The Regulation of Liver Glucose
Production and Uptake
Vanderbilt University Medical Center
Nashville, TN USA
Dale Edgerton, PhD
An Organ Systems Approach to Experimental Targeting of the Metabolic Syndrome
July 21, 2011
DAILY GLUCOSE PROFILE
“Ordinary Daily Life”
Diabetes Technol Ther. 2009 Jul;11(7):457-60.
OGTT
DAILY GLUCOSE PROFILE
Int J Obes Relat Metab Disord. 2002 Sep;26 Suppl 3:S9-17.
MEASUREMENT OF GLUCOSE PRODUCTION IN VIVO
Tracer Method
3-3H Glucose infusion
Data analysis with two compartment model
A-V Difference Method
Blood glucose difference across organ
Blood flow across organ
CALCULATIONS
([Portal]*BFP)
+
([Arterial]*BFA)
([Hepatic]*BFTotal)
MEASUREMENT OF GLUCONEOGENESIS
AND GLYCOGENOLYSIS IN VIVO
Glucose Production =
Glycogenolysis + Gluconeogenesis –
Lactate Production – Glucose Oxidation
Pancreatic Clamp
150
ARTERIAL
PLASMA
GLUCOSE
( mg/dl )
100
50
0
30
ARTERIAL
PLASMA
INSULIN
( U/ml )
75
Glucagon
20
50
10
25
Insulin
0
0
4
GLUCOSE
PRODUCTION
( mg/kg/min )
3
} GLY
2
1
} GNG
0
-40
0
60
120
TIME ( Min )
180
ARTERIAL
PLASMA
GLUCAGON
( pg/ml )
EFFECT OF A SELECTIVE INCREASE IN INSULIN
Pancreatic Clamp
Insulin
Pancreatic Clamp
Saline
100
100
Portal
PLASMA
INSULIN
( U/ml )
50
50
Arterial
0
0
100
100
Portal
PLASMA
GLUCAGON
( pg/ml )
50
50
Arterial
0
0
-40
0
60
120
TIME ( Min )
180
-40
0
60
120
TIME ( Min )
180
EFFECT OF A SELECTIVE INCREASE IN INSULIN
Pancreatic Clamp
+/- Insulin
Pancreatic Clamp
+/- Insulin
200
3
ARTERIAL
PLASMA
100
GLUCOSE
( mg/dl )
2
NET
GLY
( mg/kg/min) 1
0
0
3
3
NET
HEPATIC
GLUCOSE
OUTPUT
( mg/kg/min)
Control
2
Insulin
1
2
GNG
FLUX
( mg/kg/min) 1
0
0
-40
0
60
120
TIME ( Min )
180
-40
0
60
120
TIME ( Min )
180
EFFECT OF SELECTIVE INSULIN DEFICIENCY
Pancreatic Clamp
Insulin
Pancreatic Clamp
Saline
40
PLASMA
INSULIN
( U/ml )
40
Portal
20
20
0
0
100
100
Art
Portal
PLASMA
GLUCAGON
( pg/ml )
50
50
Arterial
0
0
-40
0
60
120
TIME ( Min )
180
-40
0
60
120
TIME ( Min )
180
EFFECT OF SELECTIVE INSULIN DEFICIENCY
Pancreatic Clamp
+/- Insulin
Pancreatic Clamp
+/- Insulin
ARTERIAL
PLASMA
GLUCOSE
( mg/dl )
NET
HEPATIC
GLUCOSE
OUTPUT
( mg/kg/min)
300
6
200
100
4
NET
GLY
( mg/kg/min) 2
0
0
10
6
Insulin
4
GNG
FLUX
( mg/kg/min) 2
5
0
Control
0
-5
-40
0
60
120
TIME ( Min )
180
-40
0
60
120
TIME ( Min )
180
INSULIN AND GLUCOSE PRODUCTION
NET
HEPATIC
GLUCOSE
OUTPUT
( mg/kg/min )
8
Dog
4
0
0
Basal
80
120
HEPATIC SINUSOIDAL INSULIN
( U/ml )
150
GLUCOSE
PRODUCTION
-2
-1
( mg.m .min )
40
** Man
100
50
0
0
40
80
120
Basal
ESTIMATED HEPATIC SINUSOIDAL INSULIN
( U/ml )
** ( Redrawn from Holther-Nielsen et al.: Metabolism 45: 82-91, 1996 )
+
( Sherwin et al.: Journal of Clinical Endocrinology and Metabolism 45: 1104-1107, 1977 )
EFFECT OF A SELECTIVE INCREASE IN GLUCAGON
Pancreatic Clamp
Glucagon
Pancreatic Clamp
Saline
30
30
Portal
PLASMA
INSULIN
( U/ml )
PLASMA
GLUCAGON
( pg/ml )
20
20
10
10
0
0
200
200
150
150
100
100
50
50
0
0
-40 0
60
120
TIME ( Min )
180
Arterial
Portal
Arterial
-40 0
60
120
TIME ( Min )
180
EFFECT OF A SELECTIVE INCREASE IN GLUCAGON
200
ARTERIAL
PLASMA
GLUCOSE
( mg/dl )
NET
HEPATIC
GLUCOSE
OUTPUT
( mg/kg/min)
Pancreatic Clamp
+/- Glucagon
Pancreatic Clamp
+/- Glucagon
8
150
50
6
NET
GLY
4
( mg/kg/min)
2
0
0
10
8
8
6
GNG
FLUX
4
( mg/kg/min)
2
100
6
Glucagon
4
2
Control
0
0
-40
0
60
120
TIME ( Min )
180
-40
0
60
120
TIME ( Min )
180
EFFECT OF SELECTIVE GLUCAGON DEFICIENCY
30
PLASMA
INSULIN
( U/ml )
Pancreatic Clamp
Saline
Pancreatic Clamp
Glucagon
30
20
20
10
10
Portal
Arterial
0
0
120
120
Portal
80
PLASMA
GLUCAGON
( pg/ml )
40
80
0
0
Arterial
40
-40 0
60
120
TIME ( Min )
180
-40 0
60
120
TIME ( Min )
180
EFFECT OF SELECTIVE GLUCAGON DEFICIENCY
200
ARTERIAL
PLASMA
GLUCOSE
( mg/dl )
NET
HEPATIC
GLUCOSE
OUTPUT
( mg/kg/min)
Pancreatic Clamp
+/- Glucagon
Pancreatic Clamp
+/- Glucagon
3
150
2
NET
GLY
( mg/kg/min) 1
100
50
0
0
3
3
Control
2
GNG
FLUX
( mg/kg/min) 1
2
1
Glucagon
0
0
-40 0
60
120
TIME ( Min )
180
-40 0
60
120
TIME ( Min )
180
GLUCAGON VS GLUCOSE PRODUCTION
( INSULIN BASAL AND FIXED )
14
12
10
GLUCOSE
8
PRODUCTION
( mg/kg/min )
6
Human
Dog
4
2
0
0
200
400
600
800
1000
1200
Basal HEPATIC SINUSOIDAL GLUCAGON
Level
( pg/ml )
1400
CATECHOLAMINES AND STRESS
3000
ARTERIAL
PLASMA
EPINEPHRINE
( pg/ml )
1500
1000
500
0
800
ARTERIAL
PLASMA
NOREPINEPHRINE
( pg/ml )
600
400
200
0
Overnight Moderate Infection
Fast
Exercise
Ketoacidosis
Hypoglycemia
(40 mg/dl)
EFFECT OF A SELECTIVE INCREASE IN EPINEPHRINE
Pancreatic Clamp
Epinephrine
Pancreatic Clamp
Saline
1500
1500
PLASMA 1000
EPI
( pg/ml )
500
1000
Arterial
500
Portal
PLASMA
NOREPI
( pg/ml )
0
0
600
600
400
400
200
200
0
0
-40
0
60
120
TIME ( Min )
180
-40
0
60
120
TIME ( Min )
180
EFFECT OF A SELECTIVE INCREASE IN EPINEPHRINE
Pancreatic Clamp
+/- Epinephrine
Pancreatic Clamp
+/- Epinephrine
200
4
ARTERIAL
PLASMA
100
GLUCOSE
( mg/dl )
NET
GLY
2
( mg/kg/min)
0
0
8
4
NET
HEPATIC
GLUCOSE
OUTPUT
( mg/kg/min)
3
1
6
3
Epinephrine
GNG
FLUX
2
( mg/kg/min)
4
2
1
Control
0
0
-40
0
60
120
TIME ( Min )
180
-40
0
60
120
TIME ( Min )
180
EFFECT OF A SELECTIVE INCREASE IN
SINUSOIDAL NOREPINEPHRINE
Pancreatic Clamp
Norepinephrine
Pancreatic Clamp
Saline
PLASMA
EPI
( pg/ml )
PLASMA
NOREPI
( pg/ml )
200
200
150
150
100
100
50
50
0
0
6000
6000
4000
4000
2000
2000
Arterial
Portal
Portal
Arterial
0
0
-40
0
60
120
TIME ( Min )
180
-40
0
60
120
TIME ( Min )
180
EFFECT OF A SELECTIVE INCREASE IN
SINUSOIDAL NOREPINEPHRINE
Pancreatic Clamp
+/- Portal Norepi
Pancreatic Clamp
+/- Portal Norepi
200
4
ARTERIAL 150
PLASMA
100
GLUCOSE
( mg/dl )
50
NET
GLY
2
( mg/kg/min)
0
0
4
4
NET
HEPATIC
GLUCOSE
OUTPUT
( mg/kg/min)
3
1
Portal Norepi
3
3
GNG
FLUX
2
( mg/kg/min)
2
1
1
Control
0
0
-40
0
60
120
TIME ( Min )
180
-40
0
60
120
TIME ( Min )
180
INSULIN AND GLUCOSE AS STIMULATORS
OF HEPATIC GLUCOSE UPTAKE
Peripheral Glucose Infusion
200
BLOOD
GLUCOSE
( mg/dl )
Arterial
150
100
Portal
50
0
ARTERIAL
PLASMA
INSULIN
( U/ml )
60
60
Glucagon
40
40
20
20
Insulin
0
0
NET
HEPATIC
GLUCOSE
BALANCE
( mg/kg/min )
4
2
Output
0
-2
Uptake
-4
-30
0
60
120
TIME ( Min )
180
240
ARTERIAL
PLASMA
GLUCAGON
( pg/ml )
OGTT IN THE CONSCIOUS DOG
250
Oral Glucose
200
BLOOD
GLUCOSE
( mg/dl )
Portal
150
100
Arterial
50
0
100
ARTERIAL
PLASMA
INSULIN
( U/ml )
NET
HEPATIC
GLUCOSE
BALANCE
( mg/kg/min )
100
Glucagon
75
75
50
50
Insulin
25
25
0
0
4
2
Output
0
Uptake
-2
-4
-30
0
60
120
TIME ( Min )
180
240
ARTERIAL
PLASMA
GLUCAGON
( pg/ml )
EFFECT OF THE ROUTE OF GLUCOSE ADMINISTRATION
ON GLUCOSE DISPOSITION IN THE BODY
-30
90
0
180 min
Tracers and Indocyanine Green
SRIF + Basal Portal Glucagon
Basal Portal Insulin
4 X Basal Portal Insulin
+
Peripheral Glucose
Portal Glucose
or
Portal Glucose
Peripheral Glucose
EFFECTOF
OFTHE
THEROUTE
ROUTEOF
OFGLUCOSE
GLUCOSEADMINISTRATION
ADMINISTRATION
EFFECT
ONGLUCOSE
GLUCOSEDISPOSITION
DISPOSITIONIN
INTHE
THEBODY
BODY
ON
200
Artery
Portal
150
BLOOD
GLUCOSE
( mg/dl )
100
50
0
C
Pe
Treatment Period
Po
EFFECTEFFECT
OF THE
OF GLUCOSE
ADMINISTRATION
OFROUTE
THE ROUTE
OF GLUCOSE
DELIVERY
ON GLUCOSE
DISPOSITION
THE BODY
ON NET HEPATIC
GLUCOSEIN
UPTAKE
40
ARTERIAL
PLASMA
INSULIN
( U/ml )
ARTERIAL
PLASMA
GLUCAGON
( pg/ml )
75
30
HEPATIC
50
GLUCOSE
20
LOAD
( mg/kg/min )
10
25
0
0
100
4
75
NET
2
HEPATIC
0
50
GLUCOSE
25
BALANCE
( mg/kg/min )
0
-2
Output
Uptake
-4
-6
Control
Pe
Po
Control
Pe
Po
HEPATIC GLUCOSE LOAD VS NET HEPATIC GLUCOSE UPTAKE
Portal Signal Active
Portal Signal Inactive
12
NET
HEPATIC
GLUCOSE
UPTAKE
( mg/kg/min )
8
4
0
0
25
50
75
100
HEPATIC GLUCOSE LOAD
12
NET
HEPATIC
GLUCOSE
8
125
INSULIN VS NET HEPATIC GLUCOSE UPTAKE IN THE PRESENCE OF
BASAL GLUCAGON AND A 2X BASAL HEPATIC GLUCOSE LOAD
8
Portal Signal Active
Portal Signal Inactive
NET
HEPATIC
GLUCOSE
UPTAKE
( mg/kg/min )
6
4
2
0
0
50
100
HEPATIC SINUSOIDAL INSULIN
( U/ml )
150
ARTERIAL-PORTAL GLUCOSE GRADIENT VS NET HEPATIC GLUCOSE UPTAKE IN
THE PRESENCE OF BASAL GLUCAGON, 4X BASAL INSULIN
AND 2X BASAL HEPATIC GLUCOSE LOAD
8
NET
HEPATIC
GLUCOSE
UPTAKE
( mg/kg/min )
6
4
2
0
0
-25
-50
-75
ARTERIAL - PORTAL BLOOD GLUCOSE GRADIENT
( mg/dl )
EFFECT OF GLUCAGON ON HEPATIC GLUCOSE UPTAKE
-120
0
90
330 Min
Peripheral Somatostatin
Basal
Portal
Ins+GGN
Portal Insulin (4-Fold Basal )
Portal Glucose ( 3.8 mg/kg/min )
Peripheral Glucose ( to double HGL )
+
Hi GGN
( n=6 )
Lo GGN
( n=6 )
Portal Glucagon ( ng/kg/min )
1.2
Or
Portal Glucagon ( ng/kg/min )
0.30
0.25
0.20
Glucose Infusion
Hormone Manipulation
300
ARTERIAL
BLOOD
GLUCOSE
200
100
High GGN
Low GGN
( mg/dl )
0
40
ARTERIAL
PLASMA
INSULIN
( U/ml )
30
20
10
0
80
ARTERIAL
PLASMA
GLUCAGON
( pg/ml )
60
40
20
0
-30 0
60 90
150
210
TIME ( Min )
270
330
Glucose Infusion
Hormone Manipulation
75
HEPATIC
GLUCOSE
LOAD
50
25
( mg/kg/min )
0
20
TOTAL
GLUCOSE
INFUSION
( mg/kg/min )
15
High GGN
Low GGN
10
5
0
NET
HEPATIC
GLUCOSE
BALANCE
( mg/kg/min )
4
2
0
-2
-4
-6
Output
Uptake
-30 0
60 90
150
210
TIME ( Min )
270
330