Integración metabolica

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Chapter 32
For the individual cell, the most immediate challenge is
the safeguarding of its own energy supply. Beyond the
imperative of self-preservation, however, cells and or-
gans must cooperate unselfishly for the common good
of the body. Together they must master the everyday
challenges of fasting, feasting, and muscular activity as
well as the less routine challenges of infectious illnesses.
These challenges require the organism-wide coordi-
nation of metabolic pathways, achieved through hor-
monal and nervous signals. This chapter discusses the
metabolic adaptations to environmental challenges and
varying physiological needs, with special emphasis on
the challenges posed by overeating and the resulting
pathologies.
INSULIN IS RELEASED IN RESPONSE
TO ELEVATED GLUCOSE
Hormones coordinate the metabolic activities of dif-
ferent tissues in response to environmental challenges.
Therefore their actions can be understood only in the
context of the physiological conditions that cause their
release.
Insulin is the hormone of the well-fed state. It is re-
leased by the β-cells in the islets of Langerhans when the
levels of blood glucose and other nutrients rise after a
meal. There are approximately 1 million islets in the hu-
man pancreas. β-Cells make up 50% of their cell popula-
tion, and another 35% to 40% are glucagon-
producing
α-cells. The remainder are somatostatin-producing
δ-cells and pancreatic polypeptide–producing PP-cells.
Glucose is both the main energy source for the β-cells
and the most important stimulus for insulin secretion.
The two functions are coupled in the major pathway of
glucose-induced insulin secretion that is summarized in
Fig. 32.1. Insulin enters the cell on GLUT1 and GLUT3
carriers. While GLUT3 is a high-affinity carrier (Km for
glucose 1
mM), GLUT1 has a Km of 6
mM, a bit above
the fasting blood glucose level. In the cell, glucose is
phosphorylated by glucokinase. With a Km for glucose
of about 6
mM and a mildly sigmoidal relationship
between glucose concentration and reaction rate, glu-
cokinase can function as a glucose sensor (along with
GLUT1).
In consequence, the β-cells metabolize glucose at an
increased rate when the blood glucose level is high, and
this raises the ATP/ADP ratio in the cell. The plasma
membrane of the β-cells contains an ATP-regulated po-
tassium channel (KATP channel) that is leaky when the
intracellular ATP concentration is low but closes more
tightly when the ATP level is high. In consequence,
rising ATP caused by increased glucose supply closes
the channel and thereby partly depolarizes the plasma
membrane. Weakening of the membrane potential opens
voltage-gated calcium channels. The calcium entering
through these channels triggers the exocytosis of insulin-
containing vesicles and induces longer-term adaptations
leading to increased insulin synthesis.
To a lesser extent, insulin secretion is stimulated by
nutrients other than glucose, including amino acids,
fatty acids, and ketone bodies. It is also stimulated by
acetylcholine from the vagus nerve and by incretins,
INTEGRATION OF METABOLISM
Glucose
Glucose
Glucose-6-phosphate
Glucokinase
Glucokinase
ATP
ADP
KATP
channel
K+
Voltage-gated
calcium channel
exocytosis
Membrane
hyperpolarization CO2 + H2O
Ca2+
GLUT1,3
Fig. 32.1 Mechanism of glucose-stimulated insulin secretion
in pancreatic β-cells. ATP derived from glucose metabolism
closes an ATP-regulated potassium channel (KATP channel),
thereby depolarizing the membrane and opening voltage-gated
calcium channels. Calcium triggers exocytosis. , stimulation;
, inhibition.
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534 METABOLISM

insulin-releasing hormones from the gastrointestinal
tract. While acetylcholine releases calcium from the en-
doplasmic reticulum, the incretins enhance insulin secre-
tion through cyclic AMP.
INSULIN STIMULATES THE UTILIZATION
OF NUTRIENTS
The list of insulin effects given in Table 32.1 shows that
insulin channels excess nutrients into the synthesis of
glycogen, fat, and protein.
After a carbohydrate-rich meal, more than half of the
excess glucose is metabolized in skeletal muscle, 20% to
25% in the liver, and 10% in adipose tissue. The mech-
anisms by which insulin stimulates glucose metabolism
are different in different tissues. In skeletal muscle and
adipose tissue, insulin stimulates glucose uptake by the
glucose carrier GLUT4. In the absence of insulin, most
GLUT4 transporters are located in the membrane of in-
tracellular storage vesicles. Only 5% are on the cell sur-
face. Insulin causes the storage vesicles to move to the
cell surface and fuse with the plasma membrane, thereby
depositing GLUT4 in the plasma membrane. The pro-
cess is mediated through the insulin receptor substrate,

phosphoinositide 3-kinase, and protein kinase B (Akt)
but not through the Ras–MAP kinase pathway or mTOR.
In the liver, glucose uptake by the insulin-
insensitive
GLUT2 transporter is not rate limiting, but the

glucose-metabolizing enzymes are stimulated by
insulin.
Insulin induces the synthesis of glycolytic enzymes
and represses the synthesis of gluconeogenic enzymes
on a time scale of hours to days. The effects on gluco
neogenesis are mediated mainly by inhibition of the
FoxO transcription factor. On a minute-by-minute time
scale, insulin stimulates glycogen synthesis and glycoly-
sis while inhibiting glycogenolysis and gluconeogenesis
by reversing cAMP-induced phosphorylations. This is
achieved by two mechanisms:
1. Insulin stimulates phosphodiesterase 3B, which de-
grades cAMP to AMP.
2. Insulin stimulates phosphatase-1, the enzyme that
dephosphorylates the important targets of the cAMP-
activated protein kinaseA: glycogen synthase,glycogen
phosphorylase, phosphorylase kinase,
PFK-2, and

others (see Chapter 24).
Glucose metabolism in brain and erythrocytes is not in-
sulin dependent. These tissues are inept at metabolizing
alternative fuels. They must keep consuming glucose,
even in the fasting state, when the insulin level is low.
Insulin’s most important effect on fat metabolism
is a powerful inhibition of lipolysis in adipose tissue.
This ensures that dietary nutrients rather than fatty
acids from adipose tissue are metabolized in the well-
fed state. In the liver it induces the conversion of excess
Table 32.1 Metabolic Effects of Insulin
Tissue Affected Pathway Affected Enzyme
Liver ↑ Glucose phosphorylation Glucokinase
↑ Glycolysis Phosphofructokinase-1,* pyruvate kinase†
↓ Gluconeogenesis PEP-carboxykinase, fructose-1,6-bisphosphatase,*
glucose-6-phosphatase
↑ Glycogen synthesis Glycogen synthase†
↓ Glycogenolysis Glycogen phosphorylase†
↑ Fatty acid synthesis Acetyl-CoA carboxylase,†
ATP-citrate lyase, malic enzyme
↑ Pentose phosphate pathway Glucose-6-phosphate dehydrogenase
Adipose tissue ↑ Glucose uptake Glucose carrier
↑ Glycolysis Phosphofructokinase-1
↑ Pentose phosphate pathway Glucose-6-phosphate dehydrogenase
↑ Pyruvate oxidation Pyruvate dehydrogenase†
↑ Triglyceride utilization (from lipoproteins) Lipoprotein lipase
↑ Triglyceride synthesis Glycerol-3-phosphate acyl transferase
↓ Lipolysis Hormone-sensitive lipase†
Skeletal muscle ↑ Glucose uptake Glucose carrier
↑ Glycolysis Phosphofructokinase-1
↑ Glycogen synthesis Glycogen synthase†
↓ Glycogenolysis Glycogen phosphorylase†
↑ Protein synthesis Translational initiation complex
Most of the other insulin effects included here are actions on the rate of synthesis or degradation of the affected enzyme.
PEP, Phosphoenolpyruvate.
* Insulin acts indirectly by promoting the dephosphorylation of phosphofructokinase-2/fructose-2,6-bisphosphatase, thereby increasing the level of
fructose-2,6-bisphosphate.
†
Insulin acts by promoting the dephosphorylation of the enzyme.
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carbohydrate to fat through glycolysis, pyruvate dehy-
drogenase reaction, and fatty acid biosynthesis.
PROTEIN SYNTHESIS IS COORDINATED BY THE
mTOR COMPLEX
Insulin stimulates protein synthesis as well as carbohy-
drate utilization. It can act as a growth factor by stim-
ulating cell growth or proliferation (depending on the
cell type) through the Ras protein and the MAP kinase
cascade, leading to the activation of the extracellular
signal–regulated kinases ERK1 and ERK2.
Insulin actions on protein synthesis are mediated by
the mTOR (mammalian target of rapamycin, or mecha-
nistic target of rapamycin) complex.The core component
of this complex is a protein kinase that phosphorylates
numerous target proteins on serine and threonine side
chains. It forms two complexes that share some of their
subunits but not others: mTOR complex 1 (mTORC1)
assembles on the surface of the lysosome membrane,
and mTOR complex 2 (mTORC2) assembles under the
plasma membrane.
Both mTOR complexes mediate cellular adaptations
to nutrient availability. Little is known about the precise
roles of mTORC2, except that it is involved in the early
steps of insulin signaling leading to the activation of
Akt2, the insulin-regulated isoenzyme of protein kinase
B. Far more is known about the functions of mTORC1.
This complex integrates signals of nutrient availabil-
ity and coordinates the appropriate cellular responses.
Fig. 32.2 shows the main mechanisms by which its ac-
tivity is regulated.
Attachment of mTORC1 to the lysosomal membrane
depends on the small G proteins Rag A/B and Rag C/D.
These G proteins are activated by free amino acids.
Leucine and arginine are especially effective, although
their mechanism of action is not fully known. However,
once at the lysosomal membrane, mTOR can be acti-
vated by other stimuli. Most of them act through the
tuberous sclerosis complex (TSC complex in Fig. 32.2),
which is coupled to mTORC1 though the G protein
Rheb. The active, GTP-bound form of Rheb activates
mTORC1, and the TSC complex inactivates Rheb by
stimulating its GTPase activity. Hence, the TSC complex
inhibits mTORC1.
The stimuli that regulate the TSC complex include
the usual suspects. Insulin and growth factors, acting
through tyrosine protein kinase receptors, inhibit the
TSC complex (thereby activating mTORC1) by in-
hibitory phosphorylations, both through Akt and the
extracellular signal–regulated kinases (ERKs). Other
signaling cascades that impinge on the TSC complex
include the Wnt cascade, which we encountered as a

cancer-promoting signaling system in Chapter 19.
Nutrient deficiency inhibits mTORC1 by activating
the AMP-activated protein kinase, which activates the
TSC complex. Also other cellular stresses, including
DNA damage, endoplasmic reticulum stress, and hy-
poxia, can activate the TSC complex through various
mechanisms.
The effects of mTORC1 activation are shown in
Fig. 32.3. Most prominent are effects on global protein
metabolism. Ribosomal protein synthesis is increased
rather nonspecifically by two mechanisms. One is phos-
phorylation of 4EBP (4E binding protein), an inhibitor
of eukaryotic initiation factor 4E. The phosphorylation
inactivates this inhibitor. A second mechanism is an ac-
tivating phosphorylation of S6 kinase, which facilitates
protein synthesis by phosphorylating, among other sub-
strates, one of the ribosomal proteins.
Insulin
R
R
Wnt
Growth factors
PI3K
Akt
GSK3
Amino
acids
mTORC1
Rheb
TSC
GTP–
Rag –GTP
p53
DNA damage
GTP–
AMPK
ERK
Ras
Low
energy
Lysosome
Fig. 32.2 Activation of mTOR complex 1
(mTORC1) on the surface of the lysosomal
membrane. Akt, Akt protein kinase (protein
kinase B); AMPK, AMP-activated protein kinase;
ERK, extracellular signal regulated kinases;
GSK3, glycogen synthase kinase-3; mTORC1,
mTOR complex 1; PI3K, phosphoinositide
3-kinase; R, receptors; Rag, Ras, Rheb, GTP-
binding signaling proteins; TSC, tuberous
sclerosis complex. , stimulation; , inhibition.
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536 METABOLISM
The stimulation of protein synthesis is complemented
by the inhibition of lysosomal biogenesis and
autophagy.
These effects are mediated by the phosphorylation of
transcription factors, whose translocation from the cy-
toplasm to the nucleus is regulated by mTOR-induced
phosphorylations. Thus mTOR’s anabolic effects in-
clude increased protein synthesis and reduced lysosomal
protein degradation.
In addition to protein turnover, mTOR affects the
major pathways of carbohydrate and lipid metabo-
lism. It increases fatty acid biosynthesis by stimulating
the cleavage of SREBP-1c, one of the master regulators
of lipid metabolism (see Chapter 25). Stimulation of
glycolysis can be achieved through hypoxia inducible
factor-1α and the Myc protein, a transcription factor
encoded by the cellular MYC proto-oncogene.
GLUCAGON MAINTAINS THE BLOOD GLUCOSE
LEVEL
During starvation,the body covers most of its energy needs
from adipose tissue–derived fatty acids. However, neu-
rons and other specialized cell types, such as
erythrocytes,
cannot oxidize fatty acids and therefore depend on a steady
supply of glucose. Glucagon is specialized for the mainte-
nance of a normal blood glucose level during fasting. Its
secretion from the pancreatic α-cells increases twofold to
threefold in response to hypoglycemia and is reduced to
half of the basal release by hyperglycemia. Acting through
its second messenger cyclic AMP (cAMP), glucagon stim-
ulates hepatic glucose production by glycogenolysis and
gluconeogenesis. Its actions on the pathways of glucose
metabolism are opposite those of insulin (Table 32.2),
but unlike insulin, glucagon acts almost exclusively on the
liver; its effects on adipose tissue, muscle, and other extra-
hepatic tissues are negligible in humans.
CATECHOLAMINES MEDIATE THE FLIGHT-OR-
FIGHT RESPONSE
Next to fasting, physical exertion is a recurrent chal-
lenge for human metabolism. Energy generation in the
muscles needs to be augmented enormously, and energy
has to be supplied to the muscles from stored liver gly-
cogen and adipose tissue triglycerides. These responses
are coordinated by the catecholamines norepinephrine
S6 kinase
TFEB
ZKSCAN3
c-Myc
HIF1α
Insulin
Growth factors
Nutrients
Energy
SREBP-1c
4EBP
mTORC 1
Lysosomal
biogenesis
Autophagy
Glycolysis
Protein
synthesis
Lipid
synthesis
Fig. 32.3 Effects of active mTOR complex 1
(mTORC1) on cell metabolism. 4EBP, Binding
protein for translational initiation factor 4E;
HIF1α, hypoxia-inducible factor 1α; c-Myc,
cellular Myc protein; S6 kinase, ribosomal
subunit protein 6 kinase; SREBP-1c, sterol
response element binding protein-1c; TFEB,
transcription factor EB; ZKSCAN3, zinc finger
protein harboring KRAB and SCAN domains-3
(a transcription factor). , stimulation;
, inhibition.
Table 32.2 Metabolic Effects of Glucagon on the Liver*
Enzyme Affected by
Effect on Pathway Affected Enzyme
Enzyme
Induction/Repression
Enzyme
Phosphorylation Other
↓ Glycolysis Glucokinase +
Phosphofructokinase-1 +†
Pyruvate kinase +
↑ Gluconeogenesis PEP-carboxykinase +
Fructose-1,6-bisphosphatase + +†
Glucose-6-phosphatase +
↓ Glycogen synthesis Glycogen synthase +
↑ Glycogenolysis Glycogen phosphorylase +
↓ Fatty acid synthesis Acetyl-CoA carboxylase + +
↑ Fatty acid oxidation Carnitine-palmitoyl transferase-1 +
CoA, Coenzyme A; PEP, phosphoenolpyruvate.
*Both the enzyme phosphorylations and the effects on gene expression are mediated by cyclic AMP (cAMP).
†
Mediated by the cAMP-dependent phosphorylation of phosphofructokinase-2/fructose-2,6-bisphosphatase and a decreased cellular concentration of
fructose-2,6-bisphosphate.
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(noradrenaline) and epinephrine (adrenaline). The cat-
echolamines are stress hormones. They are released not
only during physical exertion, but also in response to
psychological stress. In ancestral environments, stress
usually meant the need to be prepared for physical ef-
fort: the flight-or-fight response.
The catecholamines can raise the cellular cAMP level
through β-adrenergic receptors and the calcium level
through α1-adrenergic receptors. Muscle and adipose
tissue have mainly β receptors, and the liver has both β
and α1 receptors.
Table 32.3 summarizes the important metabolic ef-
fects. Some are tissue specific. For example, glycolysis is
inhibited in the liver but stimulated in muscle. The reg-
ulatory metabolite fructose-2,6-bisphosphate activates
phosphofructokinase-1 in muscle, as it does in the liver
(see Chapter 24). However, the phosphofructokinase-
2/fructose-2,6-bisphosphatase of skeletal muscle is dif-
ferent from the liver enzyme. Its kinase activity is not
inhibited but is stimulated by cAMP-induced phosphor-
ylation. Therefore the catecholamines, acting through β
receptors and cAMP, stimulate rather than inhibit gly-
colysis in skeletal muscle.
The catecholamines are functional antagonists of
insulin that raise the blood levels of glucose and fatty
acids. They are not very important for blood glucose
regulation under ordinary conditions, but their release
is potently stimulated by hypoglycemia. Therefore hy-
poglycemic episodes in metabolic diseases are always
accompanied by signs of excessive sympathetic activity
including pallor, sweating, and tachycardia.
GLUCOCORTICOIDS ARE RELEASED IN CHRONIC
STRESS
Glucocorticoids have two physiological functions. One
is the circadian control of metabolic pathways. Cortisol
is highest in the early morning, when it stimulates

gluconeogenesis and glycogen synthesis in an attempt to
build up liver glycogen stores for the activities of the day.
Cortisol is also a stress hormone. Especially chronic
stress stimulates cortisol secretion from the adrenal
cortex through corticotropin-releasing hormone from
the hypothalamus and adrenocorticotropic hormone
(ACTH) from the anterior pituitary gland.
By and large, the actions of the glucocorticoids
(Table 32.4) are synergistic with epinephrine, but there
is an important difference. Epinephrine works through
the second messengers cAMP and calcium, whereas the
glucocorticoids are mainly gene regulators. Therefore
epinephrine induces its effects in a matter of seconds,
but most glucocorticoid effects are cumulative over
hours to days.
The glucocorticoids prepare the body for the action
of epinephrine. They stimulate the synthesis of the adi-
pose tissue lipases. They also increase gluconeogenesis
from amino acids by causing net protein breakdown
in peripheral tissues and inducing phosphoenolpyru-
vate (PEP) carboxykinase in the liver. Excess glucose-6-
phosphate produced by gluconeogenesis is diverted into
glycogen synthesis, thus providing more substrate for
epinephrine-induced glycogenolysis.
Table 32.3 Metabolic Effects of Norepinephrine and Epinephrine
Tissue Affected Pathway Affected Enzyme Second Messenger
Adipose tissue ↑↑↑ Lipolysis
↓ Triglyceride utilization from lipoproteins
Hormone-sensitive lipase*
Lipoprotein lipase‡ cAMP
Liver ↓ Glycolysis
↑ Gluconeogenesis
Phosphofructokinase-1†
Fructose-1,6-bisphosphatase† cAMP
↓↓ Glycogen synthesis
↑↑↑ Glycogenolysis
Glycogen synthase*
Glycogen phosphorylase*
Ca2+
, cAMP
↓ Fatty acid synthesis Acetyl-CoA carboxylase* cAMP
Skeletal muscle ↑↑↑ Glycolysis
↓↓ Glycogen synthesis
↑↑↑ Glycogenolysis
Phosphofructokinase-1†
Glycogen synthase*
Glycogen phosphorylase*
cAMP
↑ Triglyceride utilization from lipoproteins Lipoprotein lipase ?
↑ and ↓, Weak or inconsistent effect; ↑↑ and ↓↓, moderately strong effect; ↑↑↑ and ↓↓↓, strong effect.
cAMP, Cyclic adenosine monophosphate.
*Effects mediated by enzyme phosphorylation.
†
Mediated indirectly by phosphorylation of phosphofructokinase-2/fructose-2,6-bisphosphatase.
‡
Decreased translation.
Table 32.4 Important Metabolic Actions of Cortisol and Other
Glucocorticoids*
Tissue Affected Pathway Affected Enzyme
Adipose tissue ↑ Lipolysis Lipases
Muscle tissue ↑ Protein degradation ?
Liver ↑ Gluconeogenesis Enzymes of amino acid
catabolism,
PEP-carboxykinase
↑ Glycogen synthesis Glycogen synthase
PEP, Phosphoenolpyruvate.
* The glucocorticoid effects are mediated by altered rates of enzyme
synthesis.
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It now is apparent how cortisol and epinephrine
cooperate in a stressful situation. During an extended
hunting expedition by a stone-age caveman, cortisol in-
duced the lipases in his adipose tissue and built up the
glycogen stores in his liver. As soon as the hunter was
attacked by a cave bear, epinephrine immediately stim-
ulated the release of fatty acids from adipose tissue and
of glucose from the liver. Thanks to the supply of these
fuels to his muscles, the caveman managed to dodge the
cave bear’s attack and kill the animal with his club. This
gave him the chance to transmit his metabolic regulator
genes to us, his descendants.
For the caveman’s degenerate descendants today, the
stress hormones are troublemakers rather than lifesav-
ers. Patients suffering from infections, autoimmune dis-
eases, malignancies, injuries, surgery, or psychological
upheaval have elevated levels of glucocorticoids and
catecholamines. Cortisol-induced protein breakdown
leads to negative nitrogen balance and muscle wasting.
Because the stress hormones oppose the metabolic effects
of insulin, seriously ill patients have insulin resistance
and poor glucose tolerance. The insulin requirement of
insulin-dependent diabetic patients rises substantially
during otherwise harmless infections or other illnesses.
Some cytokines, which are released by white blood
cells during infections and other diseases, have meta-
bolic effects similar to the stress hormones. Interleukin-1
stimulates proteolysis in skeletal muscle, and tumor ne-
crosis factor promotes lipolysis in adipose tissue. These
mediators contribute to the weight loss that is common
in patients with malignancies or chronic infections.
ENERGY IS EXPENDED CONTINUOUSLY
The basal metabolic rate (BMR) is the amount of energy
that a resting person consumes in the “postabsorptive”
state, 8 to 12 hours after the last meal. It is calculated
with predictive formulas, for example, the Harris-
Benedict equation:
or the Mifflin-St. Jeor equation:
where Constant = 5 for males and −161 for females.
In these equations, BMR is calculated as kilocalories
per day. Weight is measured in kilograms, height in cen-
timeters, and age in years.
BMR depends on body composition.Men tend to have a
higher BMR per body weight than do women because men
have relatively more muscle than fat (Table 32.5). Women
need more fat as an energy reserve for pregnancy, and men
need more muscle to fight over the women. It also depends
on dietary history.In extended starvation,the BMR declines
because less thyroxine is converted to T3 in the tissues.
On top of the BMR, additional energy is spent for
postprandial thermogenesis after a meal. It is produced
by metabolic interconversions and increased biosynthesis
after a meal, and by increased futile cycling in metabolic
pathways. Postprandial thermogenesis depends on the
size and composition of the meal. The digestion, absorp-
tion, and storage of fat require only 2% to 4% of the fat
energy, but the conversion of carbohydrate to storage fat
requires 24% of the energy content of the carbohydrate.
Muscular activity is the most variable item in the
energy budget but is generally less than 1500
kcal/day
BMR Constant Weight
Height Age
= + ´
( ) +
´
( )- ´
( )
9 99
6 25 4 92
.
. .
Table 32.5 Metabolic Rates of Various Organs and Tissues
Organ
Metabolic
Rate (kcal/
kg/day)
Tissue or Organ
Weight (kg)
Percent of
Body Weight
Metabolic Rate
(% of Total)
Male Female
Child
(6 Months) Male Female
Child
(6 Months) Male Female
Child
(6 Months)
Liver 200 1.8 1.4 0.26 2.57 2.41 3.51 21 21 14
Brain 240 1.4 1.2 0.71 2.00 2.07 9.51 20 21 44
Heart 440 0.33 0.24 0.04 0.47 0.41 0.53 9 8 4
Kidneys 440 0.31 0.28 0.05 0.44 0.47 0.71 8 9 6
Muscle 13 28 17 1.88 40 29.3 25 22 16 6
Adipose
tissue
4.5 15 19 1.50 21.4 32.8 20 4 6 2
Others 12 23.2 18.9 3.06 33.1 32.6 40.7 16 19 24
Total 70 58 7.50 100 100 100 100* 100†
100‡
Data from Kinney JM, Tucker HN: Energy metabolism, New York, 1992, Raven Press.
*1680 kcal/day.
†
1340 kcal/day.
‡
390 kcal/day.
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except in people who engage in very strenuous physical
labor all day long.
Multipliers are used to calculate the caloric expendi-
ture (and dietary requirement) for different physiologi-
cal states:
STORED FAT AND GLYCOGEN ARE DEGRADED
BETWEEN MEALS
Energy is spent round the clock, but most people eat in
well-spaced meals. An ample supply is available for only
3 to 4 hours after a meal. For the rest of the day, we
depend on stored energy reserves.
Compared with free-living animals, humans have an
enormous amount of fat (Table 32.6), which keeps us
alive during extended fasting. It is easy to calculate that
with fat stores of 16
kg (a typical amount for the non-
obese) and BMR of 1500
kcal/day, people can survive
for about 100 days on tap water and vitamin pills alone,
actually 125 days if we assume that the metabolic rate
in prolonged fasting is 20% below BMR. The time to
death on a hunger strike depends on the fat reserves, but
survival times around 100 days are typical.
Compared with fat reserves, glycogen stores are
puny. Liver glycogen is depleted within a day. Glycogen
is a checking account from which withdrawals are
made on an hour-by-hour basis, whereas fat is a sav-
ings account.
Unlike fat and glycogen, protein is not a specialized
energy storage form. Still, much of the protein in muscle
and other tissues can be mobilized during fasting. Only
the protein in brain, liver, kidneys, and other vital or-
gans is taboo, even during prolonged starvation.
During long-term fasting, net protein breakdown
is required to supply amino acids for gluconeogenesis.
Because even-chain fatty acids are not substrates of glu-
coneogenesis, only amino acids are available in suffi-
cient quantity to cover the glucose requirement during
fasting. Therefore the loss of protein from muscle and
other tissues is inevitable during prolonged fasting.
Fig. 32.4 shows some of the changes in blood chem-
istry during the transition from the well-fed state to
starvation. The most important hormonal factor is the
balance between insulin and its antagonists, especially
glucagon. During fasting, the plasma level of insulin
falls, whereas first epinephrine, then glucagon, and fi-
nally cortisol levels rise.
During the first few days on a zero-calorie diet,
between 70 and 150
g of body protein is lost per
Long term fasting BMR
Sedentary lifestyle BMR
: .
: .
´
´
0 8
1 2
Lightly active BMR
Moderately active BMR
: .
: .
´
´
1 375
1 55
Very active BMR
Extremely active BMR
: .
: .
´
´
1 725
1 9
9
Nutrient
level
(mM)
5
150
100
50
10
20
30
40
pg/mL
glucagon
µU/mL
insulin
Hormone
level
4
3
2
1
4 8
Hours Days
12 16 20 24 2 3 4 5 6 3 Weeks
Glucose
Glucagon pg/mL
Insulin µU/mL
“Free” fatty acids
Ketone bodies
Fig. 32.4 Plasma levels of hormones and nutrients at different times after the last meal. mM, mmol/liter.
Table 32.6 Energy Reserves of the “Textbook” 70-kg Man
Stored Nutrient Tissue Amount Stored (kg) Energy Value (kcal)
Triglyceride Adipose tissue 10–15 90,000–140,000
Glycogen Muscle 0.3 1200
Liver 0.08* 320*
Protein Muscle 6–8 30,000–40,000
* After a meal. Liver glycogen is approximately 20% to 30% of this value after an overnight fast of 12 hours.
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540 METABOLISM
day. The rate of protein loss then declines in parallel
with the
rising use of ketone bodies. Nevertheless, 1
kg
of protein is lost within the first 15 days of starvation.
Adding 100
g of glucose to the zero-calorie diet re-
duces the need for gluconeogenesis and cuts the protein
loss by 40%. The addition of 55 g of protein per day to
the zero-calorie diet cannot prevent a negative nitrogen
balance initially, but many subjects regain nitrogen equi-
librium after about 20 days.
ADIPOSE TISSUE IS THE MOST IMPORTANT
ENERGY DEPOT
The blood glucose level declines only to a limited
extent even during prolonged fasting, but free fatty
acids rise fourfold to eightfold, and ketone
bodies
(β-hydroxybutyrate and acetoacetate) rise up to
100-fold.
Plasma free fatty acids are low after a carbohydrate
meal because insulin inhibits lipolysis in adipose tis-
sue. They are moderately high after a fat meal, because
some of the fatty acids released by lipoprotein lipase
bind to albumin, which carries them to distant parts of
the body. Insulin stimulates lipoprotein lipase in adi-
pose tissue but not in muscle after a meal, thus routing
the dietary triglycerides in chylomicrons to adipose
tissue (Fig. 32.5).
During fasting, fat synthesis in adipose tissue is re-
duced while lipolysis is stimulated by the combina-
tion of the low insulin level and high levels of insulin
TCA
cycle
Acetyl-CoA
TCA
cycle
Acetyl-CoA
(VLDL)
Chylomicrons
To liver
(for gluconeogenesis)
VLDL
To muscle and
other tissues
(for oxidation)
To liver
(for ketogenesis)
IDL
Glycerol
Glycerol
Fatty acids
Fatty acids
Glucose
Glucose
Acyl-CoA
Remnants
+
+
+
+
+
–
To liver
Glucose
Fatty acids
Fatty acids
Acyl-CoA
Glycerol
A
B
Triglycerides
Triglycerides
Glycerol- P
Glycerol- P
Glucose
LPL
LPL
Fig. 32.5 Metabolism of adipose tissue after a mixed meal containing all major nutrients and during fasting. A, After a meal.
Insulin-stimulated or insulin-inhibited steps are marked by + or −, respectively. B, During fasting. CoA, Coenzyme A, IDL,
intermediate-density lipoprotein (VLDL remnant); LPL, lipoprotein lipase; TCA, tricarboxylic acid, VLDL, very-low-density lipoprotein.
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antagonists. Non-diabetic adipose tissue is very sensitive
to insulin, and lipolysis is inhibited even at moderately
high insulin levels during the early stages of fasting.
THE LIVER CONVERTS DIETARY CARBOHYDRATES
TO GLYCOGEN AND FAT AFTER A MEAL
Being devoid of lipoprotein lipase, the liver is not
a major consumer of triglycerides after a meal al-
though it obtains some triglyceride from chylo-
micron remnants. However, the liver metabolizes
between 20% and 25% of the dietary glucose after a

carbohydrate-rich meal. Most of the rest is absorbed
by skeletal muscle. Because of the high Michaelis
constant (Km) of glucokinase for glucose, hepatic glu-
cose utilization is controlled by substrate availability.
Insulin induces the synthesis of glucokinase, but this
effect becomes maximal only after 2 or 3 days on a
high-carbohydrate diet.
The liver converts approximately two thirds of its
glucose allotment into glycogen after a meal. Most
of the rest is metabolized by glycolysis, but amino
acids rather than glucose provide most of the liv-
er’s energy needs after a mixed meal. Much of the
acetyl-
coenzyme A (acetyl-CoA) from glycolysis is
channeled into the synthesis of fatty acids and tri-
glycerides. In the liver, glycolysis is the first step in
the conversion of carbohydrate to fat. Triglycerides
and other lipids from endogenous synthesis in the
liver are exported as constituents of very-low-density
lipoprotein (VLDL). Insulin
coordinates this process
by stimulating both glycolysis and fatty acid biosyn-
thesis (Fig. 32.6).
THE LIVER MAINTAINS THE BLOOD GLUCOSE
LEVEL DURING FASTING
In the fasting state, the liver has to spoon-feed the
glucose-dependent tissues. The brain is the most de-
manding customer. It is the most aristocratic organ in
the body; therefore, it requires a large share of the re-
sources. Although the brain accounts for only 2% of
Fig. 32.6 Alternative fates of fatty acids in the liver. The regulated steps are as follows: 1 Carnitine acyl transferase-1 is
induced in the fasting state. It also is acutely inhibited by malonyl-CoA, the product of the acetyl-CoA carboxylase reaction when
fatty acid biosynthesis is stimulated after a carbohydrate-rich meal. 2 Acetyl-CoA carboxylase is induced in the well-fed state.
It is inhibited in the fasting state by high levels of acyl-CoA, low levels of citrate (direct allosteric effects), and a high glucagon/
insulin ratio (leading to phosphorylation and inactivation). 3 The tricarboxylic acid (TCA) cycle is inhibited when alternative
sources supply ATP and NADH. Therefore a high rate of β-oxidation reduces its activity. 4 The ketogenic enzymes are induced
during fasting. VLDL, Very-low-density lipoprotein.
Acetyl-CoA
Triglycerides,
Phospholipids
VLDL
Glycerol-
(Carnitine)
P
Acyl-CoA
Cytoplasm
Fatty acids
Fatty acids
Acyl-CoA
β-Oxidation
Ketone bodies
TCA
cycle
3
4
2
1
Mitochondrion
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542 METABOLISM
adult body weight, it consumes approximately 20% of
the total energy in the resting body (Table 32.5), and
up to 65% in young children. This large energy demand
is covered from glucose under ordinary conditions and
from glucose and ketone bodies during prolonged fast-
ing. The brain oxidizes 80
g of glucose per day in the
well-fed state and 30 g during long-term fasting.
Three to 4 hours after a meal, the liver becomes a net
producer of glucose. After this time liver glycogen is the
major source of blood glucose until 12 to 16 hours after
the last meal, when gluconeogenesis becomes the ma-
jor and finally the only source. This switch is required
because liver glycogen stores are almost completely ex-
hausted after 24 to 48 hours. More than half of the glu-
cose produced in gluconeogenesis is from amino acids.
Other substrates are glycerol from adipose tissue and
lactic acid from erythrocytes and other anaerobic cells
(Fig. 32.7).
In most tissues, declining insulin levels induce a
switch from glucose oxidation to the oxidation of
fatty acids and ketone bodies during the transition
from the well-fed to the fasting state. Consequently,
total body glucose consumption falls (Fig. 32.8).
Only glucose-dependent tissues, including brain and
red blood cells, do not respond to insulin and keep
consuming glucose even during long-term fasting.
The switch from glucose oxidation to fat oxidation
leads to a decline of the respiratory quotient (see
Chapter 21) from about 0.9 after a mixed meal to
slightly above 0.7 in the fasting state.
Fig. 32.7 Metabolism of the yoyo dieter’s liver. A, After a meal. Pathways that are stimulated or inhibited by insulin are marked
by + or -, respectively. B, Twelve hours after the last meal.
B
A
TCA
cycle
TCA
cycle
VLDL Glycerol
Ketone
bodies
Amino
acids
Lactate
Chylomicron remnants,
Free fatty acids
Glucose
Acetyl-CoA
Lactate
Ketone
bodies
Amino
acids
Fatty acids
Triglycerides,
Phospholipids
Pyruvate
Glycerol- P
Glucose
Glycogen
Acyl-CoA
Glucose 6-P
+ + +
–
+ –
–
VLDL Ketone
bodies
Fatty acids Glycerol Glucose Amino acids,
Lactate
Ketone
bodies
Fatty acids Glucose
Glucose 6-P
Glycogen
Acyl-CoA Acetyl-CoA
Triglycerides,
Phospholipids
Pyruvate
Amino acids,
Lactate
Glycerol- P
Continued
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10
20
30
Glucose used
(g/h)
Dietary glucose
Glycogenolysis
(liver)
Gluconeogenesis
(liver)
4h 8h 12h 16h 20h 24h 2 3 4 5 Days
6 7
Fig. 32.8 Total body glucose consumption after a meal and during fasting.
C
D
Amino acids,
Lactate
VLDL
Fatty acids
Fatty acids Glucose
Glucose
Ketone
bodies
Ketone
bodies
Glycerol
Acyl-CoA Amino acids,
Lactate
Triglycerides,
Phospholipids
Pyruvate
Glycerol-
Glucose 6-
Acetyl-CoA
Glycogen
P
P
TCA
cycle
VLDL Ketone
bodies
Amino
acids
Chylomicron remnants,
Free fatty acids Glycerol Lactate
Glucose
Ketone
bodies
Amino
acids
Fatty acids Glucose
TCA
cycle
Acyl-CoA Acetyl-CoA
Triglycerides,
Phospholipids Lactate
Glycerol-
Glucose 6-
Pyruvate
Glycogen
P
P
Fig. 32.7—cont’d C, Four days after the last meal. D, After the first good meal that follows 4 days of fasting. CoA, Coenzyme A;
TCA, tricarboxylic acid; VLDL, very-low-density lipoprotein.
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544 METABOLISM
KETONE BODIES PROVIDE LIPID-BASED
ENERGY DURING FASTING
The fasting liver spoon-feeds the other tissues with
ketone bodies as well as with glucose. In theory, both
carbohydrates and fatty acids can be converted into ke-
tone bodies through acetyl-CoA. Actually, however, the
liver forms ketone bodies from fatty acids during fasting
but not from carbohydrates after a meal.
The liver has only a moderately high capacity for
glycolysis, and much of the glycolyzed glucose is con-
verted into fat. Some is released into the blood as lactic
acid. This leaves very little for ketogenesis. However,
the liver has a very high capacity for fatty acid oxida-
tion. Over a wide range of plasma levels, about 30%
of incoming fatty acids is extracted and metabolized.
This means that hepatic fatty acid utilization is con-
trolled by substrate availability. It rises during fasting,
when adipose tissue supplies large amounts of free
fatty acids.
The fasting liver has two options for the metabolism
of these fatty acids (see Fig. 32.6). The first is esterifi-
cation into triglycerides and other lipids for export in
VLDL, which is released by the liver at all times. The
second option is uptake into the mitochondrion fol-
lowed by β-oxidation. Carnitine-palmitoyl transferase-1,
which controls the transport of long-chain fatty acids
into the mitochondrion, is induced by glucagon through
its second messenger cAMP and by fatty acids through
the nuclear fatty acid receptor peroxisome proliferator-
activated receptor-α (PPAR-α).
In the well-fed state, hepatic fatty acid oxidation is
restrained because carnitine-palmitoyl transferase-1
is inhibited by malonyl-CoA, the product of the

acetyl-CoA carboxylase reaction in fatty acid biosyn-
thesis. During fasting, however, acetyl-CoA carbox-
ylase is switched off by high levels of acyl-CoA, low
levels of citrate, and a high glucagon/insulin ratio.
Malonyl-CoA is no longer formed, and an increased
fraction of acyl-CoA is transported into the mitochon-
drion for β-oxidation.
The acetyl-CoA that is formed in β-oxidation
must be partitioned between the tricarboxylic acid
(TCA) cycle and ketogenesis. The activity of the TCA
cycle depends on the cell’s need for ATP. It is inhib-
ited by ATP and a high [NADH]/[NAD+
] ratio (see
Chapter 22). β-
Oxidation produces NADH and, indi-
rectly, ATP. By inhibiting the TCA cycle, NADH and
ATP divert
acetyl-CoA from TCA cycle oxidation to
ketogenesis.
Ketogenesis amounts to an incomplete oxidation
of fatty acids. Whereas the complete oxidation of one
molecule of palmitoyl-CoA produces 131 molecules of
ATP (see Chapter 25), its conversion to acetoacetate
and β-hydroxybutyrate produces 35 and 23 molecules
of ATP, respectively. The conversion of 50
g of fatty ac-
ids to acetoacetate during a hungry day supplies enough
energy to synthesize 190
g of glucose from lactic acid
without any need for the TCA cycle.
Why does the liver convert fatty acids to ketone
bodies when carbohydrates are scarce? The main rea-
son is that the brain can oxidize ketone bodies but not
fatty acids. Although the brain obtains almost all of its
energy from glucose under ordinary conditions, it cov-
ers up to two thirds of its energy needs from ketone
bodies during prolonged fasting, when ketone body
levels are very high. This reduces the need for gluco-
neogenesis and thereby spares body protein. Liver me-
tabolism in different nutritional states is summarized
in Fig. 32.7.
The nutrient flows in the body change dramatically
in different nutritional states. Fig. 32.9 shows the flow
of nutrients after different kinds of meals. Fig. 32.10
shows the changes during the transition from the well-
fed state to prolonged fasting. The intestine provides for
all of the body’s needs after a mixed meal, but adipose
tissue and liver assume this role during fasting.
The refeeding of severely starved patients can be
problematic. The levels of glycolytic enzymes in the
liver are very low, and patients show profound carbohy-
drate intolerance. Therefore refeeding should be started
slowly, especially in advanced cases.
OBESITY IS COMMON IN ALL AFFLUENT
COUNTRIES
Obesity is not a disease, but the normal result of over-
eating. Its prevalence depends not only on the tastiness
of the available food, but also on the definitions used.
The most commonly used measure, the body mass index
(BMI), is defined as follows:
A BMI of 18.5 to 24.9
kg/m2
is considered normal;
a BMI between 25 and 29.9 signifies overweight, and a
BMI of 30 or greater is defined as obesity. In 2010, 36%
of adults qualified as obese in the United States, 24%
in Canada, and 26% in Britain. In the United States

obesity-associated health problems make up approxi-
mately 20% of the total health care costs.
Body weight changes over the life span. In affluent
countries, women tend to gain weight between the
ages of 20 and 60 years. Men tend to gain weight
more slowly from age 20 to age 50 years and to get
thinner again after age 60. Lean body mass declines
slowly in old age, so that those who maintain a con-
stant weight are gaining in fat. Without overeating,
a slow decline of both muscle and fat is considered
normal in old age.
Until the early years of the twentieth century, body
weight was related to social class, with rich people
being heavier than poor people. Socioeconomic sta-
tus (SES) still is important today, but now poor peo-
ple are fatter than the rich. A study in the United
BMI Weight Height
= / 2
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States found that 30% of low-SES women, 16% of
middle-SES women, but only 5% of upper-SES women
were obese. A similar but weaker relationship was
seen in men.
Obesity is not a death sentence. Table 32.7 shows
the risk of death for people with different BMI. We see
that those who are classified as overweight or mildly
obese are a little less likely to die than those with an
“ideal” weight. This is especially the case for older
subjects. Only those with a BMI above 35 have a sub-
stantially elevated mortality risk. Fig. 32.11 confirms
this result for community-living persons aged 65 and
older. In this study the optimal BMI was 28, in the
overweight range.
A
B
C
Brain
Glycogen
Intestine Liver
Muscle
Adipose
tissue
Glucose
Acetyl-CoA
VLDL
Triglycerides
Glucose
Brain
Glycogen
Intestine
Liver
Muscle
Glucose
Amino acids
Pyruvate
Triglycerides
Fatty
acids
Adipose
tissue
Acetyl-CoA
Brain
Glycogen
Intestine
Fatty
acids
Amino
acids
Adipose tissue
Liver
Muscle
Glucose
Pyruvate
Ketone bodies
Triglycerides
Chylomicrons
Fig. 32.9 Disposition of nutrients after different types of meals. A, After a carbohydrate meal (insulin high, glucagon low).
B, After a protein meal (insulin moderately high, glucagon high). C, After a fat meal (insulin low, glucagon high). CoA,
Coenzyme A; VLDL, very-low-density lipoprotein.
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546 METABOLISM
However,before advocating weight gain as a way to pro-
long life, we need to consider that weight loss can be a sign
of deteriorating health. Under conditions where all healthy
people overeat and become obese, only those who are in
poor health remain thin. In old age, weight loss is part of
the normal aging process. Therefore old people with a low
BMI tend to be those in whom the aging process is more
advanced than in same-aged people with a higher BMI.
Correlation does not prove a cause-and-effect relationship.
In long-term studies extending over several decades,
not only a greater severity of obesity, but also a longer
duration of obesity is associated with higher all-cause and
cardiovascular mortality. In one study, having been obese
for 25 years or more raised the risk of death by a factor
of 2.5 compared with those who have never been obese.
Obesity is associated with some salient health problems.
For every 10% rise in relative weight, systolic blood pres-
sure rises by 6.5 mm Hg, cholesterol by 12 mg/dL, and fast-
ing blood glucose by 2
mg/dL in men. These associations
are only a bit weaker in women. Most important of all,
obesity is the most important risk factor for type 2 diabetes.
APPETITE CONTROL IS THE MOST IMPORTANT
DETERMINANT OF OBESITY
Obesity is inevitable when energy intake exceeds energy
consumption. After adjustment for age, sex, weight, and
lean body mass versus fat, obese people have virtually
the same metabolic rate as lean people. This implies that
17.5
0.90
1.00
1.10
1.20
1.30
1.40
1.50
1.60
20
Spline Model
95% Cl
Body Mass Index (kg/m2
)
Hazard
Ratio
22.5 25 27.5 30 32.5 35 37.5
Fig. 32.11 Mortality risk of community-living people aged
65 and older, related to body mass index. (Data from Winter JE,
MacInnis RJ, Wattanapenpaiboon N, Nowson CA. (2014). BMI and
all-cause mortality in older adults: A meta-analysis. American Journal of
Clinical Nutrition, 99, 875-890.)
Glucose
A
C
Intestine
Liver
Brain
Amino acids
Pyruvate
Acetyl-CoA
Triglycerides
Adipose
tissue
Muscle
Triglycerides
(chylomicrons)
Glycogen
Triglycerides
VLDL
Intestine Liver Brain
Brain
Muscle
Amino
acids
Adipose
tissue
Glucose
Pyruvate
Ketone bodies
Triglycerides
Acetyl-CoA
Fatty acids
Fatty
acids
Intestine
Glycogen
Protein
Triglycerides
Triglycerides
Liver Muscle
Adipose
tissue
Fatty acids
Triglycerides
Ketone bodies
Pyruvate
Glucose
Acetyl-CoA
Fatty
acids
Amino
acids
Protein
B
Fig. 32.10 Interorgan transfer of nutrients after a mixed
meal and during fasting. A, After a mixed meal.
B, Postabsorptive state, 12 hours after the last meal.
C, One week after the last meal. CoA, Coenzyme A; VLDL,
very-low-density lipoprotein.
Table 32.7 Association of All-Cause Mortality with Different
Body Mass Index (BMI) Categories. Hazard Ratios Are Given
Relative to a “Normal” BMI of 18.5–24.9
Hazard Ratio (95% Confidence
Interval)
BMI All Ages Age ≥65
25-29.9 0.93 (0.89–0.95) 0.90 (0.84–0.95)
30-34.9 0.94 (0.86–1.03) 0.89 (0.71–1.11)
35 + 1.25 (1.13–1.39) 1.10 (0.89–1.34)
Data from Flegal KM, Kit BK, Orpana H, Graubard BI. (2013). Association
of all-cause mortality with overweight and obesity using standard body mass
index categories. Journal of the American Medical Association 309, 71–82.
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individual variations in appetite control, rather than
metabolic rate, are the most important cause of obesity.
The broad heritability of BMI is around 70% in mod-
ern societies. Several rare monogenic forms of obesity
are known. Most of them affect brain-expressed genes
or genes whose products act on the brain. Many of the
97 common polymorphisms affecting BMI that had
been discovered by 2015 are in genes that are related
to brain function. The genes that affect obesity risk act
mainly through the mechanisms of appetite control.
Appetite is controlled by chemical signals that inform
the brain about the nutrient status of the body. High
levels of blood glucose and fatty acids signal nutrient
abundance and suppress appetite. Their effects are re-
inforced by hormones that are released by the intestine,
pancreas, or adipose tissue.
Fig. 32.12 shows the more important effects. Only
ghrelin, formed in the stomach, is released during
fasting.
Predictably, ghrelin makes us hungry. The other hor-
mones are released in response to eating and cause sa-
tiety. Two of the intestinal hormones, gastric inhibitory
polypeptide (GIP) and glucagon-like peptide-1 (GLP-1),
stimulate insulin secretion. These insulin-releasing hor-
mones are called incretins. GLP-1 is derived from the
same
messenger RNA and prohormone as glucagon by
different post-translational processing of the prohor-
mone. However, it is synthesized in different endocrine
cells, and unlike glucagon, GLP-1 is synergistic with in-
sulin. The pancreatic β-cells release not only insulin after
a meal, but also the polypeptide hormone amylin. While
insulin stimulates the metabolic pathways that utilize the
nutrients, amylin reduces nutrient supply by delaying gas-
tric emptying and reducing appetite.
Adipose tissue contributes leptin, which is released
when the adipose cells are“filled.”Its main effect is on the
hypothalamus, where it suppresses appetite, but it also
has metabolic effects that overlap with those of insulin.
Deficiency of either leptin or the leptin receptor is a rare
cause of morbid obesity. Circulating leptin levels rise after
a meal and are chronically elevated in obesity, roughly
in proportion to the increase in adipose tissue mass.
However, obesity is accompanied by leptin resistance.
Thus leptin seems to participate in the hour-to-hour regu-
lation of food intake but fails to prevent overeating when
adipose mass is excessive.
Normally, the number of adipocytes increases five-
fold between the ages of 2 and 22 years. Only 10% of
adipocytes are renewed per year during adult life, and
a common concern is that overeating at a young age
leads to adipose tissue hyperplasia that is difficult to
reverse. On the other hand, adipose tissue hypertrophy
(increased amount of fat per cell) rather than adipose
tissue hyperplasia (increased number of adipocytes) is
assumed to lead to metabolic abnormalities.
Typically, the metabolic rate of obese people drops by
15% to 20% during weight loss and remains reduced
when weight is stabilized at a lower level. Thus the ex-
obese have to live permanently with a metabolic rate that
is otherwise typical for long-term fasting. This is a likely
reason why 80% to 85% of weight-reduced obese patients
quickly regain until they reach their previous weight. We
do not know whether sustained weight reduction for at
least a decade leads to a reduced number of adipocytes.
OBESITY IS RELATED TO INSULIN RESISTANCE
Obesity is more than a cosmetic problem. It is associated
with metabolic abnormalities and indirectly with the
complications of these abnormalities. Insulin resistance
and carbohydrate intolerance are especially important.
Normally, adipose tissue releases free fatty acids into
the blood. It does so mainly during fasting, but also to
a much lesser extent after a meal when lipolysis is sup-
pressed by insulin. This implies that, everything else be-
ing equal, fat people release more fatty acids into their
blood than skinny people. Of the different fat depots,
visceral (omental and mesenteric) adipose tissue is met-
abolically more active than subcutaneous adipose tissue.
It is more sensitive to β-
adrenergic stimulation and re-
leases more fatty acids into the blood. Also, the fatty
acids released by visceral adipose tissue have immediate
access to the liver through the portal circulation.
Fatty acid metabolism inhibits carbohydrate metabo-
lism.TheATPgeneratedbyfattyacidoxidationinhibitsthe
PFK-1 and pyruvate kinase reactions of glycolysis, while
fatty acid derived acetyl-CoA stimulates pyruvate carbox-
ylase and ATP
stimulates
fructose-1,6-bisphosphatase in
Leptin
PYY
Hypothalamus
Adipose
tissue
Stomach
Upper
intestine
Lower
intestine
Vagus
nerve
β-cells
GIP
CCK
GLP-1
Ghrelin
Insulin
Amylin
Fig. 32.12 Factors affecting appetite control. Important
brain structures on which these hormones act include the
ventromedial hypothalamus and the arcuate nucleus. With the
exception of ghrelin, which is released when the stomach is
empty, the appetite-regulating hormones are released after a
meal when nutrients are abundant. CCK, Cholecystokinin; GIP,
gastric inhibitory polypeptide (or glucose-induced insulinotropic
peptide); GLP-1, glucagon-like peptide-1; PYY, peptide YY.
, stimulation; , inhibition.
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548 METABOLISM
gluconeogenesis. Pyruvate dehydrogenase is inhibited by
all products of fatty acid oxidation: acetyl-CoA, NADH,
and ATP.
In addition, oversupply of fatty acids inhibits the in-
sulin signaling cascades. The insulin receptor substrates,
IRS1 and IRS2, are important targets of regulation. These
proteins mediate the major metabolic effects of insulin
through the phosphoinositide-3-kinase–Akt2 signaling
cascade. The IRS proteins become phosphorylated on
tyrosine side chains by the activated insulin receptor, but
they can also be phosphorylated on serine side chains by a
variety of serine-threonine–specific protein kinases. Most
of the Ser/Thr phosphorylations are inhibitory.They block
insulin signaling by preventing tyrosine phosphorylation
of IRS by the activated insulin receptor.
Fig. 32.13 shows some of the mechanisms. First, the
IRS proteins can be serine/threonine-phosphorylated by
mTORC1 and by kinases downstream of mTORC1, such
as the S6 kinase, which is otherwise involved in insulin ef-
fects on ribosomal protein synthesis.This is an example of
feedback inhibition, designed to prevent overstimulation
of the cell by insulin. However, mTOR is stimulated by
fatty acids and amino acids in addition to being a target of
insulin signaling. Therefore overnutrition can contribute
to insulin resistance by stimulating mTORC1.
Another mechanism is ectopic accumulation of fat in
muscle and liver.These tissues esterify excess fatty acids into
triglycerides when fatty acids are abundant. The fat that
deposits in these organs has a fast turnover, which forms
1,2-diacylglycerol as an intermediate. Diacylglycerol acti-
vates protein kinase C (PKC), including some isoenzymes
(PKCδ and PKCθ in muscle and PKCε in the liver) that in-
duce insulin resistance by phosphorylating IRS proteins.
Fat deposition in the liver is especially problematic.
Simple fat accumulation (steatosis) can eventually trigger
inflammation (steatohepatitis), which in some
patients,
progresses to necrosis of hepatocytes and
reactive
fibrosis (cirrhosis). The condition, diagnosed as nonal-
coholic fatty liver disease, has developed into a serious
public health problem as part of the “obesity epidemic.”
In addition to accumulating in the liver, excess fat is
exported in VLDL. The resulting hypertriglyceridemia
is a risk factor for atherosclerosis and its complications.
In adipose tissue, obesity is frequently associated with
chronic low-grade inflammation. Normal adipose tissue
contains an assortment of immune cells, including a
sizeable population of macrophages. These are alterna-
tively activated (or M2) macrophages, which do routine
maintenance work without causing inflammation. They
are kept in this state by the antiinflammatory cytokines
interleukin-4 and interleukin-13, which are secreted by
eosinophils.
For unknown reasons, in obesity, these macrophages
tend to switch to the classically activated (M1) pheno-
type,which releases proinflammatory cytokines including
tumor necrosis factor-α (TNF-α). TNF-α causes insulin
resistance, at least in part by activating several protein
kinases that phosphorylate IRS proteins (Fig. 32.13).
It does so most directly as a paracrine agent in adipose
tissue but is also released into the blood and can there-
fore cause insulin resistance in other tissues as well.
The term metabolic syndrome is applied to a com-
bination of abnormalities that are frequently asso-
ciated with obesity. Different definitions have been
proposed by different organizations. For example,
the International Diabetes Federation defines meta-
DAG
Triglycerides
Protein, fat
IRS
PI3K
Akt2
mTORC1 S6K
Hormones
InsR
P P P
P
P
P
P
P
P P P P P
PKC
Kinases
TNFR
Insulin TNF-α
Gq-R
Fig. 32.13 Regulation of insulin signaling by protein kinases phosphorylating insulin receptor substrate (IRS) proteins on
serine and threonine side chains. Akt2, the insulin-stimulated isoenzyme of protein kinase B (Akt); DAG, 2,3-diacylglycerol;
Gq-R, receptor coupled to Gq proteins; InsR, insulin receptor; IRS, insulin receptor substrate; mTORC1, mTOR, complex 1;
PI3K, phosphoinositide-3-kinase; PKC, protein kinase C (δ, ε, and θ isoenzymes); S6K, S6 kinase; TNFR, tumor necrosis factor-α
receptor. These mechanisms can cause insulin resistance in patients with metabolic syndrome and type 2 diabetes.
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bolic syndrome as the presence of abdominal obesity
(with gender- and
ethnicity-specific cutoffs for waist
circumference) combined with at least two of the fol-
lowing: (1) fasting triglycerides 150
mg/dL; (2) HDL
cholesterol 40
mg/dL (men) or 50 mg/dL (women);
(3) blood pressure systolic ≥130 or diastolic ≥85 mm
Hg; (4) fasting plasma glucose 100
mg/dL or previ-
ously diagnosed type 2
diabetes. Some other definitions
also include elevation of inflammatory markers (e.g.,
C-reactive protein).
The underlying cause of metabolic syndrome is over-
eating of foods with high caloric density (also described
as gluttony). However, exceptions to these statistical as-
sociations are frequent. There are many metabolically
healthy obese individuals who develop neither insulin
resistance nor the other components of the metabolic
syndrome. Conversely, a substantial minority of type 2
diabetics are not overweight or obese, and the associa-
tions of hypertension and dyslipidemia with obesity and
insulin resistance are quite low. Therefore the usefulness
of metabolic syndrome as a diagnostic category is much
disputed.
DIABETES IS CAUSED BY INSULIN DEFICIENCY
OR INSULIN RESISTANCE
Diabetes mellitus is caused by a relative or absolute de-
ficiency of insulin action. Hyperglycemia (abnormally
elevated blood glucose) is the biochemical hallmark of
diabetes mellitus, but the pathways of all major
nutrients
are deranged. The two major primary forms of diabetes
are type 1 and type 2 (Table 32.8).
Type 1 diabetes typically starts in childhood or ad-
olescence. It is an autoimmune disease that leads to
destruction of pancreatic β-cells. Without endogenous
insulin production, patients depend on insulin injections
for life. Being a protein, insulin is not orally
active be-
cause it is destroyed by digestive enzymes. Type 1 diabe-
tes afflicts perhaps 1 in 400 individuals, and its incidence
is not strongly related to lifestyle.
Type 2 diabetes is a disease of middle-aged and
older individuals (Fig. 32.14). It is far more common
than type 1, is less severe, and has more complex ori-
gins. The pancreatic β-cells are intact in the early stages,
and the plasma level of insulin can be normal, reduced,
or elevated. These patients have either reduced insulin
secretion or insulin resistance, or a combination of both.
According to one estimate, worldwide 382 million peo-
ple had diabetes in 2013, and the prevalence rises steeply
with rising affluence. In the United States the prevalence
of diabetes among adults aged 20 years and older rose
from 5.5% in 1991 to 9.3% in 2005 to 2010.
Most patients with poorly controlled type 1 dia-
betes are thin, but most type 2 patients with diabe-
tes are obese. In one study, the age-adjusted risk for

developing type 2 diabetes was increased by a factor
of 2.7 for the overweight and 7.3 for the obese, com-
pared with normal-weight men. Obesity is not a con-
sequence of diabetes, but precedes the onset of type 2
diabetes by many years or decades. Insulin is an ana-
bolic hormone. Therefore without intervention, loss of
insulin action reduces body weight. Conversely, most
type 2 diabetics gain weight when they are placed on
insulin treatment.
Obese patients with type 2 diabetes are invariably
insulin resistant. Even nondiabetic obese individuals
have, on average, higher insulin levels than do thin
people, and their tissue responsiveness is proportion-
ately reduced. Impaired intracellular insulin signal-
ing, rather than reduced receptor number, is the main
cause of insulin resistance. Insulin resistance is com-
pensated for by increased insulin secretion, and many
obese people can remain normoglycemic for decades
because hyperinsulinemia compensates for their insu-
lin resistance.
Type 2 diabetes results only when the β-cells cannot
keep up with the demand. As the disease progresses, the
β-cells tend to “burn out” (Clinical Example 32.1). In
Table 32.8 Typical Features of the Two Major Types of
Diabetes Mellitus
Parameter Type 1 Type 2
Age at onset (years) ≤20 20
Lifetime incidence 0.2%–0.4% 20–25%
Heritability ≈50% ≈80%
Pancreatic β-cells Destroyed Initially normal
Circulating insulin Absent Normal, high, or low
Tissue response to
insulin
Normal Reduced (most
patients)
Fasting hyperglycemia Severe Variable
Metabolic
complications
Ketoacidosis Nonketotic
hyperosmolar coma
Treatment Insulin Diet, oral antidiabetics,
or insulin
20
15
10
5
18-29:
1.7%
30-39:
4.1%
40-49:
6.6%
50-59:
11.2%
60-69:
15.1%
70:
15.5%
Age
Prevalence
(%)
Fig. 32.14 Prevalence of diabetes mellitus in the United
States in 2001. The large majority of cases are type 2
diabetes. From: Mokdad, A. H., et al. (2003). Prevalence of obesity,
diabetes, and obesity-related health risk factors, 2001. Journal of the
American Medical Association, 289(1), 76-79.
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550 METABOLISM
early-stage obese type 2 diabetics, a balanced weight-
reduction diet can restore tissue responsiveness to insu-
lin and reduce blood glucose and insulin levels.
IN DIABETES, METABOLISM IS REGULATED AS
IN STARVATION
The declining level of plasma insulin mediates most of
the metabolic adaptations to food deprivation.Therefore
the metabolic changes of diabetes resemble those of star-
vation (Fig. 32.15).
The hyperglycemia of diabetes mellitus is caused by
overproduction and underutilization of glucose. The
liver makes rather than consumes glucose, and mus-
cle and adipose tissue fail to take up glucose from the
blood. There is also excessive lipolysis in adipose tissue.
The levels of plasma free fatty acids rise, and the liver
turns excess fatty acids into ketone bodies. These are
the same changes that occur in starvation, when liver
and adipose tissue keep everyone else alive by doling out
glucose, fatty acids, and ketone bodies.
The oversupply of fatty acids reduces glucose catabo-
lism in liver and skeletal muscle. As we saw before, this
is achieved both by allosteric actions of the products of
fatty acid catabolism and by actions on insulin signaling
that are mediated by protein kinases (see Fig. 32.13).
Because a high-fat diet induces insulin resistance, dietary
treatment of obese type 2 diabetics is based on the re-
Brain
Glycogen
Glucose
Pyruvate
Ketone bodies
Triglycerides
Acetyl-CoA
Fatty acids
Fatty
acids
Adipose tissue
Liver
Muscle
Amino
acids
Glucose
(accumulates)
Amino acids
Ketones
(depleted)
Protein
Triglycerides
Fig. 32.15 Disposition of the major nutrients
in diabetes mellitus (postabsorptive state).
CLINICAL EXAMPLE 32.1: Islet Amyloid
Most type 2 diabetics who live with their disease for
many years develop progressive β-cell dysfunction and
reduced β-cell mass, leading to declining insulin levels
and the need for insulin injections.
One likely reason for the “burnout” of β-cells is the
progressive deposition of islet amyloid in the islets
of Langerhans. Islet amyloid is an abnormally folded
form of the hormone amylin, which is secreted by
the β-cells together with insulin and C peptide. Amylin
has hormonal effects that are synergistic with those of
insulin. It delays gastric emptying, and it acts on the
brain to reduce appetite. In insulin-resistant patients,
the secretion of both amylin and insulin is increased.
This raises the local concentration of amylin and favors
its aggregation into amyloid fibrils.
Unlike human amylin, mouse amylin does not
form amyloid. Normal laboratory mice do not become
diabetic spontaneously. However, transgenic mice that
produce human amylin instead of mouse amylin do
develop diabetes that is frequently (but not always)
accompanied by amyloid deposition in the islets. The
diabetogenic effect is attributed to soluble oligomers
of the islet amyloid rather than the insoluble deposits.
Whether transgenic humans expressing the gene for
mouse amylin would be resistant to type 2 diabetes is
unknown.
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striction of total calories, not the replacement of carbo-
hydrates by fat.
However, endogenous fat is more problematic than
dietary fat. Incomplete suppression of adipose tissue li-
polysis by insulin in the well-fed state raises the plasma
free fatty acid level. Oxidation of these fatty acids im-
pairs glucose oxidation in muscle and liver, and it raises
triglyceride synthesis and VLDL formation in the liver.
In both healthy and diabetic individuals, more than
half of the fatty acids in VLDL triglycerides are derived
from adipose tissue, with smaller portions coming from
dietary sources and endogenous fatty acid synthesis.
Elevated VLDL is a risk factor for atherosclerosis (see
Chapter 27).
The acute complications of diabetes include diabetic
ketoacidosis in type 1 diabetes (Clinical Example 32.2)
and nonketotic hyperosmolar coma in elderly patients
with type 2 diabetes. The latter is caused by excessive
glucosuria with osmotic diuresis. If the patient forgets
to drink, dehydration can become sufficiently severe to
affect the brain.
Overtreatment of diabetes with insulin or oral an-
tidiabetic drugs leads to episodes of hypoglycemia. It
presents with dizziness, lightheadedness, sweating,
trembling, tachycardia, and pale skin and can progress
to loss of consciousness. These signs are caused by brain
dysfunction and by compensatory hyperactivity of the
sympathetic nervous system. Therefore patients must
be educated to time their insulin injections with their
meals.
Increasingly, insulin pumps with adjustable flow rate
are used by diabetic patients. Combination of an insulin
pump with a subcutaneously implanted glucose monitor
can, in theory, provide a feedback-regulated system for
the maintenance of a constant blood glucose level. Such
systems are currently being developed.
In some persons without diabetes,hypoglycemic spells
are caused by an insulinoma, a rare insulin-secreting tu-
mor of pancreatic β-cells. The diagnosis is established by
the measurement of elevated levels of circulating insulin
and C-peptide (see Chapter 15).
DIABETES IS DIAGNOSED WITH LABORATORY
TESTS
Urinalysis is a quick screening test for diabetes mel-
litus. Whenever the blood glucose level exceeds 9
to 10
mmol/L (160–180
mg/dL), glucose appears in
the urine. Also ketone bodies are excreted in dia-
betic urine and are measured routinely in addition
to glucose.
Unlike urine tests, which are semiquantitative,
blood tests provide quantitative results. A fasting
blood glucose level greater than 7.8 mmol/L (140 mg/
dL) on two different occasions frequently is used as a
diagnostic cutoff. Borderline cases can be evaluated
with the glucose tolerance test. It involves repeated
measurements of blood glucose both immediately
before and at different intervals after ingestion of a
glucose solution (Fig. 32.16). Both the fasting blood
glucose concentration and, to a far greater extent, the
CLINICAL EXAMPLE 32.2: Diabetic Ketoacidosis
The complete absence of insulin in type 1 diabetes leads
to diabetic ketoacidosis, which presents with malaise,
nausea, hyperventilation, sweating, tachycardia,
postural hypotension, and neurological derangements.
Untreated it can lead to circulatory collapse, loss of
consciousness, and death.
Ketoacidosis develops when the liver produces ketone
bodies (acetoacetic acid and β-hydroxybutyric acid) faster
than they can be oxidized. Being acids, the ketone bodies
acidify the blood. Ketosis is accompanied by blood glucose
levels that can be as high as 1000 mg/dL. Large amounts of
glucose and ketone bodies are lost in the urine, and osmotic
diuresis causes dehydration and electrolyte imbalances.
Osmotic diuresis and acidosis reduce the blood
pressure through hypovolemia and peripheral vasodilation,
respectively. Hypotension activates the sympathetic
nervous system, which attempts to restore a normal
blood pressure by stimulating the heart and contracting
peripheral resistance vessels. However, it also stimulates
fat breakdown in adipose tissue and thereby supplies the
liver with even more substrate for ketogenesis.
Because of this vicious cycle, ketoacidosis is fatal if
untreated. Proper treatment includes fluid replacement,
correction of the acidosis, and generous insulin
injections. The CNS depression in diabetic ketoacidosis
is not caused by excess glucose. Hyperglycemia is not
acutely damaging to the brain. It rather is caused by
dehydration, electrolyte disturbances, and acidosis.
Normal
range
Blood
glucose
(mg/dL)
300
200
100
Glucose
ingestion
1h 2 h
Diabetic
Time
11/2 h
1/2 h
Fig. 32.16 Glucose tolerance test. Blood glucose is
measured at different time intervals after oral ingestion
of a flavored glucose solution (75 g of glucose). In normal
individuals, but not in diabetic patients, the blood glucose
returns to the fasting level within 2 hours.
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552 METABOLISM
glucose tolerance test show wide variations among
healthy individuals. Therefore the diagnostic cut-
off between “normal” and “diabetic” is as arbitrary
as that between “pass” and “fail” on a biochemistry
examination.
Hemoglobin A1C is formed by nonenzymatic glyco-
sylation of the terminal amino groups in the α-chains
and β-chains (Fig. 32.17). It is measured to assess long-
term metabolic control of diabetes. The concentration
of glycosylated hemoglobin is proportional to the blood
glucose level. It is 4% to 5.9% in normal individuals
and greater than 6% in diabetic patients. A target value
of 7% is frequently cited for diabetes treatment, but is
difficult to achieve without serious risks of hypoglyce-
mia. Because hemoglobin has a life span of 4 months,
hemoglobin A1C provides information about the average
severity of hyperglycemia during the weeks to months
preceding the test.
DIABETES LEADS TO LATE COMPLICATIONS
Many diabetic patients develop accelerated atheroscle-
rosis, nephropathy, retinopathy, cataracts, and/or pe-
ripheral neuropathy many years after the onset of their
disease. Diabetes is an important cause of blindness,
renal failure, and excess cardiovascular mortality. Two
biochemical mechanisms have been proposed for dia-
betic complications:
1. Nonenzymatic glycosylation of terminal amino
groups (see Fig. 32.17) impairs the normal function
or turnover of proteins. This mechanism has been
suggested for the thickening of basement membranes
that is observed in the renal glomeruli of diabetic
patients.
2. Increased formation of sorbitol and fructose by
the polyol pathway (see Chapter 24) is favored by
hyperglycemia:
Glucose
NADPH, H+
NADP+
Sorbitol
Fructose
NAD+
NADH, H+
Aldose
reductase
Sorbitol
dehydrogenase
The Km of aldose reductase for glucose is near
200 mmol/L, which is 40 times higher than the normal
blood glucose level. Therefore the reaction rate de-
pends directly on the glucose concentration. Sorbitol
and fructose not only are osmotically active but also
interfere with the metabolism of inositol. Aldose re-
ductase is abundant in Schwann cells of peripheral
nerves, papillae of the kidney, and lens epithelium,
sites that are affected by diabetes.
In diabetic patients, the intracellular glucose concentra-
tion is not elevated in muscle and adipose tissue, whose
glucose uptake is insulin dependent. However, nerve
sheaths, endothelial cells, kidneys, and the retina have
insulin-independent glucose uptake. These tissues are
most vulnerable to diabetes.
Most of the late diabetic complications are related to
vascular changes. They include thickening of subendo-
thelial basement membranes, increased capillary permea-
bility, and accumulation of plasma proteins in interstitial
CH2OH
CHO
HC—OH
HC—OH
HO—CH
HC—OH
CH2OH
CH
HC—OH
HC—OH
HO—CH
HC—OH
CH2
C O
HC—OH
HC—OH
HO—CH
CH2OH
Glucose
Protein
Protein Protein
Aldimine
derivative
Stable
product
(slow, irreversible)
Amadori rearrangement
(fast, reversible)
Schiff base formation
+
N
NH2
NH
G
Fig. 32.17 Nonenzymatic glycosylation of the terminal amino groups in proteins. A stable fructose derivative is formed in these
reactions. Hemoglobin A1c and glycosylated albumin are formed this way.
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spaces below the endothelium. Proteinuria caused by
abnormalities of the glomerular basement membrane
and macular edema in diabetic retinopathy are examples
of the role of vascular changes. Therefore cardiovascu-
lar risk factors such as hypertension and dyslipidemia
should be treated aggressively in diabetic patients.
MANY DRUGS ARE AVAILABLE FOR DIABETES
TREATMENT
Patients with type 1 diabetes can only be treated with
insulin, administered by injection or infusion pump. The
main treatment challenges are adjustment of the insulin
dose and patient education to ensure proper timing of
insulin administration with meals.
There is a greater variety of treatment options for
type 2 diabetes. Lifestyle change is the first treatment
modality to be tried in early-stage, mildly affected
patients. Weight reduction by caloric restriction in-
creases insulin sensitivity and lowers both glucose and
insulin levels, especially in combination with regular
physical exercise. For nonobese patients, substantial
weight reduction is not an option but regular exercise
is recommended.
Oral antidiabetic drugs are the next line of treatment:
1. Metformin is a weak inhibitor of respiratory complex
I in the mitochondria. It causes a mild reduction in the
cellular energy charge, not enough to cause functional
impairment but enough to trigger adaptive changes.
Its most important effect is inhibition of hepatic glu-
coneogenesis. Reduced energy charge inhibits pyru-
vate carboxylase and fructose 1,6-
bisphosphatase
directly, and the AMP-activated protein kinase sup-
presses the expression of gluco
neogenic genes by
phosphorylating several transcription factors. Other
effects of AMP kinase activation include reduced fatty
acid synthesis in the liver and enhanced activity of
GLUT4 transporters in muscle and adipose tissue.
2. Sulfonylureas are insulin releasers. They bind to a
component of the KATP channel in pancreatic β-cells,
favoring its closure and thereby causing membrane
depolarization, calcium entry, and insulin release
(see Fig. 32.1). Unlike metformin, the sulfonylureas
lead to weight gain as a result of increased insulin
levels.
3. Thiazolidinediones (glitazones) sensitize cells to in-
sulin by activating the transcription factor PPAR-γ
(peroxisome proliferator activated receptor-γ). They
may increase the risk of acute myocardial infarction,
possibly by stimulating the uptake of oxidized lipo-
proteins by macrophages.
4. DPP-4 inhibitors (gliptins) inhibit dipeptidyl
peptidase-4. This enzyme inactivates the two incre-
tins GLP-1 (glucagon-like peptide-1) and GIP (gastric
inhibitory polypeptide). The effects are increased insu-
lin secretion and reduced appetite (see Fig. 32.12).
5. GLP-1 agonists activate the GLP-1 receptor. Like the
DPP-4 inhibitors, they tend to reduce food intake
and body weight in addition to raising insulin.
6. SGLT2 inhibitors block sodium-glucose transporter-2
(SGLT2), the sodium-dependent glucose carrier that
reabsorbs most of the glucose from the proximal re-
nal tubules. Rather than improving the body’s capac-
ity to metabolize glucose, these drugs remove excess
glucose by increasing its renal excretion.
Type 2 diabetics whose condition cannot be controlled
adequately with orally active drugs require insulin, ad-
ministered by injection or infusion pump.
CONTRACTING MUSCLE HAS THREE ENERGY
SOURCES
Resting skeletal muscle accounts for 20% to 25% of
the basal metabolic rate. Glucose is an important energy
source after a carbohydrate-rich meal, but fatty acids
are the major energy source in the postabsorptive state.
During vigorous contraction, the energy expenditure
of the active muscles can rise 50-fold above the resting
level. The energy is supplied by three metabolic systems.
Creatine Phosphate
During vigorous contraction, all ATP would be hydro-
lyzed to ADP and phosphate within 2 to 4 seconds. In this
situation, the fastest way to regenerate ATP is the revers-
ible creatine kinase reaction (Fig. 32.18). The reaction
equilibrium (ΔG0′ = −3.0
kcal/mol for ATP formation)
favors ATP and creatine. The concentration of creatine
phosphate in resting muscle is at least 20
mmol/kg,
whereas the ATP concentration is only 5 to 6
mmol/kg
(Table 32.9).
During contraction, creatine phosphate is utilized
while the ATP concentration is only slightly reduced
from its resting level. This system requires neither ox-
ygen nor nutrients, but it can supply ATP for only 6 to
20 seconds of vigorous exercise. It is the main energy
source for weight lifting and during a 100-m sprint.
Creatine is not degraded enzymatically, but creatine
phosphate cyclizes spontaneously to creatinine. Because
the creatinine concentration in the plasma is more or
less constant and creatinine is neither secreted nor re-
absorbed to any great extent in the kidney tubules, it is
used for determination of the glomerular filtration rate
(“creatinine clearance”).
Anaerobic Glycolysis
Stored glycogen (Glc)n is the major substrate for glycol-
ysis in skeletal muscle:
Glc ADP P
Glc Lactate ATP H O
n i
n
( ) + +
¯
( ) + + +
-
3 3
2 3 2
1 2
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Meisenberg, 978-0-323-29616-8
B978-0-323-29616-8.00032-3, 00032
554 METABOLISM
This system requires no oxygen, but it is limited by
the accumulation of lactic acid, which acidifies the tis-
sue and inhibits phosphofructokinase-1 (Fig. 32.19).
Anaerobic glycolysis is the most important energy
source between 20 seconds and 2 minutes after onset of
vigorous exercise.
Oxidative Metabolism
Oxidative metabolism produces at least 10 times more
ATP than does anaerobic glycolysis from glycogen, but
it is limited by the oxygen supply. The relative contri-
butions of carbohydrate and fat during aerobic exer-
cise depend on its intensity and duration. Fatty acids
are the main fuel during mild exercise, but carbohy-
drate in the form of stored muscle glycogen becomes
increasingly important during more vigorous con-
traction. Conversely, during prolonged exercise at a
fixed level of moderate intensity, such as running, car-
bohydrate predominates initially but its contribution
declines gradually while the proportion supplied by
fatty acids rises. This is caused by the gradual decline
of glycogen stores in the active muscles (Figs. 32.20
and 32.21). Endurance exercise, such as marathon run-
ning, depends on sufficient glycogen stores (Clinical
Example 32.3).
Glucose
Insulin,
contraction
+
+
+
+
+
+
–
–
–
–
ATP
H+
Lactate Lactate Pyruvate
CO2 + H2O
Glycogen
Insulin
Epinephrine (phosphorylation)
Ca2+ (phosphorylation)
(dephosphorylation) AMP
Epinephrine (fructose 2,6-bisphosphate)
AMP, ADP
Glucose 6-phosphate
Glucose
Fig. 32.19 Regulation of
glycogenolysis and glycolysis in
skeletal muscle. The important control
points are glycogen phosphorylase,
phosphofructokinase, and the glucose
carrier in the plasma membrane.
G
Creatine
NH2
From
arginine
From
glycine
From
SAM
ATP ADP
Creatine kinase
(muscle)
Nonenzymatic
(muscle)
CH3
Creatinine
H
O
O
Excreted in urine
N
N CH2
Creatine phosphate
O–
O–
Pi
CH3 CH3
CH2 COO–
H2N
+
N CH2 COO–
N
P
C
HN
C
HN
C H2N
+
C
Fig. 32.18 Creatine and the creatine kinase
reaction. SAM, S-adenosylmethionine.
Table 32.9 Concentrations of Some Phosphate Compounds
in the Quadriceps Femoralis Muscle at Rest
Compound Muscle Tissue (mmol/kg)
ATP 5.85
ADP 0.74
AMP 0.02
Creatine phosphate 24*
Creatine 5*
* Determined in situ, by nuclear magnetic resonance. In biopsy samples,
the ratio of phosphocreatine/creatine is approximately 3:2.
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B978-0-323-29616-8.00032-3, 00032
Meisenberg, 978-0-323-29616-8
555
Comp.
by:
Sathish
Stage:
Revises2
Chapter
No.:
32
Title
Name:
Meisenberg
Page
Number:
555
Date:
24/08/2016
Time:
09:10:58
To some extent, the muscle fibers are metabolic spe-
cialists. Fast-twitch fibers (“white” fibers) have large gly-
cogen stores, an abundance of glycolytic enzymes, and
few mitochondria. They metabolize their stored glycogen
anaerobically and are specialized for rapid, vigorous,
short-lasting contractions. Slow-twitch fibers (“red” fi-
bers), in contrast, are well equipped with mitochondria
and can maintain their activity for prolonged periods.
Their red color is caused by myoglobin and mitochon-
drial cytochromes. Human muscles consist of a mix of
fast-twitch and slow-twitch fibers in variable proportions.
CATECHOLAMINES COORDINATE METABOLISM
DURING EXERCISE
Anaerobic exercise (e.g., weight lifting) impairs the
blood supply of the muscle. It does not require external
fuels, but relies on creatine phosphate and the anaerobic
metabolism of stored glycogen.
In aerobic exercise (e.g., running, swimming), how-
ever, blood flow to the active muscles increases be-
cause lactic acid and other local mediators relax the
arterioles and precapillary sphincters. This allows
the oxidation of blood-borne nutrients in addition to
stored glycogen (see Figs. 32.20 and 32.21). Indeed,
the combined use of all nutrients is necessary for max-
imum performance.
The nutrient supply to exercising muscle is under neu-
ral and hormonal control. The plasma insulin concen-
tration decreases during strenuous exercise. Glucagon
initially is unchanged but tends to rise with prolonged
vigorous activity. Most important, however, are norepi-
nephrine and epinephrine. The plasma levels of these
two catecholamines rise 10-fold to 20-fold during stren-
uous physical activity.
In skeletal muscle itself, the catecholamines stimulate
glycogen degradation and glycolysis (see Fig. 32.19).
These effects are mediated by β-adrenergic receptors and
cyclic AMP (cAMP).
Glucose
Fatty acids
CO2 + H2O
(from liver)
Resting
muscle
Glycogen
Fatty acids
(from adipose tissue)
CO2 + H2O
Glucose
Brisk walk
Glycogen
Glucose
Fatty acids
CO2 + H2O
Jogging
Glycogen
Lactate Fatty acids
CO2 + H2O
Glucose
Lactate
100-meter sprint
Glycogen
Fig. 32.20 Muscle metabolism during exercise.
CLINICAL EXAMPLE 32.3: Carbohydrate Loading
Prolonged severe exercise (e.g., during a marathon
race) depends on muscle glycogen. Glycogen is
metabolized both aerobically and anaerobically, and its
depletion leads to severe exhaustion. This occurs when,
2 or 3 hours into a marathon, the runner encounters
the dreaded “wall” (see Fig. 32.21). The amount of
muscle glycogen depends on the carbohydrate content of
the diet. For this reason, methods of carbohydrate
loading have been devised to build up large glycogen
stores before an important athletic contest. Typically,
the athlete is placed on a 70% to 80% carbohydrate
diet for 3 to 4 days before the event.
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