Fuel Usage During the FeastStarve Cycle

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Fuel Usage During the Feast-Starve Cycle
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Glucose Homeostasis !!
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Hyperglycemia Osmotic diuresis
Importance of glucose homeostasis
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No more food coming from gut
EARLY FASTED
FED
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Formation and Degradation of Glycogen
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Review of glycogen structure
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Some dietary background info

• Calorie kcal
• Typical daily expenditure 2500 Cal
• Typical source of calories for Americans
• 40 fat
• 45 CHO
• 15 protein

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Glycogen content, liver

• Maximum 742 kcal
• Typically after a meal 300 kcal
• After O.N. fast 200 kcal
• After 24-36 hr fast 15 kcal

Rule of thumb Liver stores are gone in 24 hr.
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Glycogen content, muscle

• After O.N. Fast 500 kcal
• After a meal 600 -700 kcal
• After CHO Loading 1000 kcal
• After prolonged fast 250 kcal

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Structure-Function

• Why store glucose as a polymer?
• What is the advantage of branching?

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Physiological Importance ofGlycogen
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In regulating blood glucose
Physiological importance

• During absorptive phase glycogenesis in liver
  and muscle prevents hyperglycemia
• Glcblood Glycogenliver, muscle
• During fasting phase and exercise
  glycogenolysis in liver prevents hypoglycemia
• Glcblood

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Allows muscle to performstrenuous exercise
Physiological importance
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Clinical Aspects
Physiological importance

• Inborn errors of metabolism
• Diabetes

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Illustration of metabolic regulation
Significance regarding basic biochemical concepts

• Different pathways for synthesis and degradation
• Reciprocal regulation
• Role of hormones -- signal transduction

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Catabolism of Glycogen
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Pi
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Phosphorylytic cleavage (Step 4 in Fig 1)
Enzyme Glycogen phosphorylase
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Phosphorylase attacks nonreducing termini
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Reducing end
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Fates of G1P in liver and muscle
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Liver only!
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Debranching
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Birds-eye view of glycogenolysis
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Glycogen Synthesis(glycogenesis)
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Key concepts

• Synthesis cannot be a reversal glycogenolysis--
  thermodynamically unfavorable
• Synthesis requires activated building block
  UDP-glucose
• Separate pathways allow for reciprocal regulation.

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Synthesis of UDP-Glucose
Subsequent hydrolysis of PP drives rx to
completion
pyrophosphatase
2 Pi
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Addition of new glucosyl residue

• Occurs at non-reducing terminus
• Enzyme glycogen synthase
• requires a primer
• if no primer exists, one is made by the enzyme
  glycogenin.
• some primer is usually available.

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Formation of the branches

• Requires a branching enzyme
• Block of 7 residues is transfered from terminus
  to interior

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Summary of synthesis and degradation
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Energetics of Storage
(1) Glucose ATP ÿ Glucose 6-phosphate (2)
Glucose 6-phosphate ÿ glucose 1-phosphate (3)
Glucose 1-phosphate UTP ÿ UDP-glucose
PPi (4) PPi H2O ÿ 2 Pi (5) UDP-glucose
glycogenn ÿ glycogenn1 UDP (6) UDP ATP ÿ
UTP ADP (nucleoside diphosphate kinase)
_________________________________
_______________________________ Sum
Glucose 2 ATP glycogenn H2O ÿ glycogenn1
2 ADP 2 Pi
Requires 2 ATP to store 1 glucose residue as
glycogen
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Energy cost of storage, cont

• Glucose Glycogen 6 loss
• Glucose Fatty acids 25 loss

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Regulation of Glycogen Synthesis and Degradation
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The general problem in metabolic regulation --
futile cycles
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Examples of potential futile cycles
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1. In glycolysis-gluconeogenesis
F-6-P ATP ? F16BP ADP (PFK-1) F16BP H2O
? F-6-P Pi (F1,6-bisphosphatase) Net ATP
H2O ? ADP Pi
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2. In glycogen synthesis-degradation
Overall synthesis of glucosyl residue from G6P
(1) G6P ATP glycogenn H2O ?
glycogenn1 ADP 2 Pi Breakdown of glycogen
to G6P (2) glycogenn1 Pi ? glycogenn
G1P (3) G1P ? G6P _________________
_________________________________________ Net
reaction ATP H2O ? ADP Pi
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General solution coordinated control
reciprocal regulation

• One pathway switched on other off
• Usual target committed enzymes
• Mechanisms of regulating committed enzymes
• phosphorylation
• allosteric activation/inhibition

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Example of committed enzyme glycogen synthase
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Phosphorylase is the key regulatory enzyme in
glycogenolysis
Glycogen synthase is the key regulatory enzyme in
glycogenesis
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Phosphorylation/DephosphorylationThe most
important mechanism of regulation in fuel
metabolism
Regulation of committed step
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Regulatory scheme...
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Pi
Pi
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Key hormones in fuel metabolism

• Insulin
• Counter-regulatory hormones
• glucagon
• catecholamines (epinephrine, norepinephrine)
• cortisol

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Liver vs MusclePhysiological considerations
rationale for regulatory effects
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Tissue ObjectivesMuscle vs Liver

• Use glycogen as fuel for intense exercise
• Replenish stores when possible (fed, rest)
• Do NOT release Glc for other tissues

• Buffer blood glucose
• remove Glc from blood after meal
• release Glc into blood during fast or heavy
  exercise

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Therefore...
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RegulationMuscle vs
Liver

• Signals for glycogenolysis
• nerve impulse
• epinephrine
• Signal for glycogenesis
• insulin

• Signals for glycogenolysis
• glucagon
• epinephrine
• Signal for glycogenesis
• insulin

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Therefore...

• Liver has receptors for
• insulin
• glucagon
• epinephrine
• Muscle has receptors for
• insulin
• epinephrine
• NOT GLUCAGON

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To complete the picture...
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Adipose tissue

• Mobilizes fat in fasting state
• stimulated by glucagon, epinephrine
• Deposits fat in well fed state
• stimulated by insulin
• Therefore...adipose has receptors for insulin,
  glucagon, and epinephrine.

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Details of Glycogen RegulationA
Signal-TransductionAmplification Cascade

• Liver

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Transduction of Signal

• Glucagon or epinephrine is the first messenger
  (extracellular)
• cyclic AMP is the second messenger (intracellular)

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Structure of cyclic AMP
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Step 2 of Cascade Detail of Protein
Kinase A Activation
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Effect of insulin dephosphorylation
Activates protein phosphatase -1
(PP-1)
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Amplification
One definition Effect of one first-messenger
molecule on the ratio of active/inactive forms of
target protein
Theoretical amplification is astronomical. In
vivo amplification in this system is
about 10-fold.
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Epinephrine also acts at alpha-receptors
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Details of Glycogen Regulation

• Muscle

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Key Exercise Signals

• Epinephrine (external)
• flight or fight response
• Ca2 (internal)
• from neuronal impulse
• AMP (internal)
• from ATP hydrolysis for contraction

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Glycogen Storage Diseases
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Andersens
McCardles
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PompesA Lysosomal Storage Disease
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McCardles Disease (muscle phosphorylase
deficiency)Clinical Features

• Exercise Intolerance
• Cramps
• Blood in urine after exercise
• Second wind

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