1 Henderson

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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]



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



Outline of Topics for T. Henderson’s Lectures

(continued)•Glycolysis

•Tricarboxylic Acid Cycle

•Brief Overview of Oxidative Phosphorylation

•Gluconeogenesis

•Glycogen Synthesis and Degradation



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)



Glucose HomeostasisGlucose Homeostasis

Glycolysis

Gluconeogenesis

Glycogen metabolismRoles of Insulin & Glucagon

Role of fat & protein as energy sources or

carbon skeletons for glucose synthesis



Fuel MetabolismFuel Metabolism

Introduction and OverviewIntroduction and Overview



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



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



These chemical reactions involved in:These chemical reactions involved in:

moving

growth & development

reproduction

nerve transmission

production of specialized biochemicals





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



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





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



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)



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



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))



Caloric content of dietary componentsCaloric content of dietary components

kcal/g

• Carbohydrates 4

• Proteins 4

• Fat 9

•

Alcohol (ethanol) 7



Fuel composition of average70-kg manfollowing 12 hour fast



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



The Fed StateThe Fed State

oror

Absorptive PhaseAbsorptive Phase

Marks 2Marks 2ndnd ed. Chpt 2ed. Chpt 2



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



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.



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



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.



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



Triacylglycerol (TAG) + 2 H2O →

Monoacylglycerol + 2 Fatty Acids

• Transport of digested fat more complicated than

monosaccharides and amino acids.

Digestive EnzymesDigestive Enzymes

⇓



• 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



• 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



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



Diabetic

Normal

Time (hours)

Bloodglu

cose

(mmol/L

)

⇑ I n s u l i n

⇓ G l u c a g o n



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



Fig. 2.1 The fed state



Ingestedfood



Glucose(6C)

2 Pyruvate2 X (3C)

2 Acetyl-CoA(2C)

TCAcycle

CO2

GlycolysisGlycolysis



Acetyl CH3-C-O-

O

Pyruvate CH3-C-O-

O O



Glucose(6C)

Fatty Acids Pyruvate(3C)

Acetyl-CoA(2C)

TCAcycle

CO2



Glucose(6C)

Amino AcidsFatty Acids Pyruvate(3C)

Acetyl-CoA(2C)

TCAcycle

CO2





Glucose entry into skeletalmuscle requires insulin

bound to its receptor

+I



+I

Glucose entry into adipose

cell requires insulin bound to its receptor

An intermediate in Glycolysis

Intermediate in Glycolysisconverted to glycerol -P

i





Fate of Fuels in Exercising Skeletal MuscleFate of Fuels in Exercising Skeletal Muscle



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



Fate of Glucose in Liver During Absorptive PhaseFate of Glucose in Liver During Absorptive Phase





Fate of Glucose in Brain All of the TimeFate of Glucose in Brain All of the Time





Fate of Glucose in RBC’s All of the TimeFate of Glucose in RBC’s All of the Time




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.









Fasting StateFasting State

Marks’ 2Marks’ 2ndnd

ed., Chpt. 3ed., Chpt. 3• Basal State (Overnight Fast)Basal State (Overnight Fast)



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



⇓ Insulin

⇑ Glucagon

Normal

Time (hours)

B

loodgluc o

se(mm

ol/L)



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)



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



Fig. 3.1Fig. 3.1

Basal stateBasal state

(12-hr fast)(12-hr fast)



From Devlin, Textbook of Biochemistry with Clinical Correlations, Wiley -Liss, 4/e, (1997)

Figure 7.47



KB = Ketone bodiesKB = Ketone bodies

AA = Amino acidsAA = Amino acids

FA = Fatty acidsFA = Fatty acids



CH3-C-CH2-COO-

O

CH3-C-CH2-COO-

OH

β -Hydroxybutyrate

Acetoacetate

Ketone bodiesKetone bodies

Acetone CH3-C-CH3

O



Urine

Acyl-CoA

Acetyl-CoA

Ketone

bodies

Ketone

bodies

Ketone

bodies

Lungs

TCA

cycleTCA

cycle

Acetyl-CoA

LIVER BLOODEXTRAHEPATIC

TISSUES

FFA Acyl-CoAGlucose





H2 N-C-NH2

O

UreaUrea

A neutral uncharged compoundA neutral uncharged compound







Fasting StateFasting State

• Starved StateStarved State



Fig. 3.3Starved state







Sources of glucose during prolonged fast



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



Fig. 3.4. Changes in plasma fuel concentration duringg g p g

prolonged fast prolonged fast





1 Henderson

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