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: jbjo@dtu.dk