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TISSUES. Brain: Fuel reserve: essentially none (small glycogen store in some non-neuronal cells) Metabolism: strictly aerobic Preferred fuel: glucose (obligatory), uses ketone bodies during prolonged fast, can use lactic acid Fuel exported: none.

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slide2

Brain:

Fuel reserve: essentially none (small glycogen store in some non-neuronal cells)

Metabolism: strictly aerobic

Preferred fuel: glucose (obligatory), uses ketone bodies during prolonged fast, can use

lactic acid

Fuel exported: none

slide3

·        High respiratory rate. Accounts for ~ 20% of bodies oxygen consumption in adult.

·        Glucose is an obligate metabolic fuel. Brain utilizes about 120g glucose a day.

·        Because brain does not synthesis or store glycogen it is dependent on a continuous supply

of glucose from circulation.

·        Under normal of elevated blood [glucose] rate of blood-to-brain transfer exceeds rate

of brain glucose metabolism. At low blood [glucose], blood-to-brain transfer becomes limiting.

·        Can adapt to use of ketone bodies during fast (note: long chain FA cannot cross blood

brain barrier and cannot be used as fuel by brain) but still require carbohydrates. KB

may account for as much as 60% of fuel after prolonged fast.

slide5

Skeletal muscle:

Fuel reserve: glycogen (P-creatine)

Metabolism: at rest or during prolonged activity - aerobic

short, vigorous activity – glycolytic (anaerobic)

Preferred fuel: fatty acids, glucose during vigorous activity

Fuel exported: lactate, alanine

Hormones: insulin, adrenalin

·accounts for ~ 30% of O2 consumption at rest. This may increase to as much

as 90% during vigorous exercise.

slide8

·        effects of exercise

·short, vigorous (eg 100 M sprint)

·fueled by P-creatine and glycolytic ATP

·in 10 sec. sprint muscle P-creatine decreases from 9.1 to 2.6 mM

ATP from 5.2 to 3.7 mM (what is the effect of this on glycolytic rate?).

blood lactate increases from 1.6 to 8.3 mM and

blood pH decreases from 7.42 to 7.24. Acidosis causes fatigue.

·longer (eg, 1000 M run)

·aerobic energy, oxidation of muscle glycogen - energy produced at a slower

rate so pace is slower.

slide10

·very long periods of exercise (eg marathon)

·uses liver as well as muscle glycogen supply - even slower rate of energy

production.

Muscle and liver glycogen combined are insufficient to provide fuel required

for marathon (require about 150 mols ATP, muscle and liver glycogen

provide at most about 105 mols).

Difference made up from fat reserves - but this is even slower rate of energy

production so pace slow further.

Elite runners stretch out glycogen supply and can maintain faster pace longer. )

slide11

21 year old Kenyan wins New York marathon 1994

How much glycogen is this person using?

slide12

Heart muscle:

Fuel reserves: glycogen (P-creatine)

Metabolism: strictly aerobic

Preferred fuel: fatty acids, also uses ketone bodies and glucose

Fuel exported: none

Hormones: insulin, adrenalin

slide13

Adipose tissue:

Fuel reserve: TAGs, some glycogen

Metabolism: aerobic

Preferred fuel: fatty acids, also uses glucose

Fuel exported: fatty acids, glycerol

Hormones: insulin, adrenalin

slide14

Adipocytes con’t

·TAGs may account for as much as 65% of weight of fat cell.

·FFAs bind to serum albumin for transport in serum.

·receives exogenous TAGs in chylomicron from intestinal system

(note: these travel to circulation via lymphatic system and largely

bypass liver)

·high bld glucose - glucose used for FA and TAG synthesis

·requires source of glucose to make TAGS (lacks glycerol kinase)

slide15

Liver:

Fuel reserve: glycogen

Fuel exported: glucose, fatty acids (VLDLs)

Metabolism: aerobic

Preferred fuel: fatty acids, also uses glucose

Hormones: insulin, adrenalin, glucagon

Other roles: N detoxification and export of urea, synthesis of serum proteins,

synthesis of bile acids, cholesterol (incorporated into VLDLs)

slide16

Liver con’t

·critical in maintenance of glucose homeostasis

·most incoming nutrients are delivered to liver via the portal vein

(chylomicron are the exception) where they are processed to fuels and

precursors for other tissues.

·glucose sensors: high Km GluT2, high Km glucokinase, phosphorylase

·fasting state: glycogenolytic/gluconeogenic/lipolytic

·fed state: glycogenesis/glycolytic/lipogenic

slide17

Liver con’t

·  Metabolism of fats

·        FA used for local P-lipids

·        FFA are major oxidative fuel for liver

·        synthesis of ketone bodies when CHO are limiting and there is large

mobilization of TAGs from adipose tissue.

·        AcCoA used for synthesis of FA, cholesterol, ketone bodies

synthesizes lipoproteins and forms VLDL for delivery of fats to other tissues.

slide18

Liver con’t

·amino acids

·high protein diet - amino acids are used for the synthesis of liver proteins and the

majority of serum proteins, including albumin. (Low serum albumin levels is

diagnostic of liver pathology.)

Amino acids also catabolized to provide precursors for gluconeogenesis and for

energy production via the TCA cycle.

·detoxifies N through formation of urea. (ala/glucose cycle)

·high CHO/low protein - most amino acids pass through because of high Km of

catabolic enzymes for amino acids.

Note: all except elite endurance athletes obtain adequate protein in diet and

protein supplements not required!

slide19

Liver con’t

·carbohydrate

·stores CHO as glycogen and exports glucose derived from glycogen

gluconeogenesis: synthesis glucose from low Mr precursors - lactate., alanine

TCA cycle intermedicates

Cori cycle

Alanine/glucose cycle

slide20

Red blood cell

Fuel reserve: none

Metabolism: anerobic

Preferred fuel: glucose (obligatory)

Fuel exported: lactic acid

·formation of 2, 3 bis-phosphoglycerate for maintenance of low affinity form of haemoglobin

·role of HMPS in maintaining NADPH and reduced glutathione

slide21

Kidney

·role in N metabolism: secretion of NH4+, urea

· during kidney disease N end products (urea, creatinine, uric acid) accumulate.

high CHO diet with amino acids limited to essential amino acids may help

regulate this – liver can synthesize non-essential amino acids.

·secretion of excess ketone bodies

·some gluconeogenic activity - eg from glutamine via a-ketoglutarate

·acid-base regulation: excess H+ secreted as NH4+, during acidosis renal activity

for the production of NH4+ increases ( NH4+ , gluconeogenesis) and urea

production  by liver decreases.

During alkalosis liver urea production increases and renal NH4+ secretion and

gluconeogenesis decreases.

·

slide22

Intestine

·small intestine: preferred fuel - glutamine

·colon: preferred fuel : short chain fatty acids produced by bacteria from

unabsorbed foods.

Excess short chain FA not used by colonocytes pass to portal vein for use by

liver.

·colonocytes also produce ketone bodies that are released into portal vein for

use by extrahepatic tissues

slide23

Tissue

fuel reserve

preferred fuel

fuel exported

hormone recep

Brain

none

glucose

(ketone bodies)

strictly aerobic

none

Skeletal muscle

glycogen

(P-creatine)

FA : aerobic

glucose vigorous activity-anaerobic

lactate

alanine (fasting, excessive activity)

adrenalin, insulin

heartmuscle

glycogen

(P-creatine)

fatty acids

(glucose, ketone bodies)

strictly aerobic

none

adrenalin

insulin

fatcells

TAGs

fatty acids: aerobic

fatty acids

glycerol

adrenalin

insulin

liver

glycogen

fatty acids

glucose

fatty acids

adrenalin

glucagon

insulin

slide25

Epinephrin/Adrenalin

target tissue: liver, muscle, fat cells

receptors: a and b (g protein linked)

source: adrenal medula

when: stress; release controlled by the nervous system

Physiological effects:

·increased heart rate

·blood pressure

·dilation of respiratory passages

·net effect: increased oxygen delivery

slide26

Metabolic effects:

·increase muscle and hepatic glycogenolysis

·increase hepatic gluconeogensis

·increase lipolysis

·glycogen breakdown(L,M) phosphorylase

·gluconeogenesis (L) F1,6 bis Pase, pyruvate kinase

·glycogen synthesis (L,M) glycogen synthase

·glycolysis (hM) PFK1 (indirectly by effect on F2,6 bis P levels)

·FA mobilization (A) TAG lipase

note: also results in increased glucagon secretion and decreased insulin secretion,

thereby reinforcing effects.

slide27

Glucagon

·Source: a-cells of pancrease

·when: low blood glucose, release stimulated by adrenalin

(release inhibited by insulin)

·target tissues: liver, fat cells, heart muscle

slide28

Metabolic effects of glucagon con’t:

·increase glycogenolysis and gluconeogenesis

·increase lipolysis and oxidation of FA

·increase uptake of amino acids

·

·

·

glycogen breakdown(L,hM) phosphorylase

Gluconeogenesis(L) F1,6 bis Pase (indirectly by effect on F2,6 bis P levels)

pyruvate kinase

glycogen synthesis (L,hM) glycogen synthase

slide29

Metabolic effects of glucagon con’t:

glycolysis (L) PFK1 levels (indirectly by effect on F2,6 bis P levels)

FA mobilization (A) TAG lipase

fatty acid synthesis (L) ACC

fatty acid oxidation (L, A) ACC (results in lower amounts of the inhibitor of ACT, malonylCoA)

insulin release from pancreas

slide30

Insulin

Source: b-cells of pancreas

target tissues: liver, muscle, fat

when: high blood glucose, amino acids (Arginine), glucagon, gastrointestinal

hormones (oral glucose is more potent than intravenous glucose in stimulating insulin release).

decreased by: fasting, exercise, a-adrenergic activity

slide31

Insulin secretion

decreased by

increased by

D-Glucose

Galactose

Mannose

Glyceraldehyde

Glucagon

Gastric inhibitory peptide

Secretin

Cholecystokinin

Vagal activity

Fasting

Exercise

Endurance training

Somatostatin

Galanin

Pancreastatin

Leptin

Interleukin 1

a-adrenageric activity

Prostaglandin E2

Protein

Arg

Lys

Leu

Ala

b-adrenageric activity

Sulfonylures drugs

Ketoacids

FFA

K+

Ca2+

slide32

Metabolic effects of insulin:

·increase glycogen synthesis (L, M)

·decrease gluconeogensis (L)

·increase glucose uptake (M, A)

·decrease lipolysis (A)

· increase amino acid uptake and protein synthesis in most tissue

glucose uptakeGlut4 (M,A)

glycogen synthesis (L,M) glycogen synthase

glycolysis (L) PFK1 (indirectly by effect on F2,6 bis P levels)

PDH (yields AcCoA for FA biosyn)

glycogen breakdown(L,M) phosphorylase

slide33

Metabolic effects of insulin con’t:

FA synthesis(L,A) ACC

TAG synthesis ( A) lipoprotein lipase

glucagon release

·

·

·

slide34

Maintenance of normal blood glucose

Normal blood glucose: 70-100 mg/100ml; 4.5 -5,5 mM

euglycemia: 90 mg/100mL, -5 mm

Blood glucose maintained by regulating balance between

insulin and glucagon

Hypoglycemia: less than euglycmic concentration; results in

neurological impairment even in acute situation

Hyperglycemia: greater than euglycmic concentration;

damage occurs after more long term hyperglycemia.

under euglycemic conditions both insulin and glucagon

·

are low

·

when [glucose] > ~4.5 mm insulin secretion is stimulated

when [glucose] < ~ 4 mM glucogon secretion is promoted.

·

Insulin secretion very low when [glucose] is less than 3

mM.

·

After a meal insulin/glucagon is about 10:1

·

between meals insulin/glucagon may be as low as 1:2

Liver normally produces about 10g/hr of glucose, during

exercise or fasting this may increase to as much as 40g/hr

Glucose consumption by skeletal muscle may increase from

about 4g/hr to as much as 40g/hr during exercise.

slide35

Relationship between plasma glucose,

insulin and glucagon levels

Insulin secretion

(times normal)

euglycemic

euglycemic

X

slide37

Glucose tolerance curves in a control subject

and in a subject with diabetes

Blood glucose level

(9mg/100ml)

Fasting subject ingests 1 gm of glucose/kg

body weight

slide38

Brain

Brain

Brain

Between meals

Between meals

Insulin

Glucagon

Glucagon

Glucose

10g/h

Liver

Fat

Muscle

4g/h

Blood

Glucose

4.5 mM

Blood

Glucose

4.5 mM

Liver

(glycogenolysis

gluconeogenesis)

6g/h

6g/h

After a meal

Insulin

Glucagon

Liver

Fat

Muscle

Glucose

0g/h

44g/h

Blood

Glucose

4.5 mM

Liver

(glycogenolysis

Glycolysis

FA synthesis)

6g/h

50g/h

CHO from food

slide39

Brain

Physical work

Insulin

Glucagon/adrenalin

Liver

Fat

Muscle

Glucose

46g/h

40g/h

Blood

Glucose

4.5 mM

Liver

(glycogenolysis

gluconeogenesis)

6g/h

slide40

Distribution of glucose after a meal

BRAIN

Liver

glycogen

17 g

15 g

Fat

2 g

Glucose in

Meal

90 g

kidneys

Fat

TAG

8 g

(as lactate)

23 g

25 g

Muscle

glycogen

Muscle

immed use

slide41

Effect of exercise on blood glucose

120

100

80

glucose (mg/100ml)

glucose

60

placebo

40

20

0

0

30

60

90

120

150

180

210

240

time of exercise (min)

slide43

III

IV

V

I

II

45

exogenous

40

35

30

25

Glucose used (g/h)

20

15

gluconeogenesis

glycogen

10

5

0

0h

4h

8h

12h

16h

20h

24h

28h

32h

2d

8d

16d

24d

32d

40d

hours

days

slide44

Well fed state

·energy requirements supplied by diet

·high insulin/low glucagon

MOST ENZYMES SUBJECT TO PHOSPHORYLATION BY PKA IN

DEPHOSPHORYLATED STATE (What are these enzymes? Which are active

and which inactive?) Glycogenolysis, glycolysis and lipogenesis favored.

·most nutrients flow to liver via portal vein,   lipids incorporated into

chylomicra and go via lymphatic ducts to circulatory system bypassing

the liver.

·high insulin promotes glucose uptake by muscle and fat cells because

of increased GluT4 glucose transporters in cell surface membranes

·glucose in liver is used for glycogen deposition,  hexose monophosphate

shunt (NADPH for biosynthesis) and glycolysis.  Pyruvate is used to

synthesize fatty acids

slide45

Well fed state con’t

·much of glucose passes through liver for delivery to other organs: 

brain and other tissues for oxidation to CO2;

red blood cell to lactate and pyruvate (why not to CO2?); 

adipose tissue to fat; 

muscle to glycogen as well as glycolysis and TCA cycle.

·note: lactate and or pyruvate produced in tissues other than liver is not

converted to glucose by liver (ie.  no Cori cycle under these conditions, 

gluconeogensis not active in absence of glucagon)

·glucose,  lactate,  pyruvate and amino acids support fatty acid synthesis

by liver under well fed conditions.  These fatty acids are largely exported

in the form of VLDL.

slide46

Well fed state con’t

·Protein:  hydrolysed to amino acids in intestine.

·most amino acids pass through liver and are not catabolized in liver

except when concentration is very high (ie in well fed state) due to high

Km of catabolic enzymes.

·amino acids used by liver and other organs for protein synthesis.

·Excess amino acids catabolized by liver to yield urea.  Carbons used

mainly for fatty acid synthesis

·Dietary fatty acids delivered to adipose tissue in chylomicra,  lipases

release FA that are taken up by fat cells and stored as TAGs.

·high insulin promotes synthesis of TAGs

·availability of glucose promotes TAG synthesis by supplying glycerol

phosphate  (ie.  DHAP converted to glycerol phosphate)

slide47

Early fasting  (stage ii)

CONSERVATION OF GLUCOSE, LACTATE. ALANINE, PYRUVATE

·glucagon increases/insulin decreases, adrenalin levels increase

Activation of PKA and inhibition of PP. Greater phosphorylation of

regulatory enzymes (Which are activated? Which inhibited?)

·lipogenesis reduced ( increased phosphorylation of acetylCoA

carboxylase),   lipid mobilization in fat cells increased via PKA

activation of TAG lipase.

FA oxidation increased (reduced malonly CoA)

·increase in glucagon favors gluconeogenesis and glycogenolysis

in liver

·hepatic gluconeogensis increases and lactate,  pyruvate and amino

acids otherwise used for fatty acid synthesis are diverted into

gluconeogenesis.

·Cori cycle operative

·

slide48

Early fasting  con’t (stage ii)

  • ·
  • less amino acid catabolism because dietary source of amino acids no
  • longer available
  • ·drop in insulin results in decrease in  glucose transporters from muscle
  • and fat cell surfaces resulting in decreased glucose uptake and
  • utilization by these tissues.  Glucose sparing
  • Muscle obtains more energy from fatty acid oxidation.  Results in
  • glucose sparing.
  • Inactivation of PDH in skeletal muscle by increased activity of
  • PDH kinase – activated by NADH and AcCoA from increase FA
  • oxidation.
  • ·3 major factors contribute to glucose sparing at this stage:
  • ·mobilization of liver glycogen   
  • ·mobilization of fat from adipose cells  
  • ·shift of muscle cells to increased  reliance on fatty acids for
  • energy production
slide49

3. Fasting (stage iii)

·glucagon increases/insulin decreases

·no fuel entering gut and liver glycogen largely depleted

·tissues requiring glucose are dependent on hepatic gluconeogenesis, 

primarily from pyruvate,  lactate and alanine coming from other tissues

·glycerol from lipid mobilization in fat cells continues to be an important

source of carbon for gluconeogenesis in liver.

·amino acids from protein breakdown in muscle cells provide majority of

carbon for glucose synthesis and some ketone body synthesis by liver

Increased N metabolism and urea synthesis by liver.

·liver obtains energy from fatty acids

·

slide50

Fasting (stage iii)

·OAA is diverted for gluconeogenesis and TCA cycle intermediatesfall. 

Decrease in citrate further reduces FA synthesis (loss of activation of

phosphorylated AcCoA carboxylase by citrate)  and enhanced FA

oxidation (less inhibition of acylcarnitine transferase I because of

further decrease in malonylCoA)

·increased FA oxidation and amino acid catabolism leads to increase

in ketone body formation by liver.

·N secretion in the urine shows transient increase during early stages

(up to day 3),  as a result of increase in urea production and shunting

of glutamine to kidney,   but then declines.  Decline related to glucose

sparing effect as ketone body formation kicks in.

slide51

4.  Starvation (stage iv and v)

·glycogen depleted

·blood glucose level decreased by approx.  50%,  but this level

maintained for months

·first priroity:  maintain blood glucose - required for brain,  red blood cells

·second priority:  spare protein

·fuel shifted in large measure from carbohydrate to fatty acids and

ketone bodies (derived largely from FA,  but also from amino acids)

·muscle shifts almost entirely to FA (note:  increase in AcCoA inhibits

PDH and activates PDH kinase preventing oxidation of pyruvate

and favoring use of pyruvate,  lactate and alanine for gluconeogenesis

by liver.)

·

slide52

Starvation (stage iv and v) con’t

  • major change after 3 days is increase in ketone body formation by liver and increased use of ketone bodies by brain (the brain continues to require a supply of glucose in addition to ketone bodies. Why?).
  • This has the effect of sparing protein (less required for gluconeogenic precursors) and protein breakdown actually decreases after several weeks of fasting.  (Note:  brain cannot use circulating fatty acids as fuel because they do not cross the blood brain barrier;  ketone bodies however do)
  • as long as ketone body levels are maintained by hepatic fatty acid oxidation,  there is less requirement for gluconeogenesis and glucogenic amino acids and therefore less need to breakdown muscle protein.
slide53

Well fed (high insulin/low glucagon)

Glycolytic/lipogenic

Allosteric control Phophorylation –dephospho state

Regulator enzyme enzyme

F-1-P + reg protein glucokinase phosphorylase

F-2,6-bis PPFK1/F1,6,bisP glycogen synthase

F1,6,bisP PK PFK2

Pyruvate PDH / PDH kinase F 2,6 bis Pase

Citrate pACC1 PK (decreased PDH kinase)

MalonylCoA ACC1 ACC

TCA cycle “ ticks over” to provide required ATP, but most citrate used for

FA synthesis. How?

Adapted from Devlin

slide54

Fasting low insulin/high glucagon

Gluconeogenic/lipolytic, ketone body formation

Allosteric Phosphorylation (phospho state)

Regulator enzyme enzyme

F-6-P + reg protein glucokinse p-phosphorylase

AcCoA Pyr Carbox p-glycogen syn

PDH kinase p-PFK-2

PDH p-F 2,6 bis Pase

p- pyruvate kinase

NADH TCA cycle p- PDH (due to PDH kinase)

PDH p-ACC (note low citrate)

Fatty acyl CoA ACC

TCA cycle able to provide ATP but most OAA diverted to gluconeogenesis

Adapted from Devlin

slide57

Energy metabolism during fasting

(high glucagon/low insulin)

liver

glucose

glucose

ketone bodies

Fat cells

glycerol

TAGs

ketone bodies

Muscle/brain

FFA

Ac CoA

CO2 + H2O

slide58

Energy metabolism during uncontrolled diabetes

(no insulin)

liver

glucose

glucose

ketone bodies

Fat cells

glycerol

TAGs

ketone bodies

amino acids

FFA

Ac CoA

protein

CO2 + H2O

Enhanced mobilization of TAGs and breakdown

of protein in spite of high serum glucose. Glucose

levels continue to increase.

Muscle