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Update on the Closed-Loop Artificial Pancreas Project

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Presentation on theme: "Update on the Closed-Loop Artificial Pancreas Project"— Presentation transcript:

1 Update on the Closed-Loop Artificial Pancreas Project
CWD Friends For Life 7 July 2011 Update on the Closed-Loop Artificial Pancreas Project Stuart A Weinzimer, MD Associate Professor of Pediatrics Yale University School of Medicine

2 Rationale for a Closed-Loop System
Present methods of diabetes treatment improve, but don’t normalize, blood glucose levels, even with CGM Burden of care extremely high CL would advance our ability to control BG levels while at the same time REDUCE burden on user

3 JDRF- and NIH-funded Closed-Loop Control AP Research
JDRF funding JDRF & NIH funding NIH funding Benaroya Boston W. Ontario Yale W. Australia Oregon Cambridge Mayo Stanford Rensselaer UCSD Virginia Colorado Montpellier Pavia/Padova UCSB/Sansum Jaeb Center Israel

4 Potential Pathway to an Artificial Pancreas

5 Medtronic ePID closed-loop system
We brought 17 teenagers into the inpatient HRU for 36 hours of closed loop control. As you can see, they had two sensors placed, and a standard insulin pump capable of receiving RF signals. We used a laptop to run the algorithm. The next round of studies will use the smaller transmitter and also a smaller handheld PDA-like device. We had IVs placed so we could measure venous blood glucose levels every minutes during the study. Paradigm 715 insulin pump MMT sensor adapted for one-minute transmission Laptop computer with software program and algorithm

6 PID algorithm components
Proportional – to the glucose level Integral – slowly adaptive to normalize glucose Derivative – rate-of-change of the glucose Steil GM, Rebrin K, Janowski R, Darwin C, Saad MF. Modeling beta-cell insulin secretion--implications for closed-loop glucose homeostasis. Diabetes Technol Ther 2003;5: Steil GM, et al. Diabetes Technol Ther. 2003;5:


8 Late post-prandial hypoglycemia in CL

9 Hybrid control improves performance
300 setpoint Closed Loop (N=8) meals Hybrid CL (N=9) 200 Glucose (mg/dl) 100 PP = postprandial 6A Noon 6P MidN 6A Noon 6P Mean Daytime Peak PP Full CL 147  58 154  60 219  54 Hybrid 138  49 143  50 196  52 Weinzimer SA. Diabetes Care 2008; 31:

10 Conclusions of study CL control feasible in youth with T1D
Manual insulin “priming bolus” improved meal excursions Tendency to late post-prandial hypoglycemia Limitations No OL control Subjects were sedentary

11 Effect of daytime exercise on risk of subsequent nocturnal hypoglycemia
60 48 % 50 40 28 % Subjects (%) 30 20 10 Sedentary Exercise - DirecNet, J Pediatr 2005; DirecNet, Pediatr Diabetes 2007

12 Study objective To evaluate whether use of a CL system reduces the risk of delayed (nocturnal) hypoglycemia following antecedent daytime exercise

13 Study Protocol 12 subjects admitted to Inpatient HRU on two separate occasions: routine pump therapy (OL) or sensor-driven pump therapy (CL) Two 24-h evaluation periods: 8AM d#2 - 8AM d#4 Meals in both conditions are provided at 8AM, noon, and 5PM. Subjects consume identical meals under both conditions. Manual pre-meal bolus given (0.05 units/kg) Hypoglycemia  60 mg/dL (3.3 mmol)

14 Exercise Protocol One 1 of the 2 study days
Treadmill walking to target HR for 15 min x 4, followed by 5 min rest Supplemental CHO to give boost starting BG>120 mg/dL (6.7 mmol)

15 Glucose Histogram – Night after sedentary
2 % 97 % 1 % 5 % 86 % 9 % p=0.02

16 Glucose Histogram – Night after Exercise
6 % 90 % 4 % 11 % 72 % 17 % p=0.003

17 Nocturnal Hypoglycemia
All Nocturnal Hypo 1 14 Night Following Exercise p=0.06 25 22 20 15 Closed Loop Number of Treatments Given Open Loop 10 5 3 p=0.05

18 Summary and Conclusions
CL control was associated with: Greater time within target range at night compared to OL for both sedentary and exercise days Fewer episodes of frank hypoglycemia Use of a CL, even if only at night, may be effective in reducing hypoglycemia Prandial glycemic excursions still undesirable

19 Next study questions Can the addition of pramlintide improve the performance of a CL system by reducing the peak post-prandial glucose excursions?

20 Pramlintide Analog of human amylin
Co-secreted with insulin from -cell Used as adjunct to insulin in T1D to reduce post-prandial glycemic excursions Delay gastric emptying Suppress endogenous glucagon

21 Study Protocol 8 subjects admitted to Inpatient HRU for CL control
Two 24-h evaluation periods: 8AM d#2 - 8AM d#4 Meals provided at 8AM, 1PM, and 6PM. Subjects consume identical meals under both conditions. Pramlintide 30 mcg given prior to each meal on one study day Hypoglycemia  60 mg/dL (3.3 mmol)

22 Glucose excursions with/without pramlintide

23 Pramlintide reduced peak post-prandial BG
150 * Pramlintide Control 100 BG excursion (mg/dl) 50 Breakfast Lunch Dinner *p=0.03

24 Gastrointestinal None !
Adverse Effects Hypoglycemia No BG < 60 (3.3) <70 (3.9) Pramlintide (2%) Control (1%) Gastrointestinal None !

25 Summary and conclusions
Pramlintide had modest effect on prandial glucose Would require manual injection or at best, manual bolus Faster insulin absorption / action clearly needed

26 Next Steps Evaluation of other incretins
Strategies to accelerate insulin absorption / action

27 InsuPatch infusion site warming device
Heating element that adheres to an insulin pump catheter site Warms skin to 38-39°C Activated manually or automatically with insulin bolus Putative accelerates insulin absorption through increased local blood flow

28 Effect of InsuPatch on Insulin Action
60 120 180 240 300 0.0 2.0 4.0 6.0 8.0 (n=8) No InsuPatch With InsuPatch GIR0-90min 2.4 ± 1 3.7 ± 2 Tmax GIR (min) 133 ± 27 84 ± 18 T early 50% (min) 66 ± 16 41 ± 15 AUC GIR 0-90min 226 ± 100 343 ± 141 GIR (mg/kg/min) No InsuPatch With InsuPatch Time (min) Cengiz, DTS Meeting 2010

29 Effect of InsuPatch on meals
Cengiz, unpublished

30 Other approaches to AP “Control to Range” OL when BGs within target
Automatic pump suspension for actual or predicted hypoglycemia Pump augmentation for hyperglycemia

31 Automatic pump suspension for predicted hypoglycemia

32 The take-home message Pumps and sensors are becoming increasingly integrated and automated, but self-care burden is still high Full CL delivery is possible with current technologies but will likely require manual interfaces to completely optimize BG control Dual hormonal control will improve performance of CL systems but will add additional regulatory complexity Path to a true product will be iterative

33 Thank you! Yale Closed Loop Team Stu Weinzimer Jennifer Sherr
Eda Cengiz William Tamborlane Grace Kim Lori Carria Amy Steffen Kate Weyman Melinda Zgorski

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