The Artificial Pancreas for
People with Type 1 Diabetes
www.diacongroup.org
Technical University of Denmark Hvidovre Hospital
The DIACON Consortium
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Zealand Pharma
The DIACON Group
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Organization • PI and Chairman of the Steering Committee
– Henrik Madsen, DTU Compute • Scientific Director and Coordinator
– John Bagterp Jørgensen, DTU Compute • Medical Director
– Kirsten Nørgaard, Hvidovre Hospital • Institutional/Company Representatives
– Henrik Egesborg, Medtronic Denmark ApS – Trine Skovlund Ryge Neerup, Zealand Pharma A/S – Rasmus Stig Jensen, HypoSafe A/S – Finn Kristensen, JDRF Denmark – Niels Kjølstad Poulsen, DTU Compute – Hans Henrik Niemann, DTU Electrical Engineering – Rolf Johansson, Lund University – Signe Schmidt, Post Doc, Hvidovre Hospital – Anne Katrine Duun-Henriksen, Post Doc, DTU Compute
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Advisory Board
• Jan Bolinder – Karolinska Institutet, Stockholm
• Claudio Cobelli – University of Padova
• Aaron Kowalski – JDRF Artificial Pancreas Consortium
• Kurt Højlund – Danish Diabetes Academy
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MODEL PREDICTIVE CONTROL
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Systematic Model Building
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Model Predictive Controller
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Regulator
Estimator
System
Sensors
Targets Inputs
Model Predictive Controller
Outputs
Measure-ments
State-/parameter-estimate
Model Predictive Control
MPC =
Estimation + Regulation Moving horizon
implementation
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Filtering and Prediction - EKF
Filtering
Prediction
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Optimal Control Problem
Integrator (Runge-Kutta Methods) • DOPRI54 (non-stiff systems) • ESDIRK12 / ESDIRK23 / ESDIRK34 (stiff systems)
Sensitivities • Forward, Adjoint
Optimization • SQP • Single-shooting • Multiple-shooting 11
The Artificial Pancreas
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DIACON - 1
Insulin Administration System for
People with Type 1 Diabetes
Glucose Metabolism and Diabetes
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Glucose Homeostasis
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The Pancreas and its Hormones
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Blood glucose control The blood glucose must stay within certain upper and lower bounds!
– Too low: coma (immediate effect) – Too high: blindness and other long-term effects
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Diabetes Complications • Cardiovascular disease
– Major cause of death in people with diabetes
– >50% of all fatalities – Dissabilities
• Kidney disease • Nerve disease
– Ulceration and amputation of toes, feet and lower limbs
• Eye disease – Damage to retina. May lead
to loss of vision
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Prevalence of Diabetes 2012
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Diabetes: Costs and Prevalence
• Annual cost of diabetes – $130 billion in USA – 10% of health care budget
• WHO estimates (world)
– 171 million diabetics 2000 – 366 million diabetics 2030
An Artificial Pancreas (beta-cell)
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Portable Artificial Pancreas (beta cell)
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Physiological Models – The Virtual Patient
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Clinical Trials • Gastric emptying trials (left) • Clinical trials collecting data for modeling
(right)
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Example of a Clinical Experiment
8:00 Insert lines
12:30 Exercise
15:00 Snack
10:00 Meal/ bolus
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Clinical Setup
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Identification Results
27 Model is fit to the CGM signal. The intravenous glucose concentration is also shown (thick line) for comparison
The DTU Type 1 Diabetes Model
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Insulin Administration Strategies
NMPC Pre-meal Insulin Allowed
NMPC No Pre-meal Insulin
MDI (Pen Based) Insulin Treatment
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Closed-Loop Studies by NMPC Meals not announced Meals announced at meal-time
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Insulin Sensitivity Increases
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Cohort - Insulin Sensitivity Increases
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Overnight Stabilization – A Cohort
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GUI to Controller
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Clinical Closed Loop Studies
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Clinical Closed Loop
36 OPEN-LOOP CLOSED-LOOP
Glucose - Mean and Variability Open and Closed Loop
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Meal
Challenges
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OPEN-LOOP CLOSED-LOOP
The Artificial Pancreas
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DIACON - 2
Safety - Multiple CGMs - EEG hypoglycemic detector - Glucagon Everyday Life Efficacy - Ultra Fast Acting Insulin - Glucagon - Meal, Exercise, Alcohol challenges
Safe Artificial Pancreas Avoid Hypoglycemia
• Multiple CGMs – More safe in case of wrong CGM values – Take precautions if the CGMs do not agree
• Hypoglycemic Detector – EEG signal to redundantly detect hypoglycemia
• Glucagon – Use a glucagon pump in addition to insulin pump
to be able to increase BG in case of low values
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Portable Artificial Pancreas – 2 CGMs
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Hypoglycemic Detector
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Normal BG Low BG
EEGs for normal and low blood glucose
• Avoid low blood glucose values even if the CGMs are erroneous
• Redundancy • EEG measure that detects
hypoglycemia
Safety - Avoid Hypoglycemia
Artificial Pancreas Insulin + Glucagon
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Glucagon • Glucagon
– Not stable in liquid solution - Cannot be used in pump
- Glucagon Analogue (Zealand Pharma) - Stable in liquid solution - Can be used in a pump
- Purposes - Safety mechanism in case of low BG - Allow addition of more insulin at meals =>
more efficent treatment 45
Zealand Pharma
The Effect of Insulin Absorption Time
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Ideal closed-loop profiles for
NMPC and a meal scenario.
Maximal glucose concentration for “virtual” insulin with different absorption
times when injected by NMPC and a meal scenario.
Insulins - Pharmacokinetic Profiles
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Insulin Absorption
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Ultra Fast Acting Insulin
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Target Profiles – New Insulin Analogues
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In an Artificial Pancreas, we will only use the ultra fast acting insulin.
New Artificial Pancreas
• Portable • Dual CGMs • EEG Hypoglycemia Alarm • Ultra Fast Acting Insulin • Glucagon Analogue
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Possible Projects – DTU Compute Ph.D / M.Sc / B.Sc
• Simulator for glucose-insulin-glucagon dynamics – People with T1D – Healthy people
• Software for systematic model building – Parameter estimation in dynamic models – Optimal experimental design
• Model Predictive Control – Nonlinear MPC – Linear MPC
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DIACON Group - Contact
Dr. John Bagterp Jørgensen Technical University of Denmark DTU Compute Matematiktorvet Building 303B, Office 110 DK-2800 Kgs Lyngby Denmark E-mail: [email protected]