Pathways to Achieving a Bionic Pathways to Achieving a Bionic Pancreas Pancreas

Jay S. Jay S. SkylerSkyler, MD, MACP, MD, MACPProfessor, Division of Endocrinology, Diabetes, and MetabolismProfessor, Division of Endocrinology, Diabetes, and Metabolism

and Associate Director, Diabetes Research Instituteand Associate Director, Diabetes Research InstituteUniversity of Miami Miller School of MedicineUniversity of Miami Miller School of Medicine

Adjunct Professor, Barbara Davis Center for Childhood DiabetesAdjunct Professor, Barbara Davis Center for Childhood DiabetesUniversity of Colorado University of Colorado

•• Was on Board of Directors of Was on Board of Directors of MinimedMinimed, Inc. , Inc. (prior to acquisition by Medtronic) at time of (prior to acquisition by Medtronic) at time of development of the first subcutaneous development of the first subcutaneous continuous glucose monitoring systemcontinuous glucose monitoring system

•• Currently on Board of Directors of Currently on Board of Directors of DexComDexCom, , Inc Inc ––

““the Glucose Sensor Companythe Glucose Sensor Company””

Disclosure of Relevant Financial Disclosure of Relevant Financial RelationshipsRelationships

““The BeginningsThe Beginnings”” 1960s1960s

KadishKadish

AH: Trans Am Soc AH: Trans Am Soc ArtifArtif

Intern Organs 1963;9:363Intern Organs 1963;9:363––367.367.

Glucose Enzyme ElectrodeGlucose Enzyme Electrode

•• NatureNature; volume 214; 986; volume 214; 986--988, June 3, 1967988, June 3, 1967

•• SJ Updike and GP HicksSJ Updike and GP Hicks

Glucose Oxidase

silver

platinum

+

-

600 mv

Concept of MiniaturizationConcept of Miniaturization

Essential ComponentsEssential Components

•• Glucose MeasurementGlucose Measurement•• Algorithm for RegulationAlgorithm for Regulation•• Insulin DeliveryInsulin Delivery

Bedside Bedside ““Artificial PancreasArtificial Pancreas”” 1970s1970s

GCIISGCIISSuccess in developing GCIIS was achieved Success in developing GCIIS was achieved

nearly simultaneously in the 1970s by nearly simultaneously in the 1970s by groups in: groups in:

•• Toronto, CanadaToronto, Canada•• Ulm, GermanyUlm, Germany•• Montpellier, FranceMontpellier, France•• Sydney, Australia Sydney, Australia •• Osaka, JapanOsaka, Japan

Pfeiffer EF, Pfeiffer EF, et alet al. 1974.. 1974.

BiostatorBiostatorGlucose Controlled Insulin Infusion SystemGlucose Controlled Insulin Infusion System

Nikkiso STGNikkiso STG--2222

Continuous Subcutaneous Continuous Subcutaneous Insulin Delivery (CSII)Insulin Delivery (CSII)

1980s1980s

Latest Pump TechnologyLatest Pump Technology

Implantable Implantable ““Artificial PancreasArtificial Pancreas”” 1990s1990s

Physiologic Insulin Delivery Physiologic Insulin Delivery

PancreasSystemic

Circulation

Portal Vein

Liver

InsulinAmylin

Peritoneal Insulin AbsorptionPeritoneal Insulin AbsorptionAbsorption following 1 u/kg IP injectionAbsorption following 1 u/kg IP injection

Double tracer method in dogsDouble tracer method in dogs

PortalPortal

PeripheralPeripheralPeak AbsorptionPeak Absorption

20 min20 min

28 min28 min

Proportion Absorbed 51%Proportion Absorbed 51%

49%49%

Radziuk et al Am J Physiol 1994; 266:E750Radziuk et al Am J Physiol 1994; 266:E750--E759E759

Implantable Insulin PumpImplantable Insulin Pump

Implantable Insulin Pump & External ControllerImplantable Insulin Pump & External Controller

Implantable Glucose SensorImplantable Glucose Sensor

Implantable Glucose SensorImplantable Glucose Sensor

DS Bindra, Y Zhang, GS Wilson, R Sternberg, DR Thévenot, D Moatti, G Reach,, Anal. Chem.,1991:63: 1692-1696

Implantable Glucose SensorImplantable Glucose Sensor

Implantable Sensor & PumpImplantable Sensor & Pump

Implantable Sensor & PumpImplantable Sensor & PumpSensor Tip

Abdominal Lead Assembly (ALA)

Catheter Tip for Insulin Delivery

Catheter Header with Inlet Port

Sensor Connection to the Pump

Inlet to Pump

2007B

Implanted Closed LoopImplanted Closed Loop

““MoonMoon”” ––

The First Implantable Closed The First Implantable Closed

Loop SystemLoop System

5050100100

150150200200

250250300300

350350

400400

16 Wed16 Wed 17 Thu17 Thu 18 Fri18 Fri 19 Sat19 Sat 20 Sun20 Sun 21 Mon21 Mon 22 Tue22 Tue 23 Wed23 WedAugust 2000August 2000

Gluc

ose (

mg/

dL)

Gluc

ose (

mg/

dL) CLOSED LOOP CONTROLCLOSED LOOP CONTROL

ManualManualControlControl

ManualManualControlControl

Automatic ControlAutomatic ControlBeginsBegins

ControlControlTerminatedTerminated

Closed Loop Glucose Regulation withClosed Loop Glucose Regulation withImplanted Pump & Implanted Glucose SensorImplanted Pump & Implanted Glucose Sensor

Pancreatectomized CaninePancreatectomized Canine

First Human Closed Loop ResultsFirst Human Closed Loop Results

6989D-vivo-4/6(+10%)

70g 70g 40g 15g15g

70g

70g 40g 5g

0

50

100

150

200

250

300

350

10

20

30

40

50

0.0

0.1

0.2

12PMApr 2001

11 Wed 12PM 12 Thu 12PM

Sensor & Reference Glucose, Insulin Assay, Carbs, Pump StrokesSensor # 6989

Glu

cose

(m

g/dL

) Insulin Assay

Insu

lin (

Uni

ts)

Closed Loop Closed Loop -- Patient #3Patient #3

0306090

120150180210240270

0

2

4

12PM

Aug 2001

29 Wed 12PM 30 Thu 12PM

Glucose and Insulin Graph for 7037.....................15076From 8/27/01 To 8/30/01 10:44:00 AM

Glu

cose

(m

g / d

L)

Insu

lin

(U)

Date & Time [Insulin Bin Size = 30 min]

SubcutaneousSubcutaneous Continuous Glucose Monitoring Continuous Glucose Monitoring

(CGM)(CGM) 2000s2000s

Continuous Glucose Monitoring System (CGMS)Continuous Glucose Monitoring System (CGMS)

Guardian Telemetered Glucose Monitoring Guardian Telemetered Glucose Monitoring SystemSystem

50

GlucoWatchGlucoWatch®®

Biographer Biographer

Perspiration Detectors

Battery Compartment

DexCom Seven PlusDexCom Seven Plus Continuous Glucose MonitorContinuous Glucose Monitor

Sensor Delivery Unit

NavigatorNavigator Continuous Glucose MonitorContinuous Glucose Monitor

ReceiverTransmitter

Current Glucose SensorsCurrent Glucose Sensors

External External ““Artificial PancreasArtificial Pancreas”” 2000s2000s

External Closed Loop DeliveryExternal Closed Loop Delivery

External ClosedExternal Closed--Loop Setup for Loop Setup for Canine StudiesCanine Studies

Q W E R T Y U I O P { } |

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1 2 3 4 5 6 7 8 9 0 _ +

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PUMP

(U/h

)PU

MP (U

/h)

manualmanual closedclosed--looploop

6am6am noonnoon 6pm6pm midnightmidnight 6am6am00

22

44

66

88

recalibrationrecalibration

mealmeal mealmeal

Plasma GlucosePlasma GlucoseSensor GlucoseSensor Glucose

GLUC

OSE

(mg/

dl)

GLUC

OSE

(mg/

dl)

00

100100

200200

300300

400400

500500

Closed Loop Glucose Regulation withClosed Loop Glucose Regulation withCSII & Subcutaneous Glucose SensorCSII & Subcutaneous Glucose Sensor

Pancreatectomized CaninePancreatectomized Canine

59

Glucose Control During ClosedGlucose Control During Closed--LoopLoop

6A Noon 6P MidN 6A Noon 6P0

100

200

300 Reference BGSensor Glucosesetpoint

Glu

cose

(mg/

dl)

MeanMean DaytimeDaytime Peak PPPeak PP

All SubjectsAll Subjects 142 142

5353 148 148

5454 207 207

5454

Weinzimer et al. Diabetes Care 31:934 May 2008

6A Noon 6P MidN 6A Noon 6P0

100

200

300Closed Loop (N=8)

mealssetpoint

Hybrid CL (N=9)

Glu

cose

(mg/

dl)

Reference Glucose Levels in Reference Glucose Levels in Closed Loop vs. Hybrid ControlClosed Loop vs. Hybrid Control

MeanMean DaytimeDaytime Peak PPPeak PP

Full CLFull CL 147 147

5858 154 154

6060 219 219

5454HybridHybrid 138 138

4949 143 143

5050 196 196

5252Weinzimer et al. Diabetes Care 31:934 May 2008

•• Testing of the robustness and sensitivity of control algorithmsTesting of the robustness and sensitivity of control algorithms•• Experiments with extreme scenarios that cannot be tested in Experiments with extreme scenarios that cannot be tested in

vivovivo•• Accelerated development of closedAccelerated development of closed--loop controlloop control

In Silico Experiments allow for:In Silico Experiments allow for:

Reaction of three “subjects” to the same meal containing 75g CHO

Insulin pump failure locking the pump at maximum insulin infusion rate

Time (hours) Acknowledgment: B. Kovatchev and C. Cobelli 61

Realistic Virtual Clinical TrialsRealistic Virtual Clinical Trials•• A complete artificial A complete artificial --cell system testing platform, allowing:cell system testing platform, allowing:

–– Systematic analysisSystematic analysis–– Component Verification and ValidationComponent Verification and Validation–– Complete system V&VComplete system V&V–– PnP for PnP for in silicoin silico patientspatients–– PnP for control algorithmsPnP for control algorithms

Dassau  Dassau  et alet al., 2009, "., 2009, "In Silico In Silico Evaluation Platform for Artificial Pancreatic Evaluation Platform for Artificial Pancreatic ‐‐Cell Development Cell Development ––

a Dynamic Simulator for Closeda Dynamic Simulator for Closed‐‐Loop Control with HardwareLoop Control with Hardware‐‐

inin‐‐thethe‐‐Loop." Loop." Diabetes Technol Ther 11(3): 187Diabetes Technol Ther 11(3): 187‐‐194194

• Overnight Control• Full 24 hour Control

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ElEl--Khatib F H et al. Sci Transl Med 2010;2:27ra27Khatib F H et al. Sci Transl Med 2010;2:27ra27--27ra2727ra27

Boston Boston closedclosed--loop BG control loop BG control

Next Step: Automatic Shut Off for Projected Next Step: Automatic Shut Off for Projected HypoglycemiaHypoglycemia

•• All automatic pump suspensions All automatic pump suspensions ≥≥

60 min during prior CL study60 min during prior CL study

•• Plasma and sensor glucose at the Plasma and sensor glucose at the time of suspension time of suspension

•• Nadir plasma and sensor glucose Nadir plasma and sensor glucose for each suspension eventfor each suspension event

Pathway to a ClosedPathway to a Closed--Loop Artificial PancreasLoop Artificial Pancreas

Very Low Glucose Very Low Glucose Insulin Off PumpInsulin Off Pump

Shuts off due to userShuts off due to usernot responding tonot responding tolowlow--glucose alarmglucose alarm

HypoglycemiaHypoglycemiaMinimizerMinimizer

Predictive hypoPredictive hypoalarms alarms →→reductionreduction

or cessation ofor cessation ofinsulin delivery belowinsulin delivery below

LOW THRESHOLDLOW THRESHOLD

11 22Hypo/HyperHypo/Hyper

HyperglcemiaHyperglcemiaMinimizerMinimizer

Same as (2), butSame as (2), butallows insulin dosingallows insulin dosing

above above HIGH THRESHOLDHIGH THRESHOLD(ie above 200mg/dl)(ie above 200mg/dl)

33

Automated Automated Basal / HybridBasal / HybridClosed LoopClosed Loop

Fully closed loopFully closed loopwith mealwith meal--time manual time manual

assist bolusingassist bolusing

44

Fully AutomatedFully AutomatedInsulin Insulin

Closed LoopClosed Loop

55

Fully AutomatedFully AutomatedInsulin +Insulin +

AntiAnti--insulininsulinClosed LoopClosed Loop

66

Issues to Be ResolvedIssues to Be Resolved

causes hyper/hypo peaks

•• Current insulins work too slowly and last too Current insulins work too slowly and last too longlong

•• Amylin Amylin –– the second the second

cell hormone cell hormone ––

is is

missing in people with type 1 diabetesmissing in people with type 1 diabetes•• Glucagon may be needed to obviate Glucagon may be needed to obviate

hypoglycemiahypoglycemia