≥ 65% -cell defect
Defective -cellsNormal -cells
Insulin ResistanceInsulin Resistance
Genetic Predisposition Environmental Factors
Obesity
TYPE 2 DIABETES
Hyperinsulinemia withNormal Glucose Tolerance
Impaired Glucose Tolerance
Figure A1.
Glucose injection
Insulin injection
Minimal Model
Insulin sensitivity (SI)
Β-cell response
Glucose levels
Insulin levels
Figure A2.
0
2
4
6S
I
0
2000
4000
AIR
G(0
-19)
basal 1-2 3-4 5-6 7-8 9-10 11-12
Weeks on Fat
0.00
0.25
0.50
0.75
1.00
Insu
lin C
lea
ran
ce
I II III IV
I: Basal
II: Uncompensated Resistance
III: -cell Compensation
IV: Reduced Insulin Clearance
Figure A3.
0 1 2 3 4 5 6 7 80
500
1000
1500
2000
2500
Week 2Week 4Week 6
Week 0
Insulin Sensitivity
Se
cre
tio
n
Figure A4.
Insulin Resistance
Increased fasting glycemia
and/or impaired glucose tolerance
Cause of Hyperinsulinemia?
Conventional wisdom:
Hyperinsulinemia(Increased secretion,Reduced clearance)
Figure A4Figure A5
Figure A5.
**
* * * ** * *
* * *
*
pM
Insulin
6 WKS FAT FEEDINGBASELINE
Glucose
mg
/dL
Cortisol
GLP-1
FFA
mM
pM
GH
ng
/mL
μg
/mL
0
100
200
300
** *
**
*
6am 9 12pm 3 6pm 9 12am 3 6am0.0
0.2
0.4
0.6
0.8
1.0
*
75
100
125
*
0.0
3.0
6.0
9.0
0.0
2.0
4.0
6am 9 12pm 3 6pm 9 12am 3 6am0.0
2.0
4.0
6.0
8.0
**
Figure A6.
PlasmaLymph
Insulin Levels
Rd
Glucose disposal
INSULIN IN PLASMA AND INTERSTITIAL FLUID
Hand-in-glove relationship between
interstitial insulin and glucose disposal
Glu
cose
Up
take
0
2
4
6
10
0 60 240 360Time (minutes)
120 180 300
8
Lym
ph
In
suli
n (
uU
/ml)
0
10
20
30
50
40
Figure A7.
GL
UC
OS
E D
ISP
OS
AL
[mg
/kg
per
min
]
Insulin injection
Plasma
Interstitial fluid
Glucose uptake
into cells
INS
UL
IN[μ
U/m
l]IN
SU
LIN
[μU
/ml]
Figure A8.
0
4
8
12
16UPTAKE
0 30 60 90 120 150 180
INSULIN
3.33 mU/min per kg
Glu
cose
Flu
x (m
g/m
in p
er
kg)
Time (minutes)
0 30 60 90 120 150 180
-1
0
1
2
3
4
Glu
cose
Flu
x (m
g/m
in p
er
kg)
Time (minutes)
LIVER OUTPUT
INSULIN
3.33 mU/min per kg
HGONHGORd
Figure A9.
Figure A10.
GLUCOSE PRODUCTION
FFA
Transendothelial transport barrier
adipocytes
Insulin
Figure A11.
*
Week 0 Week 6
Do
g 1
Do
g 2
Do
g 3
Do
g 4
Weeks on diet
Bo
dy
Wei
gh
t (k
g)
+110%
+115%Omental
SubQ
Bo
dy
Fat
(cm
3 )
-2 0 2 4 620
25
30
35
**
* * * *
Week 0 Week 60
250
500
750
1000 *
Figure A12.
Resistant LiverVisceral Fat
FFAPEPCK
G6Pase
SREBP1
FABP
TNF-IL-6
Leptin
Adiponectin
PPARSREBP-1
HSLLPL
Figure A13.
β3-blockade
Fre
e F
atty
Aci
ds
0.1
0.2
0.3
0.4
0.1
0.2
0.3
0.4
0.1
0.2
0.3
0.4
-0.05
-0.02
0.01
0.04
0.07
0.10
-0.05
-0.02
0.01
0.04
0.07
0.10
-0.08
-0.03
0.02
0.06
0.11
0.16
-0.05
-0.02
0.01
0.04
0.07
0.10
0 10 20 30 40 50 60-0.05
-0.02
0.01
0.04
0.07
0.10
0 10 20 30 40 50 60-0.08
-0.03
0.02
0.06
0.11
0.16
11 pulses
DOG 2
DOG 3
DOG 4 DOG 10
DOG 7
DOG 5
TIME (min) TIME (min)
9 pulses
8 pulses
9 pulses10 pulses
10 pulses
Figure A14.
“Constitutive Lipolysis”GHTSH, PTHANPGlucocorticoids“intrinsic”
“Pulsatile Lipolysis”
Figure A15.
Top Related