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Thomas O. Henderson, Ph.D.Thomas O. Henderson, Ph.D.Professor EmeritusProfessor Emeritus
Department of Biochemistry &Department of Biochemistry &
Molecular GeneticsMolecular Genetics
•Office:Office: 321 CMW321 CMW
•Phone: 312 996-5978Phone: 312 996-5978
•email: [email protected]: [email protected]
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Outline of Topics for Henderson’s LecturesOutline of Topics for Henderson’s Lectures
• Will generally useWill generally use Marks’ Basic Medical Marks’ Basic Medical Biochemistry Biochemistry, 2, 2ndnd ed., 2005ed., 2005
• Overview of fuel metabolism in humans during absorptive and
fasting phases
§Insulin and Glucagon§Organ relationships
§Fuels for specific tissues as function of feeding cycle
• Metabolism of Glucose and related carbohydrates
§Overview of digestion & absorption of carbs
§Metabolic fates of glucose
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Outline of Topics for T. Henderson’s Lectures
(continued)•Glycolysis
•Tricarboxylic Acid Cycle
•Brief Overview of Oxidative Phosphorylation
•Gluconeogenesis
•Glycogen Synthesis and Degradation
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Blood Glucose Concentration:Blood Glucose Concentration:
In normal (i. e., nondiabetic) people, the concentration of glucose
in the blood is maintained in a rather tightly controlled range.
• Post-absorptive Phase:
4.5 - 5.5 mMole/L (80 -100 mg/dL)
• Absorptive Phase:
6.5 - 7.2 mMole/L (115 - 130 mg/dL)
• Fasting (3-4 days):
3.3 - 3.9 mMole/L (60 - 70 mg/dL)
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Glucose HomeostasisGlucose Homeostasis
Glycolysis
Gluconeogenesis
Glycogen metabolismRoles of Insulin & Glucagon
Role of fat & protein as energy sources or
carbon skeletons for glucose synthesis
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Fuel MetabolismFuel Metabolism
Introduction and OverviewIntroduction and Overview
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Outline of topics for TOH’s lectures on FedOutline of topics for TOH’s lectures on Fed
and Fasting stateand Fasting stateMarks 2nd ed., Chapter 1, p. 1 - 7
Marks 2nd ed., Chapters 2 & 3 - All
Overview of metabolism in humans during absorptive
(fed) and fasting states
• Insulin and Glucagon
•Organ relationships
• Fuels for specific tissues as a function of
feeding cycle
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We require sources of fuel to survive, since weare not able to carry out photosynthesis
Fuels are used to drive the chemical reactions
of the body
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These chemical reactions involved in:These chemical reactions involved in:
moving
growth & development
reproduction
nerve transmission
production of specialized biochemicals
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We will deal with these situations in a generalized
fashion over the next few lectures.
We will brieflybriefly look at:
dietary fuel sources and processing basic patterns of fuel metabolism in major organs in
the body
changes in these patterns as a function of feeding pattern
the biological signals which modulate these changes
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Major Dietary Fuels
• Carbohydrates
• Proteins
• Lipids (Fats)
When these fuel molecules are oxidized to CO2 and H2O
in cells, energy is released by the transfer of electrons(e-) to O2
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TCA = TricarboxylicTCA = Tricarboxylic
acid cycleacid cycle
Electron transport systemElectron transport system
&&
Oxidative phosphorylationOxidative phosphorylation
The oxidation of fuels to generate ATP is calledThe oxidation of fuels to generate ATP is called
respiration.respiration.
Generation of ATP from fuels at cellular level
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The energy released in this oxidative process isreleased in the form of heat and also captured in
high-energy compounds which can be used in a hostof cellular activities.
The most important high energy compoundThe most important high energy compound
(i. e., most widely used) is adenosine(i. e., most widely used) is adenosine
triphosphate (ATP)triphosphate (ATP)
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Main purpose of fuel oxidation is generation of ATP.
ATP is used for most of energy-requiring reactions andactivities of the cell.
ATP provides energy for:
biosynthetic reactionsbiosynthetic reactions
nerve transmissionnerve transmission
transport of solutes across celltransport of solutes across cell membranesmembranes
muscle contractionmuscle contraction
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As ATP-utilizing activities proceed, ATP is converted back toAs ATP-utilizing activities proceed, ATP is converted back to
ADP + inorganic phosphate (PADP + inorganic phosphate (Pii))
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Caloric content of dietary componentsCaloric content of dietary components
kcal/g
• Carbohydrates 4
• Proteins 4
• Fat 9
•
Alcohol (ethanol) 7
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Fuel composition of average70-kg manfollowing 12 hour fast
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Energy reserves of humans followingEnergy reserves of humans following
12 hour fast12 hour fast
Stored fuel __ Tissue (g)_ (kcal)Stored fuel __ Tissue (g)_ (kcal)
Glycogen Liver 70 280
Glycogen Muscle 120 480
Glucose Body Fluids 20 80Fat Adipose 15,000 135,000
(Protein)*(Protein)* (Muscle)(Muscle) 6,0006,000 24,00024,000
*NOTE: No specific storage form of protein*NOTE: No specific storage form of protein
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The Fed StateThe Fed State
oror
Absorptive PhaseAbsorptive Phase
Marks 2Marks 2ndnd ed. Chpt 2ed. Chpt 2
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GlucoseGlucose
SynthesisSynthesis(Many compounds)(Many compounds)
OxidationOxidation
(Energy)(Energy)StorageStorage
(Glycogen, TAG)(Glycogen, TAG)
Amino acidsAmino acids
OxidationOxidation
(Energy)(Energy)
ProteinProteinsynthesissynthesis
Synthesis of Synthesis of
Nitrogen-containingNitrogen-containing
compoundscompounds
FatsFats
SynthesisSynthesis
(Membrane lipids)(Membrane lipids)
OxidationOxidation
(Energy)(Energy)StorageStorage
(TAG)(TAG)
Fig. 2.1 Major fates of fuel in the fed stateFig. 2.1 Major fates of fuel in the fed state
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Omnivorous diet of most Americans is a mixture of
carbohydrates, fats, proteins, plus a variety of
micronutrients of both animal and plant origin.
This is ingested, digested, taken up into the general
circulation, then absorbed by cells in the various
tissues.
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The period of time from ingestion to absorptionThe period of time from ingestion to absorption
into tissues constitutes theinto tissues constitutes the absorptive stateabsorptive stateor phaseor phase
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Following ingestion, complex macromolecules digested mainly in
small intestine to yield constituent building blocks by digestive
enzymes which catalyze addition of water to bonds holding them
together.
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Digestive EnzymesDigestive Enzymes
⇓Starch + (H2O)n-1 → (Glucose)n
Protein+ (H2O)n-1 → (Amino Acids)n
• The end products are water soluble and are absorbed into the
hepatic portal systemhepatic portal system and transported to the liver and the
rest of the body
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Triacylglycerol (TAG) + 2 H2O →
Monoacylglycerol + 2 Fatty Acids
• Transport of digested fat more complicated than
monosaccharides and amino acids.
Digestive EnzymesDigestive Enzymes
⇓
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• Monoacylglycerol (MAG) + 2 fatty acids reconverted to TAG
in intestinal mucosal cells and secreted into lymph in form
of a large complex lipoprotein called chylomicronschylomicrons.
• Chylomicrons in lymph dumped into general circulation at
thoracic duct
• TAG then delivered to various tissues where fatty acids in
TAG are oxidized for energy or stored as TAG in adipose
cells
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• Some of absorbed glucose, amino acids, and fats oxidized for
ATP production
• Some of glucose stored as glycogen
• Most of amino acids used for protein synthesis• Fuel absorbed in excess of these needs is converted to TAG in
liver and transported as Very Low Density LipoproteinsVery Low Density Lipoproteins
(VLDL)(VLDL) and (mainly) stored in adipose cells
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Following a typical relatively highFollowing a typical relatively high
carbohydrate meal:carbohydrate meal:
• blood glucose concentration increases
• this leads to secretion of insulin (from the pancreas)into blood stream
• insulin is a peptide hormone secreted by β -islets of
pancreas in direct response to ↑[glucose] blood
Di b ti
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Diabetic
Normal
Time (hours)
Bloodglu
cose
(mmol/L
)
⇑ I n s u l i n
⇓ G l u c a g o n
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Insulin is powerful hormonal signal• increases rate of uptake of blood glucose, especially by
adipose and skeletal muscle
• promotes conversion of glucose to glucose-6-P in liver
• promotes synthesis of fuel storage molecules, glycogen and
TAG
• promotes synthesis of proteins
Simplistically, insulin signals the well-fed stateSimplistically, insulin signals the well-fed state
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Fig. 2.1 The fed state
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Ingestedfood
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Glucose(6C)
2 Pyruvate2 X (3C)
2 Acetyl-CoA(2C)
TCAcycle
CO2
GlycolysisGlycolysis
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Acetyl CH3-C-O-
O
Pyruvate CH3-C-O-
O O
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Glucose(6C)
Fatty Acids Pyruvate(3C)
Acetyl-CoA(2C)
TCAcycle
CO2
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Glucose(6C)
Amino AcidsFatty Acids Pyruvate(3C)
Acetyl-CoA(2C)
TCAcycle
CO2
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Glucose entry into skeletalmuscle requires insulin
bound to its receptor
+I
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+I
Glucose entry into adipose
cell requires insulin bound to its receptor
An intermediate in Glycolysis
Intermediate in Glycolysisconverted to glycerol -P
i
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Fate of Fuels in Exercising Skeletal MuscleFate of Fuels in Exercising Skeletal Muscle
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Summary of Fed State
• Ingested fuels are oxidized to meet immediate
energy needs• Excess fuels stored mainly as TAG in adipose and
lesser amounts of glycogen in muscle and liver
• Amino acids used in protein synthesis, especially in
muscle
Recap of Absorptive PhaseRecap of Absorptive Phase
R f Ab ti PhR f Ab ti Ph
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Fate of Glucose in Liver During Absorptive PhaseFate of Glucose in Liver During Absorptive Phase
Recap of Absorptive PhaseRecap of Absorptive Phase
R f Ab ti PhR f Ab ti Ph
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Fate of Glucose in Brain All of the TimeFate of Glucose in Brain All of the Time
Recap of Absorptive PhaseRecap of Absorptive Phase
R f Ab ti PhR f Ab ti Ph
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Fate of Glucose in RBC’s All of the TimeFate of Glucose in RBC’s All of the Time
Recap of Absorptive PhaseRecap of Absorptive Phase
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Current evidence suggests that during the first 3 - 4 hours after a
carbohydrate - containing meal:
• about 1/3 of the glucose is taken up by the liver
• 1/3 by the muscle, and
• 1/3 by the rest of the tissues (notably nervous system and adipose).
• glucose taken up by the liver can be utilized for glycogen synthesis
efficiently.• conversion of glucose to TAG for net increase in body fat begins after
~500(?) grams of glucose are converted to liver and muscle glycogen.
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Fasting StateFasting State
Marks’ 2Marks’ 2ndnd
ed., Chpt. 3ed., Chpt. 3• Basal State (Overnight Fast)Basal State (Overnight Fast)
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At end of absorptive state:At end of absorptive state:• get ↓[glucose] blood
• insulin secretion is reduced
• ↓ [glucose] blood leads to glucagon secretion (from pancreas) into
the blood stream
• glucagon is peptide hormone secreted by α -islet cells of
pancreas in direct response to ↓[glucose] blood
Diabetic
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⇓ Insulin
⇑ Glucagon
Normal
Time (hours)
B
loodgluc o
se(mm
ol/L)
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GlucagonGlucagon
• Promotes breakdown of liver glycogen to glucose
• Promotes gluconeogenesis from amino acids,lactate, glycerol, etc., in the liver
• Promotes breakdown of TAG in adipose to fatty
acids + glycerol
Primary function of glucagon is to increase the supply of Primary function of glucagon is to increase the supply of
glucose in the blood in post-absorptive phase to supportglucose in the blood in post-absorptive phase to support
energy needs of central nervous system and other glucose-energy needs of central nervous system and other glucose-
dependent cells (such as erythrocytes)dependent cells (such as erythrocytes)
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Major energy source for liver and muscle (skeletal andheart) in post-absorptive phase is fatty acids (or
derivatives).
• NOTE:NOTE:glucagonglucagon promotes breakdown of promotes breakdown of
triacylglycerol (TAG) in adipose to fatty acids plustriacylglycerol (TAG) in adipose to fatty acids plus
glycerolglycerol
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Fig. 3.1Fig. 3.1
Basal stateBasal state
(12-hr fast)(12-hr fast)
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From Devlin, Textbook of Biochemistry with Clinical Correlations, Wiley -Liss, 4/e, (1997)
Figure 7.47
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KB = Ketone bodiesKB = Ketone bodies
AA = Amino acidsAA = Amino acids
FA = Fatty acidsFA = Fatty acids
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CH3-C-CH2-COO-
O
CH3-C-CH2-COO-
OH
β -Hydroxybutyrate
Acetoacetate
Ketone bodiesKetone bodies
Acetone CH3-C-CH3
O
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Urine
Acyl-CoA
Acetyl-CoA
Ketone
bodies
Ketone
bodies
Ketone
bodies
Lungs
TCA
cycleTCA
cycle
Acetyl-CoA
LIVER BLOODEXTRAHEPATIC
TISSUES
FFA Acyl-CoAGlucose
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H2 N-C-NH2
O
UreaUrea
A neutral uncharged compoundA neutral uncharged compound
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Fasting StateFasting State
• Starved StateStarved State
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Fig. 3.3Starved state
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Sources of glucose during prolonged fast
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Origin of blood glucose:(I) Exogenous; (II) Glycogen, Liver gluconeogenesis;
(III) Liver gluconeogenesis, Glycogen;(IV & V)Liver and Kidney gluconeogenesis
Major fuel of brain:
(I) - (III) Glucose; (IV) Glucose, ketone bodies;(V) Ketone bodies, glucose
Fig. 3.4. Changes in plasma fuel concentration duringFig. 3.4. Changes in plasma fuel concentration during
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Fig. 3.4. Changes in plasma fuel concentration duringg g p g
prolonged fast prolonged fast
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