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
·
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.
Metabolic reserves in brain
Fuel
time
Metabolites downstream of G3PDH,
(eg pyruvate, TCA cycle inter.),
amino acids
6.5 min
Glycogen (glial cells)
5.5 min
P-creatine
21 sec
ATP
10.5 sec
Other NTPs
3.5 sec
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.
fuel
max rate ATP
production
mmol/sec
Total ~P
available
Muscle ATP
-
223
muscle P-creatine
73
446
muscle glycogen to
lactate
39
6,700
muscle glycogen to
CO2
17
84,000
liver glycogen to
muscle CO2
6.2
19,000
adipose FA to
muscle CO2
6.2
4,000,000
How much glycogen is this person using?

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.
How much glycogen is this person using?
 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. )
21 year old Kenyan wins New York marathon 1994
How much glycogen is this person using?
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
Adipose tissue:
Fuel reserve: TAGs, some glycogen
Metabolism: aerobic
Preferred fuel: fatty acids, also uses glucose
Fuel exported: fatty acids, glycerol
Hormones: insulin, adrenalin
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)
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 pr
synthesis of bile acids, cholesterol (incorporated into VLD
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
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.
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!
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
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 o
haemoglobin

role of HMPS in maintaining NADPH and reduced glutathione
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.
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
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
activityanaerobic
lactate
alanine (fasting,
excessive
activity)
adrenalin,
insulin
heart muscle
glycogen
(P-creatine)
fatty acids
(glucose, ketone
bodies)
strictly aerobic
none
adrenalin
insulin
fat cells
TAGs
fatty acids:
aerobic
fatty acids
glycerol
adrenalin
insulin
liver
glycogen
fatty acids
glucose
fatty acids
adrenalin
glucagon
insulin
GLUCAGON, ADRENALIN AND INSULIN
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
Metabolic effects:
 increase muscle and hepatic glycogenolysis
 increase hepatic gluconeogensis
 increase lipolysis
 glycogen breakdown(L,M)
 gluconeogenesis (L)
phosphorylase
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.
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
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)
 Gluconeogenesis (L)
 glycogen synthesis (L,hM)
phosphorylase
F1,6 bis Pase (indirectly by effect on F2,6 bis P levels)
pyruvate kinase
glycogen synthase
Metabolic effects of glucagon con’t:
glycolysis (L)
PFK1 levels (indirectly by effect on F2,6 bis P levels)
FA mobilization (A)
fatty acid synthesis (L)
TAG lipase
ACC
fatty acid oxidation (L, A)
malonylCoA)
insulin release from pancreas
ACC (results in lower amounts of the inhibitor of ACT,
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
Insulin secretion
increased by
D-Glucose
Galactose
Mannose
Glyceraldehyde
Protein
Arg
Lys
Leu
Ala
Ketoacids
FFA
K+
Ca2+
Glucagon
Gastric inhibitory peptide
Secretin
Cholecystokinin
Vagal activity
b-adrenageric activity
Sulfonylures drugs
decreased by
Fasting
Exercise
Endurance training
Somatostatin
Galanin
Pancreastatin
Leptin
Interleukin 1
a-adrenageric activity
Prostaglandin E2
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 uptake
glycogen synthesis (L,M)
glycolysis (L)
Glut4
(M,A)
glycogen synthase
PFK1 (indirectly by effect on F2,6 bis P levels)
PDH (yields AcCoA for FA biosyn)
glycogen breakdown(L,M)
phosphorylase
Metabolic effects of insulin con’t:
FA synthesis(L,A)
TAG synthesis ( A)



glucagon release
ACC
lipoprotein lipase
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.
Relationship between plasma glucose,
insulin and glucagon levels
euglycemic
euglycemic
X
Glucose tolerance curves in a control subject
and in a subject with diabetes
Fasting subject ingests 1 gm of glucose/kg
body weight
Between meals
Glucagon
Liver
(glycogenolysis
gluconeogenesis)
Insulin
Glucose
10g/h
Blood
Glucose
4.5 mM
4g/h
Liver
Fat
Muscle
6g/h
Brain
After a meal
Glucagon
Liver
(glycogenolysis
Glycolysis
FA synthesis)
CHO from food
Insulin
Glucose
0g/h
50g/h
Blood
Glucose
4.5 mM
44g/h
Liver
Fat
Muscle
6g/h
Brain
Physical work
Glucagon/adrenalin
Liver
(glycogenolysis
gluconeogenesis)
Insulin
Glucose
46g/h
Blood
Glucose
4.5 mM
40g/h
Liver
Fat
Muscle
6g/h
Brain
Distribution of glucose after a meal
Liver
glycogen
Fat
Fat
TAG
BRAIN
17 g
2g
25 g
Muscle
glycogen
15 g
Glucose in
Meal
90 g
8g
(as lactate)
kidneys
23 g
Muscle
immed use
glucose (mg/100ml)
Effect of exercise on blood glucose
120
100
80
60
40
20
0
glucose
placebo
0
30 60 90 120 150 180 210 240
time of exercise (min)
METABOLIC EFFECTS OF FASTING AND STARVATION
I
III
II
IV
V
45
Glucose used (g/h)
40
exogenous
35
30
25
20
15
10
glycogen
gluconeogenesis
5
0
0h 4h 8h 12h 16h 20h 24h 28h 32h 2d 8d 16d 24d 32d 40d
hours
days
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
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.
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)
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
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
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
Fasting (stage iii)

OAA is diverted for gluconeogenesis and TCA cycle intermediates fall.
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.
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.)

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.
Well fed (high insulin/low glucagon)
Glycolytic/lipogenic
Phophorylation –dephospho state
Allosteric control
Regulator
enzyme
enzyme
F-1-P + reg protein glucokinase
phosphorylase
F-2,6-bis P
PFK1/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
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
PDH kinase
PDH
NADH
TCA cycle
PDH
p- glycogen syn
p- PFK-2
p- F 2,6 bis Pase
p- pyruvate kinase
p- PDH (due to PDH kinase)
p-ACC (note low citrate)
Fatty acyl CoA
ACC
TCA cycle able to provide ATP but most OAA diverted to gluconeogenesis
Adapted from Devlin
Changing metabolism during a fast
Amount produced or
consumed per day (g)
Amount produced or
consumed per day (g)
3rd day
40th day
glucose
100
40
ketone bodies
50
100
Adipose lipids
180
180
Muscle protein
75
20
glucose
150
80
ketone bodies
15
150
Fuel used by brain
Fuel mobilization
Fuel output by liver
Hormone and substrate levels in serum during a fast
Hormone or
substrate
Well fed
state
12 h after
feeding
3 day fast
6 week
fast
Insulin (uU/ml)
40
15
8
6
Glucagon (pg/ml)
80
100
150
120
Ins/glu
0.5
0.15
0.05
0.05
Glucose (mM)
6.1
4.8
3.8
3.6
FA (mM)
0.14
0.6
1.2
1.4
AcAc (mM)
0.04
0.05
0.4
1.3
b hydroxy
butyrate (mM)
0.03
0.1
1.4
6.0
Lactate (mM)
2.5
0.7
0.7
0.6
Pyruvate (mM)
0.25
0.06
0.04
0.03
ATP equi (mM)
313
290
380
537
From Devlin Clinical Biochemistry
Energy metabolism during fasting
(high glucagon/low insulin)
glucose
liver
glucose
ketone bodies
Fat cells
glycerol
ketone bodies
TAGs
Muscle/brain
FFA
Ac CoA
CO2 + H2O
Energy metabolism during uncontrolled diabetes
liver
(no insulin)
glucose
glucose
ketone bodies
Fat cells
glycerol
ketone bodies
TAGs
FFA
Ac CoA
protein
Enhanced mobilization of TAGs and breakdown
of protein in spite of high serum glucose. Glucose
levels continue to increase.
CO2 + H2O
Muscle
amino acids
?