This document summarizes Francesca Piccinini's presentation on minimal and maximal models of glucose metabolism. It discusses various minimal models used to measure parameters of glucose and insulin dynamics, including the intravenous glucose tolerance test (IVGTT) minimal model, oral glucose tolerance test (OGTT) minimal model, and beta-cell responsivity minimal model. It provides examples of applying these models to compare insulin sensitivity, beta-cell function, and other indices between young and elderly subjects. The document also discusses using tracers to validate the models and segregate glucose disposal from production, as well as applications of the models in pathophysiology.

1. Minimal and Maximal Models of
Glucose Metabolism
Francesca Piccinini
PhD Student
Department of Information Engineering
University of Padova, Italy
Eindhoven, NL, December 12th, 2013

2. The Glucose-Insulin System
BRAIN
PRODUCTION
LIVER
GLUCOSE
-
UTILIZATION
Insulin Sensitivity
β-CELLS
+
SECRETION
β-cell Responsivity
INSULIN
+
DEGRADATION
MUSCLE
TISSUES

3. Minimal Models
 Models to measure parameters
Maximal Models
 Models to perform In Silico Trials

4. The Glucose-Insulin System
BRAIN
PRODUCTION
LIVER
-
GLUCOSE
UTILIZATION
Insulin Sensitivity
β-CELLS
SECRETION
INSULIN
+
DEGRADATION
MUSCLE
TISSUES

5. IVGTT Glucose Minimal Model
(Bergman & Cobelli, 1979)
IVGTT
k5
k1
GLUCOSE
LIVER
TISSUES
k4
SI
k6
REMOTE INSULIN
PLASMA INSULIN
k2
k3
SI: Insulin Sensitivity (liver & periphery)

6. Young vs Elderly Subjects
N = 59 vs 145 (Basu et al, 2006)
IVGTT
[mg/dl]
350
GLUCOSE
250
Elderly
150
Young
50
0
0
60
[pmol/l]
900
120
180
t [min]
240
INSULIN
700
500
300
100
0
t [min]
0
[pmol/l]
2000
60
120
180
240
C-PEPTIDE
1600
1200
800
400
0
t [min]

7. IVGTT Glucose Minimal Model
(Bergman & Cobelli, 1979)
Number of Papers Published / Year
60
50
40
30
20
10
0
1980
1985
1990
Year
1995
2000
2005 2009

8. Young vs Elderly Subjects
N = 59 vs 145 (Basu et al, 2006)
IVGTT
200
GLUCOSE
[mg/dl]
[mg/dl]
350
MEAL
250
Young
50
0
0
60
180
Elderly
Young
80
t [min]
240
0
120
500
900
700
500
300
240
360
420
t [min]
240
360
420
t [min]
INSULIN
INSULIN
[pmol/l]
[pmol/l]
120
160
120
Elderly
150
300
100
100
0
t [min]
2000
60
120
180
3000
C-PEPTIDE
1600
1200
800
2000
1000
400
0
0
240
[pmol/l]
0
[pmol/l]
GLUCOSE
t [min]
120
C-PEPTIDE

9. Oral Glucose Minimal Model
(Dalla Man & Cobelli, 2002)
OGTT/MEAL
Gastrointestinal Tract
k5
k1
GLUCOSE
LIVER
SI
TISSUES
k4
k6
INSULIN
k2
REMOTE
INSULIN
k3
SI: Insulin Sensitivity (liver & periphery)

10. Oral Glucose Minimal Model
(Dalla Man & Cobelli, 2002)
OGTT/MEAL
?
Gastrointestinal Tract
k5
k1
GLUCOSE
LIVER
SI
TISSUES
k4
k6
INSULIN
k2
REMOTE
INSULIN
k3
SI: Insulin Sensitivity (liver & periphery)

11. Oral Glucose Minimal Model
(Dalla Man & Cobelli, 2002)
Glucose Ra
k5
k1
GLUCOSE
LIVER
SI
TISSUES
k4
k6
INSULIN
k2
REMOTE
INSULIN
k3
SI: Insulin Sensitivity (liver & periphery)

12. Fluxes Validation: Triple Tracer Meal
[1-13C] glucose oral
i.v. [6,6D 2] glucose
i.v. [6-3H]glucose
mimicking meal rate of appearance
mimicking endogenous glucose
production
Oral tracer ingested with the meal
Tracer-to-tracee clamp technique
virtually model-independent glucose fluxes
Endogenous Glucose Production
Model
Model
10
Triple Tracer
1.5
1
mg/kg/min
mg/kg/min
2
Rate of Appearance
12
2.5
Triple Tracer
8
6
4
0.5
0
2
0
60
120
180
240
min
300
360
420
0
0
60
120
180
240
min
300
360
420

13. SI Validation
Triple Tracer Method
(Dalla Man et al., 2004)
35
Euglycemic Clamp
(Dalla Man et al., 2005)
R=0.86, p<0.001
20
R=0.81, p<0.001
30
15
OGTT
SI
25
20
15
10
10
5
5
0
0
0
5
10
15
20
SIref
25
30
35
0
10
20
Clamp
30

14. Insulin Sensitivity
[10-4 dl/kg/min per mU/ml]
59 Y vs 145 E (Basu et al, 2006)
* p<0.05
SI
20
*
15
10
5
0
Y
E
E
Y
16
60
14
50
12
10
8
40
30
6
20
4
2
0
10
0

15. The Glucose-Insulin System
BRAIN
PRODUCTION
GLUCOSE
LIVER
UTILIZATION
MUSCLE
β-CELLS
+
SECRETION
β-cell Responsivity
INSULIN
DEGRADATION
TISSUES

16. C-peptide and Insulin System
(Toffolo et al, 2006)
C-PEPTIDE
k2,1
ISR
CP1
LIVER
k1,2
k0,1
ISR
-CELLS
INSULIN
IDR
I
LIVER
n
CP2

17. β-Cell Responsivity Minimal Model
(Toffolo et al, 2001; Breda et al, 2001, 2002)
Glucose
SECRETION
Φs
Delay
k21
Static Phase
Releasable
Insulin
CP1
k12
Dynamic Phase
k01
Φd
Rate of Increase of Glucose (first 50-60
minutes)
Φd: Dynamic βeta-Cell Responsivity
Φs: Static βeta-Cell Responsivity
Φtot: Total βeta-Cell Responsivity
CP2

18. β-Cell Responsivity Validation
(Steil et al, 2004)
(nmol/min per mmol/l)
Φsmeal
Static β-cell Responsivity vs
Hyperglycemic Clamp
ΦsHGC
(pmol/min per mmol/l)

19. β-Cell Responsivity Indices
59 Y vs 145 E
Φs
Φd
40
400
30
20
200
10
0
0
Y
E
14
30
25
12
10
8
6
Y
E
Y
16
[min]
*
600
[10-9 min-1]
[10-9]
800
E
E
Y
25
20
60
50
40
20
15
30
15
10
20
10
4
2
0
5
5
0
0
10
0
* p<0.05

20. FULL
Meal: 420 min – 21 samples
0 5 10 1520 30 40 50 60
75 90
120
150
180
210
240
260
280
300
OGTT: 300 min – 11 samples
0 10
20 30
60
90
120
REDUCED
120 min – 7 Samples
0 10
20 30
60
90
120
150
180
240
300
360
420

21. OGTT
Meal
(N=100)
40
30
8
20
4
10
0
0
0
full
30
40
50
60
8
4
10
0
0
800
0
400
200
200
0
red
0
500
1000
1500
2000
2500
3000
full
full
Φs
40
120
R=0.88,
p<0.0001
50
80
red
60
40
20
500
1000
1500
full
Φs
90
R=0.90, p<0
.0001
70
30
40
30
0
80
100
(10-9 min-1)
60
0
red
60
20
red
full
(10-9 min-1)
800
100
0
50
600
200
500
40
1000
300
1000
30
R=0.91
p<0.0001
1200
red
(10-9 )
red
400
20
1400
400
1500
10
full
500
2000
600
0
red
Φd
600
3000
2500
30
20
full
R=0.98, p<0.0
001
R=0.85, p<0.
0001
40
12
full
1000
(10-9 )
20
red
Φd
1200
10
50
red
12
(10-4 dl/kg/min per mU/ml)
R=0.89, p
<0.0001
50
16
SI
16
60
20
red
(10-4 dl/kg/min per mU/ml)
SI
(N=100)
50
40
30
10
20
20
10
10
0
0
0
full
red
20
40
60
full
80
100
120
0
0
0
20
40
60
80
100

22. The Glucose-Insulin System
BRAIN
PRODUCTION
LIVER
GLUCOSE
-
UTILIZATION
Insulin Sensitivity
β-CELLS
+
SECRETION
β-cell Responsivity
INSULIN
+
DEGRADATION
MUSCLE
TISSUES

23. Efficiency of the Control: Disposition Index
(Bergman & Cobelli, 1981, Cobelli et at, 2007)
Insulin Sensitivity x βeta-Cell Function= Constant
βeta-Cell
Responsivity
Increased
II
Normal
2
I
Normal Tolerance
Impaired Tolerance
Reduced
Normal
Insulin Sensitivity

24. Disposition Index
120
βeta-Cell
Responsivity
60
Y: DI= 459
E: DI=313
0
0
20
40
60
80
Insulin Sensitivity

25. Hepatic Insulin Extraction
(Toffolo et al, 2006)
C-PEPTIDE
k2,1
ISR
CP1
LIVER
k1,2
k0,1
ISR
-CELLS
INSULIN
IDR
I
LIVER
n
CP2

26. Hepatic Extraction
(N=59Y vs 145E)
Index
Profile
T
0
0
 ISR(t)dt – IDR(t)dt
ISR(t) - IDR(t)
HE(t) =
T
HE =
T
 ISR(t)dt
ISR(t)
0
1.00
1.00
ELDERLY
0.80
* p<0.05
0.80
(%)
(%)
0.60
0.40
0.60
*
0.40
0.20
YOUNG
0.20
0.00
0
60
120
180
240
t [min]
300
360
420
0.00
E
Y

27. What Happens If You Add A Tracer?
Tracers Allow Segregation of Glucose Disposal
from Production

28. Oral Glucose Minimal Model
(Dalla Man & Cobelli, 2002)
OGTT/MEAL
Gastrointestinal Tract
k5
k1
GLUCOSE
LIVER
SI
TISSUES
k4
k6
INSULIN
k2
REMOTE
INSULIN
k3
SI: Insulin Sensitivity (liver & periphery)

29. Labelled Meal/OGTT
80
Glucose
8
Insulin
[mU ml-1]
60
6
4
40
20
3
0
0
60
120
180
240
300
360
0
420
0
60
120
Time [min]
0.6
0.4
0.2
0
0
180
240
Time [min]
Stable Tracer Glucose
0.8
[mmol L-1]
[mmol L-1]
10
60
120
180
240
300
Time [min]
360
420
300
360
420

30. Disposal Insulin Sensitivity
“COLD” MINIMAL MODEL
Production
Liver
“HOT” MINIMAL MODEL
Utilization
Utilization
Glucose
SI
Insulin
Remote
Insulin
SI: Insulin Sensitivity
(Utilization + Production)
Glucose
SID
Tissues
Insulin
Remote
Insulin
SID: Disposal Insulin Sensitivity
(Utilization Only)
Tissues

31. SID
10-4 dl/kg/min per mU/ml
Meal: 59 Y vs 145 E
* p<0.01
20
*
15
10
5
0
Y
E

32. Hepatic Insulin Sensitivity
“COLD” MINIMAL MODEL
Liver
Production
“HOT” MINIMAL MODEL
Utilization
Utilization
Glucose
SI
Insulin
Remote
Insulin
From SI and SID
Glucose
SID
Tissues
Insulin
Remote
Insulin
SIL = SI – SID
Tissues

33. 20
Y
10-4 dl/kg/min per mU/ml
10-4 dl/kg/min per mU/ml
SI
15
*
10
5
10-4 dl/kg/min per mU/ml
Meal: 59 Y vs 145 E
8
Y
20
0
E
SIL
6
4
2
0
E
SI D
Y
* p<0.01
15
*
10
5
0
E

34. Use in Pathophysiology
1) Role of age and gender (Basu et al, Diabetes 2006)
2) Pathogenesis of Prediabetes (Bock et al, Diabetes 2006)
3) Type 2 Diabetes (Dr. A. Basu, Mayo Clinic Rochester, MN)
4) Role of Race (Petersen et al, Proceedings of the National Academy of Science 2006)
5) Efficiency of Anti-aging Drugs (Nair et al, New England Journal of Medicine 2006)
6) Effect of DPP-4 Inhibitors (Dalla Man et al, Diabetes Care 2009)
7) Children and Adolescent (Calì et al, Diabetes Care 2009)
8) Diurnal Variation of Glucose Tolerance
Chicago, Chicago, IL)
(Dr. E. Van Cauter,
University of

35. Role of age and gender
(Basu et al, 2006)
Subjects and Protocols
38 Elderly Men (EM), 29 Elderly Women (EW), 10 Young Men (YM), 11 Young Women (YW) underwent a
labelled mixed meal.
Elderly vs Young
SI
16
10-4 dl/kg/min per μU/ml
10-4 dl/kg/min per μU/ml
* p<0.05
SI
20
Men vs Women
16
*
12
8
12
8
4
4
0
0
Elderly
Young
Men
Women

36. Use in Pathophysiology
1) Role of age and gender (Basu et al, Diabetes 2006)
2) Pathogenesis of Prediabetes (Bock et al, Diabetes 2006)
3) Type 2 Diabetes (Dr. A. Basu, Mayo Clinic Rochester, MN)
4) Role of Race (Petersen et al, Proceedings of the National Academy of Science 2006)
5) Efficiency of Anti-aging Drugs (Nair et al, New England Journal of Medicine 2006)
6) Effect of DPP-4 Inhibitors (Dalla Man et al, Diabetes Care 2009)
7) Children and Adolescent (Calì et al, Diabetes Care 2009)
8) Diurnal Variation of Glucose Tolerance
Chicago, Chicago, IL)
(Dr. E. Van Cauter,
University of

37. OGTT in IFG vs NFG
N=32 vs 28
(Bock et al, 2006)
Plasma Glucose
Plasma Insulin
750
15
IFG
NFG
pmol//l
9
6
IFG
NFG
500
250
3
0
0
-60
0
60
120
180
240
300
360
-60
0
60
120
minutes
5
IFG
NFG
4
3
2
1
0
-60
180
minutes
Plasma C-peptide
nmol/l
mmol/l
12
0
60
120 180
minutes
240
300
360
240
300
360

38. 10-14 dl/kg/min -2 per pmol/L
10-14 dl/kg/min per pmol/L
10-14 dl/kg/min -2 per pmol/L
Disposition Indices
1200
DI
800
*
*
400
0
16000
NFG
NGT
IFG
IFG NGT
NFG IGT
*
IFG IGT
*
IFG
DM
DId
12000
*
*
8000
4000
0
1200
NFG
NGT
IFG
IFG NGT
NFG IGT
*
IFG IGT
*
IFG
DM
DIs
800
*
*
*
NFG IGT
IFG IGT
400
0
NFG
NGT
IFG
IFG NGT
*
IFG
DM

39. Use in Pathophysiology
1) Role of age and gender (Basu et al, Diabetes 2006)
2) Pathogenesis of Prediabetes (Bock et al, Diabetes 2006)
3) Type 2 Diabetes (Dr. A. Basu, Mayo Clinic Rochester, MN)
4) Role of Race (Petersen et al, Proceedings of the National Academy of Science 2006)
5) Efficiency of Anti-aging Drugs (Nair et al, New England Journal of Medicine 2006)
6) Effect of DPP-4 Inhibitors (Dalla Man et al, Diabetes Care 2009)
7) Children and Adolescent (Calì et al, Diabetes Care 2009)
8) Diurnal Variation of Glucose Tolerance
Chicago, Chicago, IL)
(Dr. E. Van Cauter,
University of

40. Type 2 Diabetes
(Basu A. et al 2009)
Φd
10-9
600
400
Φs
60
10-9 min-1
800
*
50
40
*
30
20
200
10
0
0
Diabetic Normal
Diabetic Normal
SI
DI
25
20
15
*
10
5
10-14 dl/kg/min2 per pmol/l
10-5 dl/kg/min per pmol/l
30
1600
1200
*
800
400
*
0
0
Diabetic Normal
Diabetic Normal

41. Use in Pathophysiology
1) Role of age and gender (Basu et al, Diabetes 2006)
2) Pathogenesis of Prediabetes (Bock et al, Diabetes 2006)
3) Type 2 Diabetes (Dr. A. Basu, Mayo Clinic Rochester, MN)
4) Role of Race (Petersen et al, Proceedings of the National Academy of Science 2006)
5) Efficiency of Anti-aging Drugs (Nair et al, New England Journal of Medicine 2006)
6) Effect of DPP-4 Inhibitors (Dalla Man et al, Diabetes Care 2009)
7) Children and Adolescent (Calì et al, Diabetes Care 2009)
8) Diurnal Variation of Glucose Tolerance
Chicago, Chicago, IL)
(Dr. E. Van Cauter,
University of

42. Efficiency of Anti aging Drug
- 87 elderly men e 57 elderly women underwent a mixed meal test
- After a 2 yr DHEA or Testosterone same test
SI
Men
Women
20
Placebo
DHEA
Placebo
DHEA
Testosterone
10^-4 dl/kg/min per uU/ml
15
10
5
0
Pre
Post
Pre
Post
Pre
Post
Pre
Post
Pre
Post

43. Use in Pathophysiology
1) Role of age and gender (Basu et al, Diabetes 2006)
2) Pathogenesis of Prediabetes (Bock et al, Diabetes 2006)
3) Type 2 Diabetes (Dr. A. Basu, Mayo Clinic Rochester, MN)
4) Role of Race (Petersen et al, Proceedings of the National Academy of Science 2006)
5) Efficiency of Anti-aging Drugs (Nair et al, New England Journal of Medicine 2006)
6) Effect of DPP-4 Inhibitors (Dalla Man et al, Diabetes Care 2009)
7) Children and Adolescent (Calì et al, Diabetes Care 2009)
8) Diurnal Variation of Glucose Tolerance
Chicago, IL)
(Dr. E. Van Cauter, University of Chicago,

44. Children and Adolescents
NGT_NFG
NGT_IFG
IGT_NFG
(Calì et al, Diabetes Care 2009)
INSULIN
GLUCOSE
450
160
400
140
350
120
300
100
C-PEPTIDE
250
7000
6000
5000
pmol/l
uU/ml
180
200
80
60
150
40
100
20
50
0
60
90
120
150
180
1000
0
0
30
min
5
4
3
3000
NGT_IFG
* * *
^
IGT_NFG
IGT_IFG
120
150
* *
^
2500
2000
10-9
6
90
180
0
30
60
1500
0
Φs
90
*
75
45
30
500
15
* p<0.05 vs NGT-NFG; ^ p<0.05 vs NGT-IFG; # p<0.05 vs IGT-NFG
*
#
60
1000
0
120
min
2
1
90
Φd
NGT_NFG
7
60
min
SI
8
3000
10-9 min-1
30
4000
2000
0
0
10-4 dl/kg/min per uU/ml
mg/dl
IGT_IFG
0
150
180

45. Minimal Models
 Parameters measurement
Maximal Models
 In Silico Trials

46. Background

Models to Simulate:
often not possible, appropriate, convenient or desirable to
perform experiments in humans, e.g. testing of glucose
sensors and insulin infusion algorithms for closed loop control
during normal life condition

Can Models to Measure be used as Models to Simulate for in
Silico Trial?
No
Models to Measure need to be minimal (parsimonious)
Models to Simulate need to be maximal (large scale)

47. 47

48. New Generation of Simulation Models
Fluxes, in addition to concentrations, available
(N=204 Normals)
Glucose
Production
Insulin
2.5
600
250
(pmol/l)
(mg/dl)
(mg/kg/min)
500
Data
Range
200
400
300
150
200
100
100
50
0
60
180
240
300
360
420
Rate of Appearance
14
12
10
8
6
4
60
120
180
240
300
360
0
60
120
180
240
t (min)
300
360
420
Utilization
1
0.5
0
60
120
8
6
4
180
240
300
360
420
300
360
420
Secretion
16
10
0
1.5
0
420
2
2
0
0
12
(mg/kg/min)
(mg/kg/min)
120
(pmol/kg/min)
0
2
14
12
10
8
6
4
2
0
0
60
120
180
240
t (min)
300
360
420
0
60
120
180
240
t (min)

49. Healthy State Meal Simulator
(Dalla Man et al, 2007)
Meal
GASTRO-INTESTINAL
TRACT
12
Rate of
Appearance
Plasma Glucose
180
10
8
6
4
2
0
0
60
120
180
240
300
360
420
160
140
120
100
80
60
0
60
120
180
240
300
360
420
Renal Excretion
MUSCLE
AND ADIPOSE
TISSUE
GLUCOSE
SYSTEM
LIVER
Production
Utilization
2
10
8
1.5
6
1
4
2
0.5
0
0
0
0
60
120
180
240
300
360
60
120
180
240
300
360
420
420
INSULIN
SYSTEM
BETA-CELL
Secretion
Plasma Insulin
700
600
500
400
300
200
500
400
100
300
0
200
0
100
0
0
60
120
180
240
300
360
420
60
120
180
240
300
360
420

50. Identification: System Decomposition
& Forcing Function Strategy
Plasma
Glucose
GASTRO-INTESTINAL Glucose Rate of
Meal
Appearance
TRACT
Plasma
Insulin
Plasma Insulin
Glucose
Production
Glucose Rate of
Appearance
MUSCLE AND
ADIPOSE TISSUE
LIVER
Plasma Glucose Rate of
Glucose
Change
Glucose
Utilization
Plasma
Glucose
Glucose
Production
Plasma
Insulin
BETA CELL
Insulin
Secretion

51. Muscle and Adipose Tissue Model
Plasma Insulin (I)
Glucose Production
(EGP)
MUSCLE AND
ADIPOSE TISSUE
Glucose Rate of
Appearance (Ra)
Plasma
Glucose (G)
Glucose
Utilization (U)
Model
I
p2U
Insulin
Action
X
p2U
Vm(X2)
G
EGP
Ra
Vm(X3)
U(t)
Vm(X1)
k21
Plasma
Gp
k12
Tissues
Gt
Km(X3) Km(X2)
Kg
Ki
U
Km(X1)
Gt(t)
X1<X2<X3

52. Results
Utilization
Glucose
180
data
fit
8
7
data
fit
160
G (mg/dl)
U (mg/kg/min)
9
6
5
4
3
2
140
120
100
80
1
60
0
0
60
120
180
t (min)
240
300
360
420
0
60
120
180
240
300
360
420
t (min)
52

53. 24 h Simulation: average model
Glucose
Insulin
(mg/kg/min)
(mg/dl)
(pmol/l)
160
1.2
200
140
120
100
100
Production
1.8
300
180
0.6
80
0
60
3
6
9
12
15
18
21
0
6
24
9
12
15
18
21
24
6
9
12
15
18
21
24
0
Rate of Appearance
Utilization
10
8
6
4
6
4
2
9
12
15
18
21
6
9
12
15
18
t (hours)
t (hours)
45 g 70 g
24
70 g
6
4
0
0
6
8
2
2
0
Secretion
10
(pmol/kg/min)
8
(mg/kg/min)
(mg/kg/min)
12
21
24
6
0
9
12
15
t (hours)
18
21
24

54. Inter-Subject Variability
Rate Constant of Liver
Insulin Action
Liver
Insulin Sensitivity
Liver
Glucose Effectiveness
100
100
100
80
80
80
60
60
60
40
40
40
20
20
20
0
0
0
min^-1
mg/kg/min/(pmol/l)
min^-1
Rate Constant of Peripheral
Insulin Action
Peripheral
Insulin Sensitivity
Peripheral
Glucose Effectiveness
100
100
100
80
80
80
60
60
60
40
40
40
20
20
20
0
0
0
mg/kg
mg/kg/min per pmol/L
min^-1

55. Generation of virtual subjects

56. Generation of In Silico Normal Subjects
#1
#2
Glucose
Glucose
#3
Glucose
180
180
150
150
150
120
90
120
90
60
60
20
25
30
35
30
40
120
90
60
20
25
30
35
30
40
20
25
t (hours)
t (hours)
30
35
40
35
40
t (hours)
# 100
Glucose
200
180
.....
150
(mg/dl)
30
(mg/dl)
200
(mg/dl)
200
180
(mg/dl)
200
120
90
60
30
20
25
30
t (hours)

57. Healthy State Simulator
12 Differential Equations, 26 Parameters
Pre-diabetes Simulator
12 Differential Equations, 26 Parameters
Type 2 Simulator
12 Differential Equations, 26 Parameters
Type 1 Simulator
13 Differential Equations, 26 Parameters

58. What is an Artificial Pancreas?

59. Traditional vs. Accelerated Development
Concept
Concept
Animal Trials
In Silico Trials
Clinical Trials
Clinical Trials
Product
Product
Saves
Years

60. Model of Type 1 Diabetes
Meal
Insulin
Pump
GASTRO-INTESTINAL
TRACT
SC
Insulin
Kinetics
Rate of
Appearance
Renal Excretion
LIVER
Production
• Tested against, and showing
excellent agreement with:
Common clinical knowledge
Lab traces of induced
hypoglycemia
Field data of children with
T1DM
BETA-CELL
Secretio
n
PLASMA
GLUCOSE
PLASMA
INSULIN
Utilization
Degradation
MUSCLE
& ADIPOSE
TISSUE

61. Artificial Pancreas In Silico Trial
Meal
GASTRO-INTESTINAL
TRACT
Plasma Glucose
Subcutaneous
Subcutaneous
Insulin
Subcutaneous
Insulin
Subcutaneous
Infusion
Insulin
Subcutaneous
Infusion
Insulin
Pump Insulin
Infusion
Pump A
Infusion
Pump B
Infusion
Pump C
Pump D
Rate of
Appearance
180
160
140
120
100
80
60
0 60 120 180 240 300 360 420
LIVER
2
1.5
1
0.5
0
0
Production
PLASMA
GLUCOSE
60 120180 240 300360420
BETA-CELL
Secretion
700
600
500
400
300
200
100
0
0
12
10
8
6
4
2
0
0
PLASMA
INSULIN
60 120 180 240 300 360 420
Renal Excretion
Utilization
10
8
6
4
2
00
MUSCLE
AND ADIPOSE
TISSUE
60 120180 240 300360 420
Degradation
Plasma Insulin
500
60 120 180 240 300 360 420
400
300
200
100
0
Controller A
Controller
Controller B
Controller C
Controller D
0
60 120180 240 300 360 420
Sensor
Sensor I II
Sensor III
Sensor IV
Sensor
61

62. Blood Glucose (mg/dl)
In Silico Selection of Control Strategy:
Proportionl-Integral-Derivative vs Model Predictive Control
0
12
24
36
48
60
Time (hours)
Health
T1DM + PID controller
T1DM + Model Predictive Control
72

63. Traditional vs. Accelerated Development
Concept
Animal Trials
Concept
In Silico Trials
Clinical Trials
Clinical Trials
Product
Product
January 18, 2008:
Simulation accepted by FDA
as substitute to animal trials
(Master file #1521)
Regulatory Approval for clinical trials
based entirely on in silico testing:
April 17, 2008 (UVA IDE);
May 20, 2008 (Padova EC)

64. Conclusions
• Importance of System Models in Diabetes
• Minimal Models:
• Powerful Tools to Measure
Pathophysiology of Diabetes
&
Understand
the
• Maximal Models:
• Importance of prediabetes, type 2 and type 1 diabetes
simulators for in silico trials