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 hypoglycemia60
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 Action60
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