1. Update on Artificial Pancreas Project
Are We There Yet?
Eda Cengiz, MD, MHS
Assistant Professor of Pediatrics
Yale University School of Medicine

2. Artificial Pancreas / Bionic Pancreas ?
utilizing electronic devices and mechanical parts to assist humans in performing difficult, dangerous, or intricate tasks, as by supplementing or duplicating parts of the body
Artificial intelligence runs the algorithm

3. The Promise of Artificial Pancreas
Glucose Sensor
Algorithm
Insulin Pump & Insulin
Sensor signals transmitted to a laptop computer that displays the sensor glucose and calculates rate of insulin delivery
Rate of insulin delivery is transmitted to the insulin pump
Determine insulin requirement real time, deliver proper insulin to achieve euglycemia.

4. Medtronic Closed-loop System c. 2011
CGM
Insulin Pump
Laptop
Controller
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.

5. When is it going to be ready?
During a Typical Clinic Visit at Yale Diabetes Center…
How is it going with the Artificial Pancreas Dr. C?
When is it going to be ready?
What is taking so long ?

6. Challenges & Solutions: Artificial Pancreas (Closed-Loop System)
Glucose Sensors
Insulin Delivery Algorithm
Insulin Pumps
Insulin (ultrafast action)
Progress to date
Pitfalls
Solutions
Future closed-loop studies
(hot off the press!)

7. JDRF Road Map to Artificial Pancreas
What is the plan?
JDRF Road Map to Artificial Pancreas

8. Do we need to wait until we have the Fully Automated Artificial Pancreas?

9. Progress to date
Artificial Pancreas
SENSOR-AUGMENTED
PUMP THERAPY

10. CGM improved A1c, but not in everyone
JDRF CGM Study Group. N Engl J Med 2008; 359:

11. Average Days of CGM Use by Age Group
JDRF CGM Study Group. N Engl J Med 2008; 359: 11

12. Medtronic STAR 3 Sensor-Augmented Pump Trial
3/27/2017
Medtronic STAR 3 Sensor-Augmented Pump Trial
The SAP group achieved a greater A1C reduction vs. MDI at 3 months and sustained it over 12 months
A1C Reduction for SAP and MDI Groups
∆ -0.2
- 0.6
P<0.001
- 0.6
P<0.001
∆ -0.8
= MDI
= SAP
n = 244
n = 241
Values are means ± SE. Comparisons between SAP group and MDI group are significant for each time period (P<0.001). 12 12

13. A1C Reduction Correlates to Increased Sensor Use
3/27/2017
A1C Reduction Correlates to Increased Sensor Use
The majority of patients used sensors ≥61% of the time
Patients who used sensors ≥81% of the time reduced their mean A1C by 1.2% at 1 year vs. baseline
n =27
n =46
n =108
n =56
Values are the difference between the means ± SE. p=0.003 for association between sensor wear and A1C reduction at 1 year. Only 7 participants had sensor use of 20% or less, with a change in A1C of at 1 year vs. baseline. 13

14. DirecNet / TrialNet Metabolic Control Study
Does the rapid normalization of BG levels at the time of diagnosis of diabetes, followed by super- intensive control of BG levels, help to preserve residual beta-cell function?
Use of an artificial pancreas in subjects AT DIAGNOSIS for 3-4 days to rapidly normalize BG levels, followed by sensor-augmented pump therapy x 2 years

15. Sensor and BG Levels During CL Therapy

16. Mean Sensor Glucose Levels Prior to, During, and Following CL Therapy

17. 6 wk f/u
3 mth f/u: A1c = 5.9 %

18. 6 wk f/u
6 mth f/u: A1c = 6.0 %
“typical” tracing
12 mth f/u: A1c = 6.3 %

19. Progress to Date Artificial Pancreas PUMP SUSPENSION FOR
ACTUAL HYPOGLYCEMIA
SENSOR-AUGMENTED
PUMP THERAPY

20. Prevention of Hypoglycemia with AP
Insulin suspension prevented low BG (<60mg/dl) in 78% of the suspensions.
Non resulted in hyperglycemia
Reduction in CGM hypoglycemia alarms

21. A Semi-Closed-Loop System: The Paradigm® Veo™*
Integrated sensor
Improved Calibration Routines
Glucose trend
Alarms
Outside target zone
Predictive
Missing insulin bolus
Minimum basal rate of U/h
Hypoglycemia suspend
Suspend for 2 hours
Re-suspend after 4 hours if needed
Keenan et al., J. Diabetes Sci. Tech., 2010; 4(1):
Buckingham et al., Diabetes Technol. Ther., 2009; 11:93-97
Attia et al., Diabetes Care, 1998; 21:
Guerci et al., J Clin Endocrinol Metab, 1999; 84:
Zisser, Diabetes Care, 2008; 31:
* Investigational device. Limited by U.S. law to investigational use.

22. Automatic Low-Glucose Suspend
LGS off
LGS on
Mean Glucose (mg/dL)
145 ± 23
148 ± 19
Time < 70 per day (min)
101 ± 68
58 ± 33 *
Time > 140 per day (min)
651 ± 240
639 ± 182
* p=0.002
Number of excursions < 70 and < 40 mg/dL reduced with LGS
Danne T, Diabetes Technol Ther 2011; 13:

23. PREDICTED HYPOGLYCEMIA
Progress to Date
Artificial Pancreas
PUMP SUSPENSION FOR
PREDICTED HYPOGLYCEMIA
PUMP SUSPENSION FOR
ACTUAL HYPOGLYCEMIA
SENSOR-AUGMENTED
PUMP THERAPY

24. Automatic pump suspension for predicted hypoglycemia

25. Exercise AP Study objective
To evaluate whether use of a AP system reduces the risk of delayed (nocturnal) hypoglycemia following antecedent daytime exercise

26. Exercise Study Protocol Schematic
48-hour evaluation period
2 overnights
48-hour evaluation period
2 overnights
Closed-Loop
Closed-Loop
Subject recruitment, consent, enrollment
(n = 12)
Open-Loop
Open-Loop
Plasma BG q30 min, insulin q30 min x meals

27. 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

28. Glucose Frequency Distribution Night after sedentary condition
1 %
99 % 0%
3 %
90 %
7 %
The benefits of CL control following a sedentary day are even more pronounced when our target blood glucose is widened to mg/dL as 99% of CL reference blood glucose values fall within this range.
P<0.0001

29. Glucose Frequency Distribution Night following afternoon exercise
3 %
93 %
4 %
8 %
76 %
16 %
When we expand our target range to mg/dL we see that 93% of our reference blood glucose fall within this range during the closed loop condition. The distribution of reference blood glucose levels closely follows the set point of our closed loop system.
P<0.0001

30. BASAL/BOLUS ACTIVATION PREDICTED HYPOGLYCEMIA
Progress to Date
Artificial Pancreas
BASAL/BOLUS ACTIVATION
FOR HYPERGLYCEMIA
PUMP SUSPENSION FOR
PREDICTED HYPOGLYCEMIA
PUMP SUSPENSION FOR
ACTUAL HYPOGLYCEMIA
SENSOR-AUGMENTED
PUMP THERAPY

31. Conceptual Scheme for “Treat-to-Range”

33. BASAL/BOLUS ACTIVATION PREDICTED HYPOGLYCEMIA
Progress to Date
Artificial Pancreas
CLOSED-LOOP BASAL
MANUAL MEALS
BASAL/BOLUS ACTIVATION
FOR HYPERGLYCEMIA
PUMP SUSPENSION FOR
PREDICTED HYPOGLYCEMIA
PUMP SUSPENSION FOR
ACTUAL HYPOGLYCEMIA
SENSOR-AUGMENTED
PUMP THERAPY

34. Studies of Overnight CL
Increased time in target BG
Reduction of hypoglycemia
Incorporation of daytime challenges
Exercise
Alcohol
Pregnancy

35. 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:

36. Late post-prandial hypoglycemia in CL

37. Progress to date Artificial Pancreas CLOSED-LOOP MULTIHORMONAL
FULL CLOSED-LOOP CONTROL
CLOSED-LOOP MULTIHORMONAL
CLOSED-LOOP BASAL
MANUAL MEALS
BASAL/BOLUS ACTIVATION
FOR HYPERGLYCEMIA
PUMP SUSPENSION FOR
PREDICTED HYPOGLYCEMIA
PUMP SUSPENSION FOR
ACTUAL HYPOGLYCEMIA
SENSOR-AUGMENTED
PUMP THERAPY

38. AP Multi-hormonal Approach
Can the addition of pramlintide improve the performance of a CL system by reducing the peak post-prandial glucose excursions?

39. 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

40. Closed-Loop + Pramlintide
Pramlintide Study Protocol Schematic
24-hour evaluation period
3 meals (BF, L, Din)
24-hour evaluation period
3 meals (BF, L, Din)
Closed-Loop
Closed-Loop
Subject recruitment, consent, enrollment
(n = 8)
Closed-Loop + Pramlintide
(30 mcg per meal)
Closed-Loop +
Pramlintide
(30 mcg per meal)
Plasma BG q30 min, insulin q30 min x meals

41. Glucose excursions with/without pramlintide

42. 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

43. ? Progress to date Artificial Pancreas FULL CLOSED-LOOP CONTROL
CLOSED-LOOP MULTIHORMONAL
CLOSED-LOOP BASAL
MANUAL MEALS
BASAL/BOLUS ACTIVATION
FOR HYPERGLYCEMIA
PUMP SUSPENSION FOR
PREDICTED HYPOGLYCEMIA
PUMP SUSPENSION FOR
ACTUAL HYPOGLYCEMIA
SENSOR-AUGMENTED
PUMP THERAPY

44. What do we need to achieve AP?
Glucose Sensors
Insulin Delivery Algorithm
Insulin Pumps
Insulin (ultrafast action)
Better accuracy, user interface, reliability.
Better algorithm
One site for CGM & Insulin

45. Single Port, Multiple Sensor
One site, two catheters for insulin infusion and glucose sensing
Single port for CGM and insulin
CGM with an optic sensor back up

46. What do we need to achieve AP?
Glucose Sensors
Insulin Delivery Algorithm
Insulin Pumps
Insulin (ultrafast action)
Better accuracy, user interface, reliability.
Better algorithm
One site for CGM & Insulin
Faster acting insulin

47. Dangerous Delays in Insulin Action after SC Injection
Delays due to the chemical properties of insulin.
Tissue delays

48. Insulin Time-Action Curves

49. InsuPatch
Temp. Sensor
The InsuPatchTM device applies controlled heat around the insulin infusion site.

50. Peak aspart insulin action curve shifted to the left .
The Effect of InsuPatch on Insulin Action
with InsuPatch activation:
Aspart insulin bolus maximum effect was 35 min earlier compared to the same dose bolus without InsuPatch activation .
Peak aspart insulin action curve shifted to the left .

51. Hyaluronidase Mechanism of Action
LAN030408ZXW ZXW
Hyaluronidase Mechanism of Action 51 51

52. DiaPort
The Accu-Chek DiaPort is a port system for continuous intraperitoneal insulin infusion.
Fixation disc
Port body
Polyester Felt
Membrane
Catheter
Infusion set with ball cannula
The catheter tip is placed in the peritoneal cavity where the insulin is directly infused.

53. Pathway to Closed-Loop (CL)
InsuPatch
Closed Loop studies at Yale
DiaPort
CL studies in France,
? in US
Hyaluronidase
(rhUPH20)
CL studies are planned.

54. Platform and Connectivity for
Ambulatory Studies
Pump

55. ? Progress to date Artificial Pancreas Outpatient studies
FULL CLOSED-LOOP CONTROL
Outpatient studies ?
CLOSED-LOOP MULTIHORMONAL
CLOSED-LOOP BASAL
MANUAL MEALS
BASAL/BOLUS ACTIVATION
FOR HYPERGLYCEMIA
PUMP SUSPENSION FOR
PREDICTED HYPOGLYCEMIA
PUMP SUSPENSION FOR
ACTUAL HYPOGLYCEMIA
SENSOR-AUGMENTED
PUMP THERAPY

57. The “Dream” Study

58. Thank you! Yale Closed Loop Team Stu Weinzimer Jennifer Sherr
William Tamborlane
Grace Kim
Miladys Palau
Camille Michaud
Lori Carria
Amy Steffen
Kate Weyman
Melinda Zgorski
Eileen Tichy