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protein made would

be functional, and that is often sufficient to allow for normal DNA repair. Mutating the

corresponding normal allele would reduce the functional enzyme level to zero, and the lack of

mismatch repair would eventually lead to mutations in genes involved in growth regulation,

resulting in uncontrolled cellular proliferation. Mutations in BRCA1 or BRCA2 involve DNArepair of double-strand breaks, not mismatches. A mutation in the PDGF receptor may lead to

transformation as a dominant oncogene, but it does not affect mismatch repair. A mutation in a p53

gene would have no effect because p53 is also a tumor suppressor, and both copies of p53 would

need to be mutated for a tumor to develop. A mutation in p53 would not, in combination with one

mutation in a mismatch repair gene, lead to uncontrolled proliferation. A mutation in the ras gene,

by itself, would lead to uncontrolled cellular proliferation because ras is a dominant oncogene,

but the mechanism would not be by inability to repair DNA mismatches.

8.The answer is C. If myc, a proto-oncogene, is overexpressed, increased cell proliferation would

result. One way myc could be overexpressed is if the miRNA regulating its expression were no

longer expressed. In that case, myc mRNA levels would increase, and myc would be inappropriately expressed in the cell. For this to occur, the miRNA would have a loss of function,

which is what defines a tumor-suppressor gene. The miRNA is downregulating, not upregulating,

the expression of myc. A gain of function (such as overexpression of the miRNA) would define an

oncogene. The miRNA is not acting as a dominant-negative effector, which is when one mutated

copy of a protein (or RNA) interferes with the functioning of a functional protein produced by a

normal allele. Myc is a transcription factor and not an enzyme needed for DNA repair.

9.The answer is E. The girl has retinoblastoma, which is caused by a mutation in the Rb gene,

which is a tumor suppressor. The normal Rb protein binds to the E2F family of transcription

factors, and when it does, transcription is inhibited. Phosphorylation of the Rb protein by cyclin–

CDK complexes at the G1/S interface of the cell cycle inactivates Rb, it dissociates from E2F, and

transcription is now initiated, allowing cells to enter the S phase of the cycle. Because the

mutation is in a tumor-suppressor gene, a loss of function is leading to tumor growth. Loss of Rb

function leads to constant E2F activity, and the cell is always stimulated to proliferate (the checks

and balances at the G1/S boundary are lost). Loss of function of a cyclin, or a CDK, would stop

cell growth (mutations in those genes would need to be gain-of-function mutations in order for a

tumor to form). The CKIs are inhibitors, and loss of their function could lead to tumor growth, but

such mutations would not be specific for retinoblastoma, as are mutations in the Rb protein.

10.The answer is D. Cadherins are membrane-bound glycoproteins involved in intracellular

adhesion. Loss of function of a specific cadherin (E-cadherin) allows cell migration within the

stomach, owing to the loss of intracellular adhesion. This allows tumor cells to

leave their site of

origin and move to other areas within the stomach (giving rise to the diffuse type of cancer found).

p53 proteins and the Rb protein help regulate cell-cycle completion and cell reproduction, but

these proteins do not regulate the ability of tumor cells to migrate. The protein produced by the

NF-1 gene (neurofibromin) binds to Ras and activates its GTPase activity, thereby reducing the

amount of time that Ras is in its active state. Caspases are cysteine proteases involved in the

apoptotic response.Ca G rbohydrate Metabolism, Fuel Oxidation, and the Generation of Adenosine Triphosphate

SECTION IV

lucose is central to all of metabolism. It is the universal fuel for human cells and the source of

carbon for the synthesis of most other compounds. Every human cell type uses glucose to obtain

energy. The release of insulin and glucagon by the pancreas aids in the body’s use and storage of glucose.

Other dietary sugars (mainly fructose and galactose) are converted to glucose or to intermediates of

glucose metabolism.

Glucose is the precursor for the synthesis of an array of other sugars that are required for the

production of specialized compounds such as lactose, cell surface antigens, nucleotides, or

glycosaminoglycans. Glucose is also the fundamental precursor of noncarbohydrate compounds; it can be

converted to lipids (including fatty acids, cholesterol, and steroid hormones), amino acids, and nucleic

acids. Only those compounds that are synthesized from vitamins, essential amino acids, and essential fatty

acids cannot be synthesized from glucose in humans.

All physiologic processes in living cells require energy transformation. Cells convert the chemical

bond energy in foods into other forms, such as an electrochemical gradient across the plasma membrane,

or the movement of muscle fibers in an arm, or assembly of complex molecules such as DNA. These

energy transformations can be divided into three principal phases: (1) oxidation of fuels (fat,

carbohydrate, and protein), (2) conversion of energy from fuel oxidation into the high-energy phosphate

bonds of adenosine triphosphate (ATP), and (3) use of ATP phosphate bond energy to drive energyrequiring processes.

More than 40% of the calories in the typical diet in the United States are obtained from starch,

sucrose, and lactose. These dietary carbohydrates are converted to glucose, galactose, and fructose in the

digestive tract (Fig. IV.1). Monosaccharides are absorbed from the intestine, enter the blood, and travel to

the tissues, where they are metabolized.

After glucose is transported into cells, it is phosphorylated by a hexokinase to form glucose 6-

phosphate. Glucose 6-phosphate can then enter a number of metabolic pathways. The three that are

common to all cell types are glycolysis, the pentose phosphate pathway, and glycogen synthesis (Fig.

IV.2). In tissues, fructose and galactose are converted to intermediates of glucose metabolism. Thus, thefate of these sugars parallels that of glucose (Fig. IV.3). The major fate of glucose 6-phosphate is oxidation via the pathway of glycolysis

(see Chapter 22),

which provides a source of ATP (the major energy currency of the cell) for all cell types. Cells that lack

mitochondria cannot oxidize other fuels. They produce ATP from anaerobic glycolysis (the conversion of

glucose to lactic acid). Cells that contain mitochondria oxidize glucose to CO2 and H2O via glycolysis

and the tricarboxylic acid (TCA) cycle (Fig. IV.4). Some tissues, such as the brain, depend on the

oxidation of glucose to CO2 and H2O for energy because they have a limited capacity to use other fuels.

The oxidation of fuels to generate ATP requires electron transfer through components of the inner

mitochondrial membrane known as the electron-transport chain (ETC).

Glucose produces the intermediates of glycolysis and the TCA cycle that are used for the synthesis of

amino acids and both the glycerol and fatty acid moieties of triacylglycerols (Fig. IV.5).Another important fate of glucose 6-phosphate is oxidation via the pentose phosphate pathway, which

generates nicotinamide adenine dinucleotide phosphate (NADPH). The reducing equivalents of NADPH

are used for biosynthetic reactions and for the prevention of oxidative damage to cells (see Chapter 25).

In this pathway, glucose undergoes oxidation and decarboxylation to five-carbon sugars (pentoses), which

may reenter the glycolytic pathway. They also may be used for nucleotide synthesis (Fig. IV.6). There are

also nonoxidative reactions, which can interconvert sixand five-carbon sugars. Glucose 6-phosphate is also converted to UDP-glucose, which has many functions in the cell (Fig.

IV.7). The major fate of UDP-glucose is the synthesis of glycogen, the storage polymer of glucose.

Although most cells have glycogen to provide emergency supplies of glucose, the largest stores are inmuscle and liver. Muscle glycogen is used to generate ATP during muscle contraction. Liver glycogen is

used to maintain blood glucose during fasting and during exercise or periods of enhanced need. UDPglucose is also used for the formation of other sugars, and galactose and glucose are interconverted while

attached to UDP. UDP-galactose is used for lactose synthesis in the mammary gland. In the liver, UDPglucose is oxidized to UDP-glucuronate, which is used to convert bilirubin and other toxic compounds to

glucuronides for excretion (see Fig. IV.7).

Nucleotide sugars are also used for the synthesis of proteoglycans, glycoproteins, and glycolipids (see

Fig. IV.7). Proteoglycans are major carbohydrate components of the extracellular matrix, cartilage, and

extracellular fluids (such as the synovial fluid of joints), and they are discussed in more detail in Chapter

47. Most extracellular proteins are glycoproteins; that is, they contain covalently attached carbohydrates.

For cell membrane glycoproteins and for glycolipids, the carbohydrate portion extends into the

extracellular space.

All cells are continuously supplied with glucose under normal circumstances; the body maintains a

relatively narrow range of glucose concentration in the blood (~70 to 100 mg/dL) in spite of the changes

in dietary supply and tissue demand as we sleep and exercise. This process is called glucose

homeostasis. Low blood glucose levels (hypoglycemia) are prevented by a release of glucose from the

large glycogen stores in the liver (glycogenolysis); by synthesis of glucose from lactate, glycerol, and

amino acids in liver (gluconeogenesis) (Fig. IV.8); and to a limited extent by a release of fatty acids from

adipose tissue stores (lipolysis) to provide an alternate fuel when glucose is in short supply. High blood

glucose levels (hyperglycemia) are prevented both by the conversion of glucose to glycogen and by its

conversion to triacylglycerols in liver and adipose tissue. Thus, the pathways for glucose use as a fuel

cannot be considered as totally separate from pathways involving amino acid and fatty acid metabolism

(Fig. IV.9).Intertissue balance in the use and storage of glucose during fasting and feeding is accomplished

principally by the actions of the hormones of metabolic homeostasis—insulin and glucagon (Fig. IV.10).

However, cortisol, epinephrine, norepinephrine, and other hormones are also involved in intertissue

adjustments of supply and demand in response to changes of physiologic state.The oxidation of our food is an energy-generating process. The first two phases of energy

transformation are part of cellular respiration, the overall process of using O2 and energy derived from

oxidizing fuels to generate ATP. We need to breathe principally because our cells require O2 to generate

adequate amounts of ATP from the oxidation of fuels to CO2. Cellular respiration uses >90% of the O2 we

inhale.

In phase 1 of respiration, energy is conserved from fuel oxidation by enzymes that transfer electrons

from the fuels to the electron-accepting coenzymes nicotinamide adenine dinucleotide (NAD+) and flavin

adenine dinucleotide (FAD), which are reduced to NADH and FAD(2H), respectively (Fig. IV.11). The

pathways for the oxidation of most fuels (glucose, fatty acids, ketone bodies, and many amino acids)

converge in the generation of the activated 2-carbon acetyl group in acetyl coenzyme A (acetyl-CoA). The

complete oxidation of the acetyl group to CO2 occurs in the TCA cycle, which collects the energy mostly

as NADH and FAD(2H).

In phase 2 of cellular respiration, the energy derived from fuel oxidation is converted to the highenergy phosphate bonds of ATP by the process of oxidative phosphorylation (see Fig. IV.11). Electrons

are transferred from NADH and FAD(2H) to O2 by the ETC, a series of electron-transfer proteins that are

located in the inner mitochondrial membrane. Oxidation of NADH and FAD(2H) by O2 generates an

electrochemical potential across the inner mitochondrial membrane in the form of a transmembrane protongradient (Δp). This electrochemical potential drives the synthesis of ATP from adenosine diphosphate

(ADP) and inorganic phosphate (Pi) by a transmembrane enzyme called ATP synthase (or F0F1ATPase).

In phase 3 of cellular respiration, the high-energy phosphate bonds of ATP are used for processes such

as muscle contraction (mechanical work), maintaining low intracellular Na+ concentrations (transport

work), synthesis of larger molecules such as DNA in anabolic pathways (biosynthetic work), or

detoxification (biochemical work). As a consequence of these processes, ATP is either directly or

indirectly hydrolyzed to ADP and Pi, or to AMP and pyrophosphate (PPi).

Cellular respiration occurs in mitochondria (Fig. IV.12). The mitochondrial matrix, which is the

compartment enclosed by the inner mitochondrial membrane, contains almost all of the enzymes for the

TCA cycle and oxidation of fatty acids, ketone bodies, and most amino acids. The inner mitochondrial

membrane contains the protein complexes of the ETC and ATP synthase, the enzyme

complex that

generates ATP from ADP and Pi. Some of the subunits of these complexes are encoded by mitochondrial

DNA, which resides in the matrix. ATP is generated in the matrix, but most of the energy-using processes

in the cell occur outside of the mitochondrion. As a consequence, newly generated ATP must be

continuously transported to the cytosol by protein transporters in the impermeable inner mitochondrial

membrane and by diffusion through pores in the more permeable outer mitochondrial membrane.

The rates of fuel oxidation and ATP use are tightly coordinated through feedback regulation of the

ETC and the pathways of fuel oxidation. Thus, if less energy is required for work, more fuel is stored as

glycogen or fat in adipose tissue. The basal metabolic rate (BMR), caloric balance, and ΔG (the change

in Gibbs free energy, which is the amount of energy available to do useful work) are quantitative ways of

describing energy requirements and the energy that can be derived from fuel oxidation. The various types

of enzyme regulation described in Chapter 9 are all used to regulate the rate of oxidation of different fuels

to meet energy requirements.Fatty acids are a major fuel in the body. After eating, we store excess fatty acids and carbohydrates

that are not oxidized as fat (triacylglycerols) in adipose tissue. Between meals, these fatty acids are

released and circulate in blood bound to albumin. In muscle, liver, and other tissues, fatty acids are

oxidized to acetyl-CoA in the pathway of β-oxidation. NADH and FAD(2H) generated from β-oxidation

are reoxidized by O2 in the ECT, thereby generating ATP (see Fig. IV.11). Small amounts of certain fatty

acids are oxidized through other pathways that convert them to either oxidizable fuels or urinary excretion

products (e.g., peroxisomal β-oxidation).

Not all acetyl-CoA generated from β-oxidation enters the TCA cycle. In the liver, acetyl-CoA

generated from β-oxidation of fatty acids can also be converted to the ketone bodies acetoacetate and β-

hydroxybutyrate. Ketone bodies are taken up by muscle and other tissues, which convert them back to

acetyl-CoA for oxidation in the TCA cycle. They become a major fuel for the brain during prolonged

fasting. The discussion of fatty acid oxidation and ketone body production occurs in Section V of this text.

Amino acids derived from dietary or body proteins are also potential fuels that can be oxidized to

acetyl-CoA or converted to glucose and then oxidized (see Fig. IV.11). These oxidation pathways, like

those of fatty acids, generate NADH or FAD(2H). Ammonia, which can be formed during amino acid

oxidation, is toxic. It is therefore converted to urea in the liver and excreted in the urine. There are more

than 20 different amino acids, each with a somewhat different pathway for oxidation of the carbon

skeleton and conversion of its nitrogen to urea. Because of the complexity of amino acid metabolism, use

of amino acids as fuels is considered separately in Section VII, Tissue Metabolism. Glucose is a universal fuel used to generate ATP in every cell type in the body (Fig. IV.13). In

glycolysis, 1 mole of glucose is converted to 2 moles of pyruvate and 2 moles of NADH by cytosolic

enzymes. Small amounts of ATP are generated when high-energy pathway intermediates transfer

phosphate to ADP in a process termed substrate-level phosphorylation. In aerobic glycolysis, the NADH

produced from glycolysis is reoxidized by O2 via the ETC, and pyruvate enters the TCA cycle. In

anaerobic glycolysis, the NADH is reoxidized by conversion of pyruvate to lactate, which enters the

blood. Although anaerobic glycolysis has a low ATP yield, it is important for tissues with a low oxygen

supply and few mitochondria (e.g., the kidney medulla) or for tissues that are experiencing diminished

blood flow (ischemia).

All cells continuously use ATP and require a constant supply of fuels to provide energy for thegeneration of ATP. Chapters 1 through 3 of this text outlined the basic patterns of fuel use in humans and

provided information about dietary components.

The pathologic consequences of metabolic problems in fuel oxidation can be grouped into one of two

categories: (1) lack of a required product or (2) excess of a substrate or pathway intermediate. The

product of fuel oxidation is ATP, and an inadequate rate of ATP production occurs under a wide variety of

medical conditions. Extreme conditions that interfere with ATP generation from oxidative

phosphorylation, such as complete oxygen deprivation (anoxia) or cyanide poisoning, are fatal. A

myocardial infarction is caused by a lack of adequate blood flow to regions of the heart (ischemia),

thereby depriving cardiomyocytes of oxygen and fuel. Hyperthyroidism is associated with excessive heat

generation from fuel oxidation, and in hypothyroidism, ATP generation can decrease to a fatal level.

Conditions such as malnutrition, anorexia nervosa, or excessive alcohol consumption may decrease

availability of thiamin, Fe2+, and other vitamins and minerals required by the enzymes of fuel oxidation.

Mutations in mitochondrial DNA or nuclear DNA result in deficient ATP generation from oxidative

metabolism.

Definitions of prefixes and suffixes used in describing clinical conditions: anWithout

-emia Blood

hyperExcessive, above normal hypoDeficient, below normal -osis Abnormal or diseased state -uria Urine

In contrast, problems arising from an excess of substrate or fuel are seen in diabetes mellitus, which

may result in a potentially fatal ketoacidosis. Lactic acidosis occurs with a reduction in oxidative

metabolism.19

Basic Concepts in the Regulation of Fuel Metabolism by Insulin, Glucagon, and Other Hormones

For additional ancillary materials related to this chapter, please visit thePoint. All cells use adenosine triphosphate (ATP) continuously and require a constant supply of fuels to provide

energy for ATP generation. Insulin and glucagon are the two major hormones that regulate fuel

mobilization and storage. Their function is to ensure that cells have a constant source of glucose, fatty

acids, and amino acids for ATP generation and for cellular maintenance (Fig. 19.1).Because most tissues are partially or totally dependent on glucose for generation of ATP and for

production of precursors of other pathways, insulin and glucagon maintain blood glucose levels near 80

to 100 mg/dL (90 mg/dL is the same as 5 mM) despite the fact that carbohydrate intake varies

considerably over the course of a day. The maintenance of constant blood glucose levels (glucose

homeostasis) requires these two hormones to regulate carbohydrate, lipid, and amino acid metabolism

in accordance with the needs and capacities of individual tissues. Basically, the dietary intake of all fuels

in excess of immediate need is stored, and the appropriate fuel is mobilized when a demand occurs. For

example, when dietary glucose is not available to cells in sufficient quantities, fatty acids are mobilized

and used by skeletal muscle as a fuel (see Chapters 2 and 30). Under these circumstances, the liver can

also convert fatty acids to ketone bodies that can be used by the brain. The fatty acids that are mobilized

under these conditions spare glucose for use by the brain and other glucose-dependent tissues (such as red

blood cells).

Insulin and glucagon are important for the regulation of fuel storage and fuel mobilization (Fig. 19.2).

Insulin, released from the β-cells of the pancreas in response to carbohydrate ingestion, promotes glucose

use as a fuel and glucose storage as fat and glycogen. Insulin, therefore, is a major anabolic hormone.

In addition to its storage function, insulin increases protein synthesis and cell growth. Blood insulin levels

decrease as glucose is taken up by tissues and used. Glucagon, the major insulin counterregulatory

hormone, is decreased in response to a carbohydrate meal and elevated during fasting. Its concentration

in the blood increases as circulating levels of glucose fall, a response that promotes glucose production

via glycogenolysis (glycogen degradation) and gluconeogenesis (glucose synthesis from amino acids and

other noncarbohydrate precursors). Increased levels of circulating glucagon relative to insulin also

stimulate the mobilization of fatty acids from adipose tissue. Epinephrine (the fight-or-flight hormone)

and cortisol (a glucocorticoid released from the adrenal cortex in response to fasting and chronic stress)have effects on fuel metabolism that oppose those of insulin. Therefore, epinephrine and cortisol are

considered to be insulin counterregulatory hormones.

Insulin and glucagon are polypeptide hormones synthesized as prohormones in the pancreatic β- and

α-cells, respectively. Proinsulin is cleaved into mature insulin and a connection peptide (C-peptide) in

storage vesicles and precipitated with Zn2+. Insulin secretion is regulated principally by changes in blood

glucose levels. Glucagon is also synthesized as a prohormone and cleaved into mature glucagon within

storage vesicles. Its release is regulated principally through changes in the level of glucose and insulin

bathing the α-cells located in the pancreatic islets of Langerhans.

Glucagon exerts its effects on cells by binding to a receptor located on the plasma membrane of target

cells for this hormone. The binding to these specific receptors by glucagon stimulates the synthesis of the

intracellular second messenger, cyclic adenosine monophosphate (cAMP) (Fig. 19.3). cAMP activates

protein kinase A (PKA), which phosphorylates key regulatory enzymes, thereby activating some while

inhibiting others. Insulin, on the other hand, promotes the dephosphorylation of these key enzymes, leading

to their activation or deactivation, depending on the enzyme. Changes of cAMP levels

also induce or

repress the synthesis of several enzymes.Insulin binds to a receptor on the cell surface of insulin-sensitive tissues and initiates a cascade of

intracellular events that differs from those stimulated by glucagon. Insulin binding activates both

autophosphorylation of the receptor and the phosphorylation of other enzymes by the receptor’s tyrosine

kinase domain (see Chapter 11, Section III.B.3). The complete routes for signal transduction between

this point and the final effects of insulin on the regulatory enzymes of fuel metabolism have not yet been

fully established. THE WAITING ROOM

Deborah S. returned to her physician for her monthly office visit. She has been seeing her physician

for more than a year because of obesity and elevated blood glucose levels. She still weighed 198

lb, despite trying to adhere to her diet. Her blood glucose level at the time of the visit, 2 hours after lunch,

was 221 mg/dL(reference range = 80 to 140 mg/dL). Deborah suffers from type 2 diabetes, an impaired

response to insulin. Understanding the actions of insulin and glucagon are critical for understanding this

disorder.

Connie C. is a 46-year-old woman who 6 months earlier began noting episodes of fatigue and

confusion in the morning before eating and sometimes after jogging. These episodes were

occasionally accompanied by blurred vision and an unusually urgent sense of hunger. The ingestion of

food relieved all of her symptoms within 25 to 30 minutes. In the last month, these attacks have occurred

more frequently throughout the day, and she has learned to diminish their occurrence by eating between

meals. As a result, she has recently gained 8 lb.

A random serum glucose level done at 4:30 P.M. during her first office visit was subnormal at 67

mg/dL. Her physician, suspecting she was having episodes of hypoglycemia, ordered a series of fasting

serum glucose, insulin, and C-peptide levels. In addition, he asked Connie to keep a careful diary of all of

the symptoms that she experienced when her attacks were most severe.I. Metabolic Homeostasis

Living cells require a constant source of fuels from which to derive ATP for the maintenance of normal

cell function and growth. Therefore, a balance must be achieved among carbohydrate, fat, and protein

intake; their rates of oxidation; and their rates of storage when they are present in excess of immediate

need. Alternatively, when the demand for these substrates increases, the rate of mobilization from storage

sites and the rate of their de novo synthesis also require balanced regulation. The control of the balance

between substrate need and substrate availability is referred to as metabolic homeostasis (Fig. 19.4). The

intertissue integration required for metabolic homeostasis is achieved in three principal ways:

The concentration of nutrients or metabolites in the blood affects the rate at which they are used or

stored in different tissues.

Hormones carry messages to their individual tissues about the physiologic state of the body and the

nutrient supply or demand.

The central nervous system uses neural signals to control tissue metabolism, either directly or

through the release of hormones.

Fatty acids provide an example of the influence that the level of a compound in the blood has on its

own rate of metabolism. The concentration of fatty acids in the blood is the major factor determining

whether skeletal muscles will use fatty acids or glucose as a fuel (see Chapter 30). In contrast, hormones

are (by definition) intravascular carriers of messages between their sites of synthesis and their target

tissues. Epinephrine, for example, is a flight-or-fight hormone that in times of stress signals an immediate

need for increased fuel availability. Its level is regulated principally through the activation of the

sympathetic nervous system.

Insulin and glucagon, however, are the two major hormones that regulate fuel storage and mobilization

(see Fig. 19.2). Insulin is the major anabolic hormone of the body. It promotes the storage of fuels and the

use of fuels for growth. Glucagon is the major hormone of fuel mobilization (Fig. 19.5). Other hormones,

such as epinephrine, are released as a response of the central nervous system to hypoglycemia, exercise,

or other types of physiologic stress. Epinephrine and other stress hormones also increase the availability

of fuels (see Fig. 19.5). The major hormones of fuel homeostasis, insulin and glucagon, fluctuate

continuously in response to our daily eating pattern.Glucose has a special role in metabolic homeostasis. Many tissues (e.g., the brain, red blood cells,

kidney medulla, exercising skeletal muscle) are dependent on glycolysis for all or a part of their energy

needs. As a consequence, these tissues require uninterrupted access to glucose to meet their rapid rate of

ATP use. In the adult, a minimum of 190 g glucose is required per day—approximately 150 g for the brain

and 40 g for other tissues. Significant decreases of blood glucose <60 mg/dLlimit glucose metabolism in

the brain and may elicit hypoglycemic symptoms (as experienced by Connie C.), presumably because the

overall process of glucose flux through the blood–brain barrier, into the interstitial fluid, and subsequently

into the neuronal cells is slow at low blood glucose levels because of the Km values of the glucose

transporters required for this to occur (see Chapter 21).

The continuous efflux of fuels from their storage depots—during exercise, for example—is

necessitated by the high amounts of fuel required to meet the need for ATP under these conditions.

Disastrous results would occur if even a day’s supply of glucose, amino acids, and fatty acids could not

enter cells normally and were instead left circulating in the blood. Glucose and amino acids would be at

such high concentrations in the circulation that the hyperosmolar effect would cause progressively severe

neurologic deficits and even coma. The concentration of glucose and amino acids would rise above the

renal tubular threshold for these substances (the maximal concentration in the blood at which the kidney

can completely resorb metabolites), and some of these compounds would be wasted as they spilled over

into the urine. Nonenzymatic glycosylation of proteins would increase at higher blood glucose levels,

altering the function of tissues in which these proteins reside. Triacylglycerols, present primarily in

chylomicrons and very-low-density lipoproteins (VLDL), would rise in the blood, increasing the

likelihood of atherosclerotic vascular disease. These potential metabolic derangements emphasize the

need to maintain a normal balance between fuel storage and fuel use.

Hyperglycemia may cause a constellation of symptoms such as polyuria and subsequent polydipsia (increased thirst). The inability to move glucose into cells necessitates the

oxidation of lipids as an alternative fuel. As a result, adipose stores are used, and a patient with

poorly controlled diabetes mellitus loses weight in spite of a good appetite. Extremely high levels

of serum glucose can cause a hyperosmolar hyperglycemic state in patients with type 2 diabetesmellitus. Such patients usually have sufficient insulin responsiveness to block fatty acid release

and ketone-body formation, but they are unable to significantly stimulate glucose entry into

peripheral tissues. The severely elevated levels of glucose in the blood compared with those

inside the cell leads to an osmotic effect that causes water to leave the cells and enter the blood.

Because of the osmotic diuretic effect of hyperglycemia, the kidney produces more urine, leading

to dehydration, which, in turn, may lead to even higher levels of blood glucose. If dehydration

becomes severe, further cerebral dysfunction occurs and the patient may become comatose.

Chronic hyperglycemia also produces pathologic effects through the nonenzymatic glycosylation of

a variety of proteins. Hemoglobin A (HbA), one of the proteins that becomes glycosylated, forms

HbA1c (see Chapter 7). Deborah S.’s high levels of HbA1c (9.5% of the total HbA, compared

with the reference range of 4.7% to 6.4%) indicate that her blood glucose has been significantly

elevated over the last 12 to 14 weeks, the half-life of hemoglobin in the bloodstream.

All membrane and serum proteins exposed to high levels of glucose in the blood or interstitial

fluid are candidates for nonenzymatic glycosylation. This process distorts protein structure and

slows protein degradation, which leads to an accumulation of these products in various organs,

thereby adversely affecting organ function. These events contribute to the long-term microvascular

and macrovascular complications of diabetes mellitus, which include diabetic retinopathy,

nephropathy, and neuropathy (microvascular), in addition to coronary artery, cerebral artery, and

peripheral artery disease and atherosclerosis (macrovascular). II. Major Hormones of Metabolic Homeostasis

The hormones that contribute to metabolic homeostasis respond to changes in the circulating levels of

fuels that, in part, are determined by the timing and composition of our diet. Insulin and glucagon are

considered the major hormone of metabolic homeostasis because they continuously fluctuate in response

to our daily eating pattern. They provide good examples of the basic concept of hormonal regulation.

Certain features of the release and action of other insulin counterregulatory hormones, such as

epinephrine, norepinephrine, and cortisol, will be described and compared with insulin and glucagon.

Insulin is the major anabolic hormone that promotes the storage of nutrients: glucose storage as

glycogen in liver and muscle, conversion of glucose to triacylglycerols in liver and their storage in