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Update on the Closed-Loop Artificial Pancreas Project Stuart A Weinzimer, MD Associate Professor of Pediatrics Yale University School of Medicine CWD Friends.

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Presentation on theme: "Update on the Closed-Loop Artificial Pancreas Project Stuart A Weinzimer, MD Associate Professor of Pediatrics Yale University School of Medicine CWD Friends."— Presentation transcript:

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

2 Rationale for a Closed-Loop System Present methods of diabetes treatment improve, but dont 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 Yale Jaeb Center Mayo JDRF & NIH fundingJDRF fundingNIH funding UCSB/Sansum Benaroya Oregon Stanford Colorado Virginia Boston Cambridge Montpellier Pavia/Padova Israel UCSD Rensselaer W. Ontario W. Australia

4 Potential Pathway to an Artificial Pancreas

5 Medtronic ePID closed-loop system 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, et al. Diabetes Technol Ther. 2003;5:953-64.

7

8 Late post-prandial hypoglycemia in CL

9 Hybrid control improves performance 6ANoon6PMidN6ANoon6P 0 100 200 300 Closed Loop (N=8) meals setpoint Hybrid CL (N=9) Glucose (mg/dl) MeanDaytimePeak PP Full CL 147 58154 60219 54 Hybrid 138 49143 50196 52 Weinzimer SA. Diabetes Care 2008; 31:934-939.

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 0 10 20 30 40 50 60 Subjects (%) SedentaryExercise 28 % 48 % - 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 Closed Loop Open Loop 0 5 10 15 20 25 3 22 All Nocturnal Hypo Number of Treatments Given p=0.05 1 14 Night Following Exercise p=0.06

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 BreakfastLunchDinner 0 50 100 150 Pramlintide Control BG excursion (mg/dl) *p=0.03 *

24 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 Time (min) GIR (mg/kg/min) No InsuPatch With InsuPatch Cengiz, DTS Meeting 2010 (n=8) No InsuPatch With InsuPatch GIR 0-90min 2.4 ± 13.7 ± 2 T max GIR (min) 133 ± 2784 ± 18 T early 50% (min) 66 ± 1641 ± 15 AUC GIR 0-90min 226 ± 100343 ± 141

29 Effect of InsuPatch on meals Cengiz, unpublished (n=9)

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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