Role of Models to

1
Role of Models to Measure Insulin
Action Chiara Dalla Man, PhD Department of
Information Engineering University of
Padova Padova, Italy MBI Endocrine Workshop,
23rd May 2007 Columbus, OH.
2
Background
Glucose Regulatory System
Glucose-insulin regulatory system guarantees that
plasma glucose remains almost constant in spite
of possible external perturbations
Impairment of the glucose regulatory system
causes several metabolic derangements, e.g.
diabetes.
3
Insulin Sensitivity
A widely used index to quantify the efficiency of
insulin control on plasma glucose is insulin
sensitivity (SI). It measures the overall action
of insulin on endogenous glucose production and
glucose utilization.
BRAIN
PRODUCTION
GLUCOSE
LIVER
-
UTILIZATION
MUSCLE

SI
TISSUES
ß-CELLS
INSULIN
SECRETION
DEGRADATION
LIVER
4
Protocols, Attributes and Information Content
Can Assess Insulin Sensitivity?
Is it Simple?
Is it
Physiological?
BASAL STATE
Yes
Yes
Yes, but limited
INTRAVENOUS PERTURBATION
Euglycemic Clamp
No
No
Yes
IVGTT
No
No
Yes, but limited without a model
ORAL PERTURBATION
Yes, but requires a model
Yes, but no
Yes
OGTT
nutrients
Yes, but requires a model
Yes
Meal
Yes
5
Euglycemic-Hyperinsulinemic Clamp
GLUCOSE ANALYZER
COMPUTER ALGORITHM
6
IVGTT Young vs Elderly SubjectsN 59 vs 145
(Dr. Rizza Basu, Mayo Clinic)
GLUCOSE
350
250
mg/dl
Elderly
150
Young
50
t min
0
0
60
120
180
240
INSULIN
900
700
pmol/l
500
300
100
t min
0
0
60
120
180
240
2000
C-PEPTIDE
1600
pmol/l
1200
800
400
t min
0
0
60
120
180
240
7
INSULIN SYSTEM
PLASMA INSULIN
PLASMA GLUCOSE
GLUCOSE SYSTEM
8
IVGTT Glucose Minimal Model (Bergman Cobelli,
1979)
Model Assumptions
NHGB
IVGTT
k5
Rdp
1)
GLUCOSE G
LIVER
TISSUES
k1
2)
k4
k6
NHGB
REMOTE INSULIN I
I1gt I2
NHGB0
PLASMA INSULIN I
P
k3
k2
I2
Q
RdL -
I1
Model Equations
3)
Rdp
I1gt I2
I1
I2
Rd0
Q
9
Reparametrization
with
Insulin Action time course
Model Indices
Glucose Effectiveness (liver periphery)
Insulin Sensitivity (liver periphery)
Parameter Estimation
Parameters SG, SI, V and p2 are estimated in each
subject with Nonlinear Least Squares
10
Number
of
Papers
Published
/
Year
Total
Number
Published
60
600
50
500
40
400
30
300
20
200
10
100
0
0
1980
1985
1990
1995
1985
1990
1995
2006
2006
2000
1980
2000
Year
Year
11
Insulin Sensitivity 59 Y vs 145 E
plt0.05
12
SI Validation with Clamp
13
I.V. vs Oral Route

• Euglycemic - hyperinsulinemic clamp
• IVGTT interpreted with the Minimal Model of
  Glucose Kinetics

Both tests are invasive and not physiological ?
not usable in large scale epidemiological and
clinical trials
14
Meal Young vs Elderly SubjectsN 59 vs 145
(Dr. Rizza Basu, Mayo Clinic)
GLUCOSE
200
mg/dl
Elderly
160
Young
120
t min
80
0
120
240
360
420
INSULIN
500
pmol/l
300
100
t min
0
120
240
360
420
C-PEPTIDE
3000
2000
pmol/l
1000
t min
0
120
240
360
420
15
Model
Oral Glucose Minimal Model (OMM)
Model Equations
Model of Ra
PLASMA
GLUCOSE
gastrointestinal tract
Ra
G(t)
GLUCOSE
PERIPHERY
LIVER
G
Model of glucose Kinetics
PLASMA
REMOTE
INSULIN
INSULIN
(I
)
I
Parameters SI, SG, V, p2, ai (i18)
Profiles X(t), Ra(t)
(Dalla Man C., Caumo A., Cobelli C., IEEE TBME
2002)
16
Insulin Sensitivity 59 Y vs 145 E
plt0.05
SI
20

15
10-4 dl/kg/min per mU/ml
10
5
0
E
Y
17
Validation
1) Validation against model-independent method
(Dr. Robert Rizza, Mayo Clinic, Rochester, MN,
USA)
Subjects
88 normal subjects (age 58 ? 2 years BMI 27 ?
0.1 kg/m2).
Protocol
triple tracer mixed meal, which allows model
independent estimate of Ra
Model Independent Raref
12
8
4
0
0
60
120
180
240
300
360
420
Reference Model (RM)
SIref
(Dalla Man C., Caumo A., Basu R., Rizza R.,
Toffolo G., Cobelli C. Am. J. Physiol 2004 Dalla
Man C., Caumo A., Basu R., Rizza R., Toffolo G.,
Cobelli C. Am. J. Physiol 2005)
18
Results
SI
(Dalla Man C., Caumo A., Basu R., Rizza R.,
Toffolo G., Cobelli C., Am. J. Physiol
2004 Dalla Man C., Caumo A., Basu R., Rizza R.,
Toffolo G., Cobelli C., Am. J. Physiol 2005)
19
2) Validation against euglycemic-hyperinsulinemic
clamp (Dr. Kenneth Polonsky, Washington
University, St. Louis, Mo, USA).
Subjects
10 NGT, 11 IGT (age 41 ? 1 years BMI 30 ?1
kg/m2)

• Labelled OGTT 75 g of glucose labelled with
  U13C6-glucose.
• Labelled Euglycemic-hyperinsulinemic clamp

Protocols
Results
SI
(Dalla Man C., Yarasheski K., Toffolo G., Caumo
A, Polonsky K.S., Cobelli C. Am. J. Physiol ,
2005 )
20
Insulin Sensitivity from Reduced Oral Protocols
21
OGTT (N100)
Insulin
Glucose
(uU/ml)
(mg/dl)
t (min)
t (min)
C-peptide
(pmol/l)
t (min)
22
FULL
OGTT 300 min 11 samples
23
OGTT
(N100)
SI
60
20
R0.89, plt0.0001
50
16
40
red
12
30
(10-4 dl/kg/min per mU/ml)
8
20
4
10
0
0
0
10
20
30
40
50
60
full
red
(Dalla Man C., Campioni M., Polonsky K.S., Basu
R., Rizza R.A., Toffolo G. and Cobelli C.
Diabetes, 2005 )
24
Tracers Allow Segregation of Glucose Disposal
from Production
25
Disposal Insulin Sensitivity Rationale
COLD MINIMAL MODEL
production
utilization
Glucose
SI
Liver and Peripheral Tissues
Remote Insulin
Insulin
SI Insulin Sensitivity (Utilization Production)
26
MEAL
80
Glucose
10
Insulin
8
60
mmol L-1
6
40
mU ml-1
4
20
3
0
0
0
60
120
180
240
300
360
420
0
60
120
180
240
300
360
420
Time min
Time min
Stable Tracer Glucose
0.8
0.6
mmol L-1
0.4
0.2
0
0
60
120
180
240
300
360
420
Time min
27
SID
Meal 59 Y vs 145 E
plt0.01
20

15
10-4 dl/kg/min per mU/ml
10
5
0
Y E
28
Hepatic Insulin Sensitivity Rationale
COLD MINIMAL MODEL
TRACER MINIMAL MODEL
production
utilization
utilization
Glucose
Glucose
SI
SID
Liver and Peripheral Tissues
Liver and Peripheral Tissues
Remote Insulin
Remote Insulin
Insulin
Insulin
From SI and SID
SIL SI SID
29
Meal 59 Y vs 145 E
SID
SI
plt0.01
20
20


15
15
10-4 dl/kg/min per mU/ml
10-4 dl/kg/min per mU/ml
10
10
5
5
0
0
Y E
Y E
SIL
8
6
10-4 dl/kg/min per mU/ml
4
2
0
Y E
30
SI Dissection
20 Normals
20.00
15.00
SIL
33
10-4 dl/kg/min per mU/ml
10.00
SI
SID
5.00
0.00
31
Disposal vs Liver Insulin Action
20 Normals
XL
1.6
0.04
XD
1.2
0.03
XD (min-1)
XL (mg/kg/min)
0.8
0.02
0.4
0.01
0
0
0
60
120
180
240
300
360
420
t (min)
32
Recently completed studies

• Age and Gender (Basu et al, Diabetes, 2006)
• Effect of DHEA (Nair et al, NEJM, 2006)
• Prediabetes (Bock et al, Diabetes, 2006)
• Ethnicity (Petersen et al, PNAS, 2006)
• Effect of nutrients (Bock et al, Diabetes,
  2007)

33
Conclusions

• Models allow to measure from a single test,
  either IVGTT or the more physiological OGTT
  meal, insulin action
• Addition of a tracer provides further insight by
  dissecting insulin action into its peripheral and
  hepatic components

34
Thanks
ROBERT RIZZA Rita Basu Ananda Basu Gerlies
Bock (Rochester, MN) KENNETH POLONSKY Kevin
Yarashesky (St. Louis, MO)
CLAUDIO COBELLI Gianna Toffolo Marco
Campioni (Padua, Italy) Andrea Caumo (Milan,
Italy)
35
Other Slides
36
Surrogate Indices
(Matthews et al, Diabetologia, 1985)
(Katz et al, JCEM, 2000)
(Matsuda DeFronzo, Diabetes Care, 1999)
(Soonthorpun, JCEM, 2003)
37
IVGTT vs Meal Insulin Sensitivity N204

20
plt0.05
15
10
5
0
Meal
IVGTT
38
SID Validation with Tracer Clamp
10 NGT 11 IGT
25
r0.83, plt0.0001
12
20
15
8
10-4 dl/kg/min per mU/ml
OGTT
10
4
5
0
0
0
5
10
15
20
25
OGTT
CLAMP
CLAMP
39
1) Role of age and gender (Dr. Robert
Rizza, Mayo Clinic, Rochester, MN, USA)
Subjects and Protocols
38 Elderly Men (EM), 29 Elderly Women (EW), 10
Young Men (YM), 11 Young Women (YW) underwent a
labelled mixed meal.
(Basu R, Breda E, Oberg AL, Powell CC, Dalla Man
C, Basu A, Vittone JL, Klee GG, Arora P, Jensen
MD, Toffolo G, Cobelli C, Rizza RA, Diabetes
2003 Basu R., Dalla Man C., Campioni M., Basu
A., Klee G., Toffolo G., Cobelli C. Rizza R.A,
Diabetes, 2006)
40
2) Pathogenesis of Prediabetes (Dr. Robert
Rizza, Mayo Clinic, Rochester, MN, USA)
Subjects and Protocols
32 Impaired Fasting Glucose (IFG) and 28 Normal
Fasting glucose (NFG) with different levels of
glucose tolerance underwent a labelled mixed meal.
Results
SI
(Bock G., Dalla Man C., Campioni M.,
Chittilapilly E. Basu R., Toffolo G, Cobelli C.,
Rizza R. A, Diabetes 2006)
41
3) Role of Race (Dr. Shulman, Yale
University, New Heaven, CT, USA)
Subjects and Protocols
49 Eastern Asians, 59 Asian Indians, 48 Blacks,
292 Caucasians, e 34 Hispanics underwent an OGTT
(Petersen K. f., Dufour S., Feng J., Befroy D.,
Dzuira J., Dalla Man C., Cobelli C., Shulman G.
PNAS 2006 )
42
4) Efficiency of Anti-aging Drug (Dr. Nair
Dr Rizza, Mayo Clinic, Rochester, MN, USA)
Subjects and Protocols
87 elderly men e 57 elderly women underwent a
mixed meal test. After a two years treatment with
DHEA or Testosterone they underwent the same test
(Nair K.S., Rizza R.A, OBrein P., Short K.R.,
Nehra A, Vittone J.L., Klee G.G, Basu A., Basu
R., Cobelli C., Toffolo G., Dalla Man C., Tindall
D.J., Melton L.J., Smith G.E., Khosla S., Jensen
M.D. New England Journal of Medicine, 2006 )
43
5) OGTT vs Meal (Dr. Robert Rizza, Mayo
Clinic, Rochester, MN, USA)
Subjects and Protocols
32 Impaired Fasting Glucose (IFG) and 28 Normal
Fasting glucose (NFG) with different levels of
glucose tolerance underwent a both a 75 g OGTT
and mixed meal.
Results
SI
plt0.05
(Bock G., Dalla Man C., Campioni M.,
Chittilapilly E. Basu R., Toffolo G, Cobelli C.,
Rizza R. A, Diabetes 2007)