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The foundation of our understanding of metabolic physiology is built on discoveries in fundamental, but isolated model systems. Results from genes to organelles and cells may belie the physiognome. . A mechanism is only as important as its functional impact in the whole organism.

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slide1

The foundation of our understanding of metabolic physiology is built on discoveries in fundamental, but isolated model systems.

Results from genes to organelles and cells may belie the physiognome.

A mechanism is only as important as its functional impact in the whole organism.

provocative or sensitizing tests
Provocative or Sensitizing Tests

Physical Exercise

Hormone and Metabolic Challenges (e.g. hyperinsulinemic, euglycemic glucose clamps)

Etcetera

maintaining 4 grams of glucose in the blood sedentary postabsorptive
Maintaining 4 Grams of Glucose in the BloodSedentary, Postabsorptive

Brain

Fat

Glucose

~4 grams

Liver

Blood

Liver

Muscle

maintaining 4 grams of glucose in the blood feeding
Maintaining 4 Grams of Glucose in the BloodFeeding

Suppression

(Insulin)

Brain

Fat

Glucose

~4 grams

Liver

Blood

Liver

GI Tract

Stimulus

(Insulin)

Muscle

maintaining 4 grams of glucose in the blood exercise
Maintaining 4 Grams of Glucose in the BloodExercise

Stimulus

Brain

Fat

Glucose

~4 grams

Liver

Blood

Liver

Muscle

Stimulus

why don t we get hypoglycemic when we exercise
Why don’t we get hypoglycemic when we exercise?

If the liver does not release more glucose during exercise

. . . Hypoglycemia

rapidly ensues

Exercise

6

Glucose

Utilization

mg・kg-1・min-1

0

6

Hepatic Glucose

Production

mg・kg-1・min-1

0

100

Arterial Plasma

Glucose

mg·dl-1

0

-30

0

60

Time (minutes)

five guiding principles to study of metabolism in vivo
Five Guiding Principles to Study of Metabolism in vivo

Glucose metabolism is all about flux control.

Glucose flux control is distributed amongst distinct systems that require an in vivo model to be fully understood.

Glucose fluxes are most sensitively regulated and therefore best studied in theconscious state.

Novel animal models can be used to bridge basic and clinical research.

Provocative tests are often necessary to precipitate phenotypes and reveal functional limitations.

endocrine and sympathetic nerve response to exercise
Endocrine and Sympathetic Nerve Response to Exercise

Exercise

16

120

Glucagon

Arterial

Insulin

80

Arterial

12

Glucagon

pg·ml-1

µU·ml-1

40

8

Insulin

0

0

300

Norepinephrine

Arterial

Catecholamines

200

pg·ml-1

100

Epinephrine

0

-60

-30

0

30

60

90

120

150

Time (min)

slide12

Investigator

sees…

Liver

sees…

head

and

upper

extremities

pancreas

liver

gut

heart

and

lungs

A Minimal Overview of the Circulation

arterial

trunk

and

lower

extremities

portal vein

venous

slide14

Investigator

sees…

Liver

sees…

arterial

trunk

and

Basal

Exercise

head

and

upper

extremities

pancreas

lower

Basal

liver

extremities

Exercise

gut

300

300

portal vein

Portal Vein

Hepatic Vein

venous

200

200

Arterial

Plasma

Glucagon

(pg·ml-1)

Plasma

Epinephrine

(pg·ml-1)

Portal Vein

100

100

Artery

Hepatic Vein

heart

and

lungs

0

0

-50

0

50

100

150

-50

0

50

100

150

Time (min)

Time (min)

protocols role of glucagon
Protocols: Role of Glucagon

150

-120 min

0

-40

Basal

Equilibration

Moderate Treadmill Exercise

Somatostatin + [3-3H]glucose + [U-14C]alanine

Exercise-Simulated Intraportal Insulin

Basal Intraportal Insulin

Saline

Variable Glucose

Protocol A

Basal Intraportal Glucagon

Protocol B

Exercise-Simulated Intraportal Glucagon

Basal Intraportal Glucagon

slide16

Exercise as a model to study glucagon action

Exercise

150

Simulated Glucagon

100

Arterial Glucagon

pg/ml

50

Basal Glucagon

0

15

Basal Glucagon

Arterial Insulin

10

µU/ml

5

Simulated Glucagon

0

-60

-30

0

30

60

90

120

150

Time (min)

slide17

Exercise-induced Increment in Glucagon Stimulates Hepatic Glucose Production

Exercise

120

Simulated Glucagon

Arterial

Plasma Glucose

mg·dl-1

80

Basal Glucagon

40

0

Simulated

Glucagon

10

Hepatic Glucose

Production

mg·kg-1·min-1

8

6

4

Basal Glucagon

2

0

-40

0

30

60

90

120

150

exercise induced increment in glucagon stimulates gluconeogenesis from alanine
Exercise-induced Increment in Glucagon Stimulates Gluconeogenesis from Alanine

400

300

200

100

0

400

300

200

100

0

Exercise

Simulated Glucagon

Gluconeogenesis

from Alanine

(% Basal)

Basal Glucagon

Simulated Glucagon

Intrahepatic

Gluconeogenic

Efficiency

from Alanine

(% Basal)

Basal Glucagon

-60

-30

0

30

60

90

120

150

Time (min)

slide19

Comparison of the Effects of Similar Increases in Glucagon at Rest and during Exercise

6

5

Increase in Endogenous

Glucose

Production

(mg·kg-1·min-1)

4

3

2

1

0

Rest

Exercise

why is glucagon so effective during exercise
Why is Glucagon so Effective during Exercise?

Brain

Autonomic

Nerve

Activity

Adrenal

Working

Muscle

Epi

Intestine

?

Adipose

Glycerol

NEFA

Pancreas

Amino

Acids

IL6

Lactate

Amino Acids

RBP4

Glucose

4 grams

Substrates

GNG

Glucagon

Signals

Insulin

Gly

Liver

why is glucagon so effective during exercise21
Why is Glucagon so Effective during Exercise?

Brain

Autonomic

Nerve

Activity

Adrenal

Working

Muscle

Body is in a ‘Gluconeogenic Mode’

Epi

Intestine

?

Adipose

Glycerol

NEFA

Pancreas

Amino

Acids

IL6

Lactate

Amino Acids

RBP4

Glucose

4 grams

Substrates

GNG

Glucagon

Signals

Insulin

Gly

Liver

why is glucagon so effective during exercise22
Why is Glucagon so Effective during Exercise?

Brain

Autonomic

Nerve

Activity

Adrenal

Working

Muscle

Body is in a ‘Gluconeogenic Mode’

Epi

Intestine

?

Adipose

Glycerol

NEFA

Pancreas

Amino

Acids

IL6

Lactate

Amino Acids

RBP4

Glucose

4 grams

Substrates

GNG

Glucagon

Signals

Insulin

Gly

Effects are Potentiated

by the Fall in Insulin

Liver

why is glucagon so effective during exercise23
Why is Glucagon so Effective during Exercise?

Brain

Autonomic

Nerve

Activity

Adrenal

Working

Muscle

Body is in a ‘Gluconeogenic Mode’

Epi

Intestine

?

Adipose

Glycerol

NEFA

Pancreas

Amino

Acids

IL6

Lactate

Amino Acids

 Glucose Uptake

Prevents

Hyperglycemia

RBP4

Glucose

4 grams

Substrates

GNG

Glucagon

Signals

Insulin

Gly

Effects are Potentiated

by the Fall in Insulin

Liver

protocol study of splanchnic amino acid metabolism during exercise
Protocol: Study of Splanchnic Amino Acid Metabolism during Exercise

-120 min

-30

0

150

Equilibration

Basal

Treadmill Exercise

15

13

[5-

N]Glutamine + [1-

C]Leucine

slide25
The Exercise-induced Glucagon Response is Essential to the Increment in Hepatic Glutamine Extraction

Simulated

Glucagon

Basal

Glucagon

0.60

*

Hepatic

*

Fractional

0.40

*

Glutamine

Extraction

0.20

0.00

Basal

25-50

75-100

125-150

Basal

25-50

75-100

125-150

Exercise Duration

Exercise Duration

(min)

(min)

the exercise induced glucagon response drives urea formation in the liver
The Exercise-induced Glucagon Response Drives Urea Formation in the Liver

Simulated

Glucagon

Basal

Glucagon

20

*

Net Hepatic

*

15

*

Urea Output

10

-1

-1

(mol·

kg

・min

)

5

0

Basal

25-50

75-100

125-150

Basal

25-50

75-100

125-150

Exercise Duration (min)

Exercise Duration (min)

slide27
The Exercise-induced Glucagon Response is Required for the Accelerated transfer of Glutamine Amide Nitrogen to Urea in the Liver

3.0

Formation of Urea from

2.0

Glutamine Amide Nitrogen

during Exercise

1.0

-1

-1

(mol·

kg

・min

)

0.0

Basal

Simulated

Glucagon

Glucagon

slide30

Studies using the Phloridzin-Euglycemic Clamp further Illustrate the Role of Glucagon in Liver Energy Balance

*

substrates and signals implicated in control of glucose fluxes to working muscle during exercise
Substrates and Signals Implicated in Control of Glucose Fluxes to Working Muscle during Exercise

Brain

Sensors

Carotid Sinus

Liver/Portal Vein

Working Muscle

Autonomic

Nerve

Activity

Feedback

Chemical

Mechanical

Feedforward

Adrenal

Epi

Intestine

IL6

Adipose

Working

Muscle

Glycerol

NEFA

Pancreas

Amino

Acids

IL6

Lactate

Amino Acids

RBP4

Glucose

4 grams

Glucagon

GNG

Substrates

Insulin

Signals

Gly

Liver

what about the famous catecholamine response to exercise
What about the Famous Catecholamine Response to Exercise?

Epinephrine plays little to no role in control of glucose production during exercise.Moates et al Am J Physiol 255: E428-E436, 1988.

Hepatic nerves are not necessary for the exercise-induced rise in glucose production.Wasserman et al Am J Physiol 259: E195-E203, 1990.

Liver specific blockade of both - and -adrenergic receptors do not attenuate the increase in glucose production during exercise.Coker et al Am J Physiol 273: E831-E838, 1997. Coker et al Am J Physiol 278: 444-451, 2000.

catecholamines
Catecholamines
  • Essential, in association with the fall in insulin, for extrahepatic substrate mobilization during exercise.
    • Muscle glycogenolysis
    • Adipose tissue lipolysis
slide35
NEFA Flux is Accelerated during Moderate Exercise by Increased Lipolysis and Decreased Re-esterification

ATP

TG

FFA

G3P

Glucose

FFA

FFA

TG

N

E

TG

Glycerol

T

G

Glycerol

G

l

y

c

e

r

o

l

slide36
NEFA Flux is Accelerated during Moderate Exercise by Increased Lipolysis and Decreased Re-esterification

ATP

TG

FFA

G3P

Glucose

FFA

FFA

TG

N

E

TG

Glycerol

T

G

Glycerol

G

l

y

c

e

r

o

l

four grams of glucose controlling rate of removal
Four Grams of GlucoseControlling Rate of Removal

Extracellular

Intracellular

glucose

6-phosphate

glucose

• hexokinase #

• hexokinase

compartmentation

• spatial barriers

• blood flow

• capillary recruitment

• spatial barriers

Membrane

• transporter #

• transporter activity

strategy
Strategy

Selectively remove sites of resistance to MGU in conscious mice by using transgenic mice or pharmacological methods.

slide39

Ohm’s Law Applied to Glucose Influx

Current (I)

V1

V2

V3

V4

Resistor3

Resistor1

Resistor2

V1 = I · Resistor1

V2 = I · Resistor2

V3 = I · Resistor3

Glucose Influx (Ig)

Ga

Ge

Gi

0

RExtracell

RTransport

RPhosp

Gextracell= Ig · Rextracell

Gtransport= Ig · Rtransport

Gphos = Ig ·RPhosp

slide40

Ohm’s Law to Determine Sites of Resistance

to Muscle Glucose Uptake

Ga

Ge

Gi

0

GLUT4Tg

HKTg

GLUT4Tg

HKTg

Glucose Influx

WT

Transgenics

slide41

Artery

Chronically Catheterized, Conscious Unstressed Mouse

Sample

[3-3H]Glc

Blood

Insulin

Glucose

[2-14C]DG

Vein

From: Glucose Clamping the Conscious Mouse by Vanderbilt MMPC 2005

ptf 2002/jea 2005

metabolic control analysis of mgu
Metabolic Control Analysis of MGU

Control Coefficient( C ) = lnRg/ln[E]

Sum of Control Coefficients in a

Defined Pathway is 1

i.e. Cd + Ct + Cp = 1

control coefficients for mgu by mouse muscle comprised of type ii fibers
Control Coefficients for MGU by Mouse Muscle Comprised of Type II Fibers

Rest

Insulin

(~80 µU/ml)

exercise protocol
Exercise Protocol

-90

0

5

30 min

Sedentary or Exercise

Acclimation

Excise

Tissues

[2-3H]DG

Bolus

sedentary and exercising mice
Sedentary and ExercisingMice

WT

GLUT4Tg

HKTg

HKTg + GLUT4Tg

Exercise

Sedentary

250

200

Blood

Glucose

(mg·dl-1)

*

*

*

150

*

*

*

*

*

100

*

*

50

0

0

5

10

15

20

25

30

0

5

10

15

20

25

30

Time (min)

Time (min)

Fueger et al. Am J Physiol; 286: E77-84, 2004

sedentary and exercising mice46
Sedentary and ExercisingMice

HKTG

HKTg

+ GLUT4Tg

GLUT4Tg

Gastrocnemius

40

Sedentary

20

Exercise

0

SVL

20

Muscle Glucose

Uptake

(mol·100g-1·min-1)

10

0

Soleus

100

50

0

WT

Fueger et al. Am J Physiol; 286: E77-84, 2004

control coefficients for mgu by mouse muscle comprised of type ii fibers47
Control Coefficients for MGU by Mouse Muscle Comprised of Type II Fibers

Rest

Insulin

(~80 µU/ml)

Exercise

distributed control of muscle glucose uptake
Distributed Control of Muscle Glucose Uptake

Transport is clearly the primary barrier to muscle glucose uptake in the fasted, sedentary state.

Transport is so effectively regulated by exercise and insulin that the membrane is no longer the primary barrier to muscle glucose uptake.

The resistance to insulin-stimulated muscle glucose uptake with high fat feeding is due, in large part, to defects in the delivery of glucose to the muscle.

The vast majority of the literature on the regulation of glucose uptake is comprised of studies in isolated muscle tissue or cells that are blind to fundamental control mechanisms involved in muscle glucose uptake.

four grams of glucose
Four Grams of Glucose

glucose

6-phosphate

gluconeogenic precursors

glycogen

Membrane

Intracellular

Extracellular

glucose

6-phosphate

glucose

Liver

Extracellular

Membrane

Intracellular

The distributed control of blood glucose allows for more precise control of glucose homeostasis, multiple mechanisms of glucose flux control, and multiple targets to correct dysregulation of metabolism such as is seen in diabetes

Carefully conducted studies in the whole animal are necessary to ascribe function to putative controllers of glucose homeostasis.