Integration of Metabolism

Question 1

BALANCE BETWEEN ENERGY PRODUCTION AND UTILIZATION IN HUMAN METABOLISM

Answer 1

The major role of metabolism is to capture chemical energy from foodstuffs as ATP and utilize that ATP for a variety of essential functions, including synthesis of
cellular components, active transport of ions and solute, and muscle work. Humans can generate ATP by oxidizing carbohydrates, fatty acids, and amino acids.

At the simplest level, energy homeostasis involves a balance between dietary fuel intake and energy expenditure so that the body is neither fuel-depleted (starvation) nor storing excess triacylglycerol (obesity). Since humans do not eat continuously, dietary fuels in excess of immediate needs are therefore processed and stored for subsequent use.

Consequently, specific metabolic pathways must be regulated and the activities of different organs coordinated to satisfy the needs of the body.

Question 2

How Much Energy Can One Get From Different
Metabolic Fuels?

Answer 2

1 kcal = 1 calorie

Carbohydrates 4 kcal/g
Triacylglycerol 9 kcal/g
Protein 4 kcal/g
Ethanol 7 kcal/g

Question 3

What Are the Fuel Stores of a Normal Person?

Answer 3

Carbohydrates.

In the fed state, the reference standard 70-kg male has about 300 g of glycogen stored in his muscles and 100 g in his liver, with only minor quantities in adipose tissue and the brain.

Triacylglycerols.

Since triacylglycerols (TAG) have a higher energy content than carbohydrates (9 kcal/g vs. 4 kcal/g) and are stored without hydration, they provide a much more compact form of energy storage than glycogen.

Normal body stores of TAG total approximately 15 kg, or 135,000 kcal, compared to only 1600 kcal for glycogen. Although nearly all of this fat is stored in adipocytes, skeletal muscle and liver each contain about 50 g of triacylglycerol, and trained endurance athletes have even greater amounts of intramuscular triacylglycerol.

Unlike the storage of carbohydrate as glycogen, the body has a virtually unlimited capacity to store TAG. An imbalance between energy intake and energy expenditure underlies
the current epidemic in obesity.

Protein.

Although there are no stores of proteins as such in the body, some of the normal cellular proteins are mobilized when amino acids are requirefor other needs, such as synthesis of new protein and providing carbon skeletons for gluconeogenesis. Most of the mobilizable proteins are found in skeletal muscle (6 kg) and in liver (0.1 kg). In cases of starvation and severe negative nitrogen balance, heart muscle proteins may also be degraded.

Question 4

The Respiratory Quotient Can Be Used to Assess Which Fuels Are Being Utilized at a Particular Time

Answer 4

The nature and quantities of fuels being utilized at a particular time by an organism can be estimated using “indirect calorimetry,” which measures oxygen consumption and carbon dioxide production rather thanheat generation during a defined interval.

The overall equations for the complete oxidation of glucose and a typical triacylglycerol molecule, in this case triolein, are used to determine the respiratory quotient (RQ =
C02/02) for each reaction:

Question 5

What Can We Learn from RQ Data?

Answer 5

A fasted person at rest has an
RQ of approximately 0.75.

Based on the equations above, the RQ value indicates that this person is primarily oxidizing fat. By contrast, when the same person begins running rapidly, say on a treadmill, the RQ value will rise to nearly 1.0, indicating that he or she is utilizing mostly carbohydrates (i.e., glycogen, blood glucose).

An RQ of 0.85 indicates that a person is utilizing a mixture of carbohydrates and fats.

Question 6

Don’t These Calculations Ignore Amino Acid Oxidation?

Question 7

WHAT ARE THE MAJOR PHYSIOLOGICAL CONDITIONS THAT AFFECT FUEL UTILIZATION?
Fasting or Basal State

Answer 7

The basal metabolic rate (BMR) is the minimum energy expenditure required for involuntary work of the body (e.g., pumping of the heart, maintenance of ion gradients, protein turnover).

BMR is measured in the morning, while the subject is in a prone position and has fasted for at least 12 hours. The measurement is made at an ambient temperature, where shivering thermogenesis and sweating is minimized.

For convenience, the resting energy expenditure (REE) is usually measured instead of BMR; measurement of REE requires a less stringent fast (2 to 4 hours) and gives slightly higher values. One can approximate the BMR for a given person as 1 kcal/kg per hour for men and 0.9 kcal/kg per hour for women, or 1680 and 1200 kcal per day, respectively, for a 70-kg (154-lb) man and a 56-kg (124-lb) woman.

The gender difference in BMR is due to the relatively greater adipose stores and lower muscle mass of women than men. Indeed, the BMR correlates primarily with lean body mass and can be increased by exercise, which promotes accrual of muscle.

Question 8

WHAT ARE THE MAJOR PHYSIOLOGICAL CONDITIONS THAT AFFECT FUEL UTILIZATION?
Fed State

Answer 8

The resting metabolic rate is higher when measured in a person who has recently eaten a meal.

The difference, sometimes referred to as the thermic effect of food, reflects the extra energy required for the digestion, transport, and storage of dietary fuels, including the active transport of solutes into cells and the activation of molecules (i.e., glucose to glucose 6-phosphate, fatty acids to acyl-CoAs).

The thermic effect of food increases energy expenditure over BMR by 10 to 15%, depending on the person and the diet, with protein-rich foods requiring the greatest amount of energy to process and dietary TAG the least.

Question 9

WHAT ARE THE MAJOR PHYSIOLOGICAL CONDITIONS
THAT AFFECT FUEL UTILIZATION?
Physical Activity

Answer 9

Voluntary movement, including normal daily activities, fidgeting, and purposeful exercise, increases energy expenditure. Physical activity is the most variable component of a person’s daily energy expenditure, and represents 20 to 40% of the total for the average person.

Physical activity is also the only component of total energy expenditure that is easily altered.

Energy expenditure during exercise is affected by the nature of the activity itself (running vs. walking); the intensity, duration, and efficiency of the activity; and the person’s body mass.

Question 10

ROLES OF DIFFERENT ORGANS IN THE
INTEGRATION OF METABOLISM

Answer 10

Adipocytes
Liver
Skeletal muscle

Question 11

ROLES OF DIFFERENT ORGANS IN THE
INTEGRATION OF METABOLISM
Liver

Answer 11

The liver plays a major role in all aspects of energy metabolism.

When glucose is plentiful, the liver utilizes glucose as fuel, stores glycogen, and metabolizes** excess
glucose to acetyl-CoA**.

The acetyl-CoA, in turn, is used to synthesize fatty acids and ultimately TAG, which is exported from the liver in the form of VLDL.

By contrast, when glucose is required by other cells, the liver switches to utilizing fatty acids to generate energy, mobilizes glycogen stores to maintain plasma glucose levels, and begins synthesizing both glucose and ketones.

Utilization of the carbon skeletons of amino acids such as alanine and glutamine for gluconeogenesis is accompanied by conversion of their amino groups to urea.

Question 12

ROLES OF DIFFERENT ORGANS IN THE
INTEGRATION OF METABOLISM
Adipose Depot

Answer 12

Triacylglycerols are the major fuel stores of the body, and adipocytes are the major site of triacylglycerol storage.

In response to hormonal (e.g., glucagon, hydrocortisone) and neuroendocrine (epinephrine) stimulation, free fatty acids are released when needed: for example, during fasting or to meet the increased energy demands of exercise, stress, and trauma. The glycerol generated when TAG is hydrolyzed is available to the liver for gluconeogenesis.

By contrast, in the fed state, the body
directs dietary fatty acids and glucose into triacylglycerol stores. Lipoprotein lipase
in adipose capillaries hydrolyzes the TAG of VLDL: the fatty acids thus released are
taken up by adipocytes, incorporated into TAG and stored. In the fed state, adipocytes also oxidize glucose, both to provide the glycerol backbone of TAG and to generate acetyl-CoA for a modest amount of fatty acid synthesis.

Question 13

ROLES OF DIFFERENT ORGANS IN THE
INTEGRATION OF METABOLISM
Skeletal Muscle

Answer 13

**Muscle in the Fed State. **

When glucose (and insulin) levels rise,
muscle cells take up glucose via GLUT4 transporters and store that glucose as
glycogen. Eating a meal and the subsequent rise in circulating insulin levels also stimulate uptake of amino acids into muscle and promote protein synthesis.

Muscle in the Fasted State.

During an overnight (or longer) fast,
skeletal muscle plays a major role in providing fuel to other organs, including the brain. Since muscle lacks glucose 6-phosphatase, muscle glycogen cannot be used to maintain plasma glucose levels. There is, however, considerable catabolism of muscle proteins during a fast. The carbon skeletons of branched-chain amino acids are primarily utilized as fuel by muscle, whereas alanine and glutamine are exported to support gluconeogenesis in liver and kidney, respectively. In the fasted state, muscles
also use plasma free fatty acids and ketones to satisfy their fuel needs.

Exercising Muscle.

Physical activity requires muscles to markedly increase the rate of ATP production. The mixture of fuels used by the muscle is dependent on both the intensity and duration of the exercise.

Question 14

ROLES OF DIFFERENT ORGANS IN THE
INTEGRATION OF METABOLISM
Skeletal Muscle
Exercising Muscle.

Answer 14

Sprinting.

The immediate source of energy for muscles during a rapid sprint is ATP
itself, along with the modest intramuscular stores of creatine phosphate, which can sustain a 6-second sprint. Muscle glycogen is also used by a sprinter, and under intense activity, muscle exports lactate into the circulation.

Walking and Similar Moderate Exercise.

Fatty acids are the preferred substrates
for exercise up to about 50% of VO2max
(the maximum amount of oxygen the body can use).

Moderate-Intensity Exercise.

As the rate of sustained exercise increases from 65% to 85% of VO2max, the relative contribution of carbohydrate to total metabolism increases, with the ratio of ATP generated from carbohydrate and fat oxidation being in the range 40:60 to 60:40. As muscle glycogen is depleted, there is greater reliance on a mixture of bloodborne fatty acids and bloodborne glucose, with a concomitant drop in RQ from > 0.9 to as low as 0.75. Under these conditions, muscle fatigue may
occur if the workload intensity is not decreased. It should be noted that it is only the glycogen stored in the exercising muscles that is depleted; the amount of glycogen in less active muscles (i.e., the arm muscles of a bicyclist) does not decrease.

Adaptations with Athletic Training.

Highly fit persons (e.g., triathletes) are able to exercise at greater workloads and sustain their activity for long intervals. Physically fit persons have greater intramuscular stores of both glycogen and TAG than those of relatively inactive persons. They also have an increased VO2max values which results in the same level of exercise (i.e., speed of running) occurring at a lower VO2, thus
permitting a greater reliance on fatty acids than glucose to satisfy their energy needs.

Question 15

ROLES OF DIFFERENT ORGANS IN THE
INTEGRATION OF METABOLISM
Heart Muscle

Answer 15

Although the heart is never at rest, its metabolism is similar to that of the skeletal muscles of a person at rest, in that when the body is at rest the heart preferentially utilizes free fatty acids as fuel.

Cardiac glycogen stores are mobilized for the greater cardiac work that exercise demands.

Question 16

INTEGRATION OF ORGAN METABOLISM IN DIFFERENT PHYSIOLOGICAL STATES
Fasting State

Answer 16

Figure 25-1 shows the role of different organs in the coordinated metabolism of
the basal metabolic state, when a person is at rest after an overnight fast.

During the night, glucagon stimulates glycogenolysis and the glycogen stores in the liver become depleted.

By morning, the major source of plasma glucose is hepatic (and to some extent, renal) gluconeogenesis. Substrates for gluconeogenesis are provided
by adipocytes (glycerol), muscle (alanine and glutamine), and erythrocytes (lactate).

The increase in the rate of protein catabolism in muscle that is associated with gluconeogenesis is accompanied by increased hepatic synthesis of urea.

beta-Oxidation of fatty acids provides the large amounts of ATP required for both gluconeogenesis and ureagenesis.

As a result of diversion of oxaloacetate from the TCA cycle to gluconeogenesis, the liver uses most of the acetyl-CoA from beta-oxidation to synthesize ketones.

During a fast, free fatty acids mobilized from TAG in adipocytes are the major
fuel supply for organs other than the brain and erythrocytes. As the fast continues, skeletal muscle cells oxidize a mixture of free fatty acids released from adipocytes, ketones produced by the liver, and branched-chain amino acids generated through catabolism of muscle proteins. Muscle cells also require a certain amount of glucose to generate the carbon skeleton of alanine, which is the means by which they export the amino groups released during the catabolism of the branched-chain amino acids.

What Happens During Prolonged Fasting?
Why Doesn’t the Brain Oxidize Fatty Acids?

Question 17

Why Doesn’t the Brain Oxidize Fatty Acids?

Answer 17

Erythrocytes lack mitochondria and therefore cannot utilize either P-oxidation or the TCA cycle, both of which are mitochondria1 processes.

By contrast, although neural cells do have
mitochondria, they do not use free fatty acids as an energy source during fasting
because free fatty acids and other lipophilic substances do not readily pass through the blood-brain barrier.

Thus, the mechanism for protecting the brain from a variety of deleterious substances renders the brain strongly dependent on a constant supply
of glucose fuel.

Question 18

What Happens During Prolonged Fasting?

Answer 18

The changes in fuel utilization that occur with long-term fasting are referred to collectively as the adaptation to starvation (Fig. 25-2).

Circulating levels of ketones rise markedly during the first few weeks of a prolonged fast and the brain begins to use ketones as well as glucose as fuel; after 2 to 3 weeks of fasting, ketones can satisfy as much as two-thirds of the energy requirement of the brain.

Although the brain still does not
use free fatty acids directly, neural oxidation of ketones represents, in essence, the brain’s ability to utilize some of the energy originally stored in fatty acids.

Increased ketone availability to the brain is facilitated by muscle, which stops oxidizing ketones and turns almost entirely to free fatty acids for energy.

As this transition occurs, there
is less demand for glucose by the brain and a concomitant decrease in the rate of
catabolism of muscle proteins to provide gluconeogenic substrate for the liver and
kidney.

At the same time, relatively more of the amino acid-derived nitrogen excreted
in the urine will be in the form of ammonium ions rather than urea. The ammonium ions buffer urinary acetoacetic acid and P-hydroxybutyric acid.

Renal production of ammonium ions is directly coupled to an increase in renal use of the carbon skeleton
of glutamine for gluconeogenesis.

Question 19

INTEGRATION OF ORGAN METABOLISM IN DIFFERENT PHYSIOLOGICAL STATES
Metabolism in the Fed State

Answer 19

The changes in metabolism in various organs that occur after ingestion of a mixed meal (carbohydrate, fat, and protein) reflect the assimilation of these nutrients and their processing for both immediate utilization and storage (Fig. 25-3).

**1. Liver. **

When the plasma glucose concentration is high, the liver extracts glucose from the blood. Some of that glucose is used for glycogen synthesis; the remainder is oxidized to acetyl-CoA and used primarily for fatty acid synthesis. The resulting long-chain fatty acids are secreted from the liver as VLDL triacylglycerol.

In the fed state, the liver utilizes amino acids primarily for protein synthesis.
However, with high protein intakes the excess amino acids are catabolized, with their carbon skeletons being converted to fatty acids and their amino groups utilized for urea synthesis.

**2. Adipocytes. **

In the fed state, the adipose depot synthesizes and stores TAG. Free fatty acids are obtained from the exogenous TAG of chylomicrons and the endogenous TAG of VLDL. Glucose is utilized to synthesize the glycerol backbone
of TAG as well as the synthesis of long-chain fatty acids.

**3. Muscle. **

When circulating levels of glucose and insulin are increased, muscle extracts glucose from the blood and uses it to synthesize glycogen.

Under normal conditions, the synthesis of muscle glycogen functions merely to replenish glycogen stores.

However, if carbohydrates are consumed after muscle glycogen has been depleted by strenuous exercise, resynthesis of glycogen may result in even higher glycogen levels than were present prior to the exercise.

Athletes commonly refer to this phenomenon as glycogen loading.

Question 20

REGULATION OF METABOLISM
Insulin

Answer 20

Insulin acts on many different tissues and has several effects in each, all of which are
consistent with the anabolic needs of the body in the fed state. Thus, insulin stimulates translocation of GLUT4 transporters to the plasma membrane and uptake of glucose into both adipocytes and muscle cells.

Insulin increases secretion of lipoprotein
lipase by adipocytes, thereby increasing the release of free fatty acids from both
chylomicrons and VLDL. Within adipocytes, insulin stimulates glycolysis, a modest amount of fatty acid synthesis, and triacylglycerol synthesis.

Concurrently, insulin promotes both glycogen synthesis and glycolysis in muscle cells as well as uptake of
amino acids into muscle and protein synthesis therein. Not all tissues are regulated by insulin.

In particular, the uptake of glucose into neural cells and subsequent glycolysis
are glucose-independent.
Although transport of glucose into hepatocytes is insulin-independent, insulin does stimulate the activity of key regulatory enzymes in the pathways that use glucose (glycogen synthesis, glycolysis) while inhibiting pathways that generate glucose (glycogenolysis, gluconeogenesis). Insulin increases the activity of acetyl- CoA carboxylase, thus stimulating hepatic fatty acid synthesis and subsequent VLDL synthesis.

In addition, increased acetyl-CoA carboxylase activity generates malonyl-
CoA, which prevents concurrent @-oxidation of fatty acids by inhibiting carnitine palmitoyl transferase (CPT- 1). Insulin also stimulates synthesis of the sterol response element-binding proteins, SREBP- 1 and SREBP-2, thereby increasing gene transcription of the lipogenic enzymes involved in fatty acid and cholesterol synthesis, respectively.

Question 21

REGULATION OF METABOLISM
Glucagon

Answer 21

Glucagon stimulates hepatocytes and adipocytes to release glucose and fatty acids, respectively, into the circulation.

In the liver, glucagon stimulates both glycogenolysis and gluconeogenesis while inhibiting the pathways of fuel storage (e.g., glycogen and fatty acid synthesis).

In adipocytes, glucagon stimulates lipolysis and release of free fatty acids and glycerol into the circulation.

Question 21

REGULATION OF METABOLISM

Answer 21

Insulin
Glucagon
Epinephrine (Adrenaline)
Hydrocortisone
Adipocytokines
Exercise

Question 22

REGULATION OF METABOLISM
Epinephrine (Adrenaline)

Answer 22

The synthesis of epinephrine from tyrosine in the adrenal medulla is stimulated by stress, endurance exercise, and hypoglycemia.

Epinephrine acts through the same
G-protein, CAMP-dependent protein kinase signaling pathway as glucagon and has similar effects in both liver and adipocytes.

Unlike glucagon, however, epinephrine
also acts on muscle cells. Since muscle cells lack glucose 6-phosphatase, the
epinephrine-stimulated breakdown of glycogen results in enhanced glycolysis.

Question 23

REGULATION OF METABOLISM
Hydrocortisone

Answer 23

Hydrocortisone, a glucocorticoid synthesized by the adrenal cortex, stimulates fuel mobilization from liver, muscle, and adipocytes.

However, unlike glucagon and
epinephrine, hydrocortisone acts primarily by regulating gene transcription and mediates longer-term metabolic changes during starvation, sepsis, and stress.

Question 24

REGULATION OF METABOLISM
Adipocytokines

Answer 24

Adipose tissue is more than a site for triacylglycerol storage; it is also an endocrine organ. The hormones and cytokines secreted by adipocytes include leptin, adiponectin, adipsin, interleukin-6, and tumor necrosis factor a (TNFa).

Production of the various adipocytokines varies with a person’s energy status (e.g., normal weight or obese) and the anatomical location of the adipose depot (e.g., visceral or subcutaneous).

Leptin signals energy sufficiency and acts to inhibit further lipid storage in
adipocytes and stimulate lipolysis of intracellular TAG. It also decreases appetite. Adipsin (acylation-stimulating protein) has effects opposite to those of leptin; adipsin stimulates glucose uptake and increases the activity of diacylglycerol acyltransferase, thus causing adipocytes to retain fatty acids in the form of TAG.

Adiponectin, another adipokine, increases fatty acid oxidation in both muscle and
liver. Increased plasma levels of adiponectin are correlated with higher levels of HDL-cholesterol and lower plasma levels of TAG.

Question 25

REGULATION OF METABOLISM
Exercise

Answer 25

In addition to the actions of hormones, sustained physical activity exerts major effects on the regulation of energy metabolism. There are many long-term metabolic adaptations to aerobic exercise, including increased muscle mass, resulting in an increase in basal energy expenditure, and up-regulation of mitochondria energy metabolism.

Exercise may also increase total energy expenditure by enhancing peroxisomal proliferation (and thus oxidation of long-chain fatty acids not directly coupled to ATP synthesis) and increasing the expression of uncoupling proteins in mitochondria.

One important regulator of muscle metabolism is AMP-kinase, which is activated when ATP depletion results in increased intracellular levels of AMP. AMP kinase inhibits acetyl-CoA carboxylase and lowers the level of malonyl-CoA in the cytoplasm, thereby stimulating fatty acid oxidation by increasing the activity of carnitine palmitoyl transferase- 1. AMP-activated protein kinase also increases glucose uptake into the muscle by insulin-independent recruitment of GLUT4 glucose transporters to the plasma membrane. This phenomenon explains why glucose uptake by skeletal
muscle is greatly increased during exercise, when there is no increase in the insulin level. Exercise also renders muscle cells more sensitive to insulin, in part by stimulating intramuscular accumulation of TAG, and removing potentially deleterious fatty acid metabolites.

Question 26

CONDITIONS WHERE NORMAL METABOLIC
INTEGRATION IS IMPAIRED
Obesity

Answer 26

Obesity is the accumulation of excess adipose tissue.

Obesity is the result of a chronic imbalance between energy intake and energy expenditure. One pound of adipose tissue represents approximately 3500 kcal[454 g x 9 kcal/g (for TAG) x 0.85 (the fraction of adipose tissue that is triacylglycerol)].

A person who consumes a caloric excess of 100 kcal/day will therefore gain 10 lb/year. Conversely, a person with a 500-kcal/day caloric deficit will lose approximately 1 lb/week. It should be noted that a person who utilizes 2000 kcal/day cannot be expected to lose more than 4 lb of adipose tissue per week even if he or she is fully fasting.

More-rapid weight-loss programs actually represent loss of water and some
muscle protein rather than the desired loss of adiposity. Most medical recommendations for weight loss suggest maintaining a healthy diet with a deficit of 500 to 1000 kcal/day. Although there are certainly wide variations in body structure and metabolism between individuals, the current epidemic of obesity in the United States and many other countries is due more to environmental than to genetic factors.

The efficient storage of excess calories as triacylglycerol may have been advantageous for our distant ancestors who were physically very active and for whom food scarcity was often the norm. However, in the current context of sedentary lifestyles and in environments where there is an overabundance of calorically dense foods containing large amounts of fats and sugars, efficient fuel storage in the form of fat can result in obesity and its undesirable medical and social sequelae.

Question 27

Type I Diabetes Mellitus

Answer 27

Type I diabetes is caused by absent or insufficient insulin production. Although the most common cause is autoimmune destruction of the p-cells of the pancreas, it can also result from chronic pancreatitis.

The resulting insulin deficiency has been
described as “starvation in the midst of plenty,” with metabolic pathways active
in fasting mode despite high plasma levels of nutrients in the blood. A lack of
insulin results in fasting hyperglycemia with both overproduction of glucose by
the liver and underutilization of glucose by both muscle and adipocytes. The high
rate of gluconeogenesis is often accompanied by extensive ketogenesis and severe ketoacidosis.

Chronic hyperglycemia results in damage to many organs, including the eyes, kidneys, blood vessels, and nerves.
Diabetes affects lipid and protein metabolism as well as that of glucose. The high glucagon/insulin ratio stimulates adipose triacylglycerol hydrolysis and increases the plasma free fatty acid concentration; increased uptake and reesterification of fatty acids in the liver results in hypertriglyceridemia.

At the same time there is increased
catabolism of muscle proteins and hyperaminoacidemia.
Currently, the only effective treatment for type I diabetes mellitus is insulin therapy.
The hormone is currently provided either by injection or using an insulin pump.
Dosage and timing must be adjusted to a person’s food intake and exercise, so as
to maintain normoglycemia. Determination of glycosylated hemoglobin (HbAlc) is
used to measure the efficacy of glucose control.

Question 28

Insulin Resistance and Type II Diabetes

Answer 28

Most people with diabetes mellitus have type II diabetes rather than type I, and it
is type II diabetes that is now reaching epidemic incidence in many countries.

Type II diabetes mellitus is characterized by insulin resistance rather than primary insulin insufficiency. A person has insulin resistance when larger-than-normal amounts of insulin are required to support insulin-dependent metabolic processes.

Insulin resistance is also commonly seen in the obese and in those with the metabolic syndrome. In most instances of insulin resistance, insulin secretion is not impaired and insulin receptors are functional. Although people in the early stages of insulin resistance can maintain normal blood glucose concentrations by increasing their insulin secretion, this compensation often becomes inadequate and they eventually progress to
hyperglycemia and eventually to type II diabetes.
Like type I diabetes, type II diabetes is characterized by hyperglycemia, hyper-
triglyceridemia, hyperaminoacidemia, and elevated levels of free fatty acids. The
high levels of free fatty acids in the blood are the result of increased TAG lipolysis
by adipocytes. Elevated free fatty acid levels, in turn, result in increased TAG syn-
thesis by the liver and export of TAG-rich VLDL particles. Unlike people with type I diabetes, those with type II diabetes usually do not develop ketoacidosis, in part because - at least in the early stages of the disease - the liver is less insulin resistant than skeletal muscle or adipocytes.

Obesity often leads to insulin resistance in muscle. In people with insulin resis-
tance, the muscle cells do not sufficiently up-regulate the acyltransferases involved in triacylglycerol synthesis to cope with the increased availability of free fatty acids.

As a result, a high intracellular concentration of metabolic intermediates inhibits glucose uptake and glycolysis by muscle cells, and higher levels of insulin are required for glucose utilization.

Although the mechanisms have not been fully elucidated, the relatively insulin-resistant state associated with obesity may be the result of an imbalance in adipokine production as well as elevated plasma levels of free fatty acids
released from the excess adipocyte stores.

Exercise stimulates both TAG and glycogen synthesis in skeletal muscle and
improves insulin sensitivity in both normal-weight and obese persons.

Among the mechanisms involved are up-regulation of GLUT4 transporters and induced expression of diacylglycerol acyltransferase. In fact, moderate exercise and weight-loss regimes are often sufficient to preclude the need for pharmacological intervention in
people with milder forms of type I1 diabetics. Type II diabetes can also be treated with a variety of drugs that stimulate insulin secretion (e.g., sulfonylureas) or increase
insulin sensitivity (e.g, thiazolidinediones), or reduce hepatic gluconeogenesis (e.g.,
metformin).

Many cases of type II diabetes, however, eventually progress to the point
of pancreatic P-cell failure and dependence on exogenous insulin.

Question 29

“Starvation Diets”

Answer 29

Weight-reduction plans usually involve a balanced diet that provides a reduced caloric intake and maintains the body’s normal adaptations to the fed and fasted states.

Under certain conditions, however, it is preferable to adopt a weight-reduction regimen that resembles starvation.

Protein-Sparing Modified Fasts (PSMF)
Diets with Only Minimal Carbohydrate
Kwashiorkor and Marasmus
Hypercatabolic States

Question 30

“Starvation Diets”
Protein-Sparing Modified Fasts (PSMF)

Answer 30

Adaptation to starvation
involves increased ketone utilization by the brain which decreases-but
does not prevent depletion of muscle protein.

PMSF diets are designed to mimic starva-
tion but prevent muscle loss. They usually provide 400 to 800 kcal/day of protein,
with essentially no carbohydrates or fat, and are reserved for the morbidly obese
(BMI > 40 kg/m2) who are under medical supervision. The very low caloric in-
take maximizes weight loss, whereas the provision of exogenous protein provides
substrate for gluconeogenesis, thus minimizing muscle wasting.

Question 31

“Starvation Diets”
Diets with Only Minimal Carbohydrate.

Answer 31

A number of popular low- carbohydrate diets utilize a variation of the PSMF in that the person consumes relatively unlimited protein and fat, but carbohydrate intake is strictly limited.

This regimen results in an initial rapid loss of water weight; however, subsequent weight loss depends on maintaining an energy deficit.

For some people the loss of appetite
that accompanies ketosis aids compliance. Very low carbohydrate diets can be helpful for insulin-resistant type II diabetic persons since there is a decreased demand for insulin; once weight loss is achieved, the person’s insulin sensitivity often improves.

However, very low carbohydrate diets are not recommended for long-term use because they restrict intake of fruits, vegetables, legumes, and dairy products, all of which provide essential nutrients.

Question 32

“Starvation Diets”
Kwashiorkor and Marasmus

Answer 32

Kwashiorkor is a form of protein-calorie malnutrition that is caused by dietary protein deficiency and is often exacerbated by infection.

The classic presentation, particularly
in poorer countries, is a young child who has been weaned to an adult diet that
lacks sufficient protein to sustain healthy growth. The characteristics of kwashiorkor
include growth failure, edema, fatty liver, and “flaky paint” patches of skin. Because
of the low protein intake, there is a deficiency of amino acids for synthesis of serum albumin and other plasma proteins, resulting in edema and the characteristic swollen abdomen and limbs.

The situation is made worse by the availability of ample dietary
carbohydrates, which stimulate insulin secretion and thus inhibit mobilization of
amino acids from skeletal muscle. This dietary carbohydrate also provides substrate for fatty acid synthesis, which in the absence of adequate protein synthesis results in fatty liver and hepatomegaly.

The clinical manifestation of a diet deficient in both protein and energy is Marasmus, which results in severe muscle wasting and marked growth retardation.

Marasmus is the form of malnutrition that occurs when an infant does not receive adequate breast milk or formula. The factors that determine whether an older child develops kwashiorkor or marasmus are complex and not fully elucidated.

Question 33

“Starvation Diets”
Hypercatabolic States

Answer 33

Sepsis, trauma, and burns result in hypercatabolic states, characterized by markedly increased fuel consumption; a negative nitrogen balance in which excretion of nitrogen-mostly
as urea-exceeds nitrogen intake; fat mobilization; and marked
catabolism of muscle proteins.

Hydrocortisone is the main mediator of these changes.

Hyperglycemia is a common finding in hypercatabolic states because, even though the insulin level may not be depressed, the metabolic effects of insulin are overcome by increases in the serum levels of the insulin-counterregulatory hormones.