relate the difference between glucose measurements and desired values and the insulin flow rate from the pump. Variations in blood glucose concentration in response to insulin infusion regulated by feedback-controlled pumps for PID. cholesterol content) of individual food items as well as the values for the whole meal (Fig. Fig. snack or dinner). the user can run GLUCOSIM and the nutritional database together to inspect the effect of different combination of foods on glycemic control. Students were asked to respond to changes in one of these elements by deciding on necessary adjustments on the others. lunch. In addition to the multiple daily insulin injections. It has been tested by biomedical and chemical engineering students in various course projects. the dashed (green) line shows the effect of the IMC. the intraperitoneal route gives better results because of lower time delay in insulin absorption to the bloodstream. The MPC provides the best controlled response with high levels of insulin release when the glucose concentration is increasing rapidly. A food table is generated for each meal and the selected foods are added automatically to the table. GLUCOSIM enables the user to experiment not only with multiple insulin injections but also with futuristic automatic control of insulin pumps. IMC and MPC control systems in blood glucose concentration over time in response to insulin infusion regulated by feedback-controlled pumps for PID.commercial use of the pumps is limited to external types where insulin infusion is regulated by the patient. insulin dosage. 3. . the user can experiment with two different insulin administration routes: intraperitoneal and subcutaneous infusions. An important component of this system is the controller algorithm that regulates the pump operation based on continuous blood glucose measurements. Development of an implantable insulin pump and a suitable control algorithm coupled with a glucose sensor that can monitor blood glucose levels at frequent intervals is an active research area in this field and is likely to yield the artificial pancreas solution for type 1 diabetes.
21–34. 4 Food table generated by the nutritional database GLUCOSIM can also be adapted for use by health-care professionals to train their patients with diabetes. M. Thesis. 2000. 1976. 1985. and H. Metabolic and Hormonal Effects of Muscular Exercise in Juvenile Type Diabetics. vol. G. F. Berchtold. 570–579. R. . 1977. R. Drost. Kley. Thesis. Kruskemper.2010 at 01:27:49 UTC from IEEE Xplore. vol. Diabetologia. 1992. Carson and D. 7.Fig. University of Wisconsin-Madison. Kawamori. Cramp. Shichiri. Downloaded on May 17. A Systems Model of Blood Glucose Control. 355–365. Chemical and Environmental Engineering Department. Wiegelmann. Thesis. 17. Department of Chemical Engineering. Puckett. M.and inter-personal variations and it should not be used for making medical decisions. Studies on Modelling Glucose Insulin Interaction in Human Body and Development of a Simulation Package. International Journal of Bio-Medical Computing. M. H. the simulator does not take into account intra. J. H. W. pp. H. Restrictions apply. Massachusetts Institute of Technology.D. A.     848 Authorized licensed use limited to: Wayne State University. F. T.C. the patients can explore how the adjustment of diet. P. H. Illinois Institute of Technology.S. A. Zimmermann-Telschow. Computers and Biomedical Research. Nomura. W. L. Dynamic Modeling of Diabetes Mellitus. Zimmermann. H. Department of Chemical Engineering. However. A Mathematical Insulin-Secretion Model and Its Validation in Isolated Rat Pancreatic Islets Perfusion. 1984. . Ph. A Physiologic Model of Glucose Metabolism in Man and Its Use to Design and Assess Improved Insulin Therapies for Diabetes. CONCLUSIONS As an educational software package GLUCOSIM has been very useful for conducting virtual experiments to simulate blood glucose and insulin dynamics in healthy individuals and patients with type 1 diabetes. Abe. GLUCOSIM should only be used for educational purposes. Ph. Sorensen. insulin dose and timing can affect their daily insulin regimen. Using the simulator. Berger. N. Gries. K. Iwama. E. pp. Erzen.D. Y. vol. It is being used to assist undergraduate and graduate biomedical and chemical engineering students in visualizing dynamic variations in blood glucose concentration in response to external variations such as food consumption and testing the performance of different control algorithms for automated pumps for insulin infusion. Muller. M. V. J. ACKNOWLEDGMENT The financial support provided by NSF (EEC-0080527) is gratefully acknowledged. pp. Yamasaki. REFERENCES   W. 13. and H. R. Cuppers.
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