CHAPTER

Diabetes Mellitus and

43
the Metabolic Syndrome
Safak Guven
Julie A. Kuenzi
Glenn Matn

D
iabetes mellitus is a chronic health problem affecting
HORMONAL CONTROL OF BLOOD GLUCOSE
more than 17 million people in the United States.1
Blood Glucose
Approximately 11 million of these people have been
Glucose-Regulating Hormones
diagnosed, leaving about 6 million undiagnosed. There are
Insulin
800,000 new cases of diabetes per year; almost all of these
Glucagon
are type 2 diabetes. The disease affects people in all age
Other Hormones
groups and from all walks of life. It is more prevalent
DIABETES MELLITUS among African Americans (13%) and Hispanic Americans
Classication and Etiology (10.2%) compared with whites (6.2%).1 Diabetes is a sig-
Type 1 Diabetes Mellitus nicant risk factor in coronary heart disease and stroke,
Type 2 Diabetes Mellitus and the Metabolic Syndrome and it is the leading cause of blindness and end-stage renal
Other Specic Types disease, as well as a major contributor to lower extremity
Gestational Diabetes amputations.
Clinical Manifestations The metabolic syndrome which is characterized by
Diagnostic Tests risk of developing diabetes mellitus and cardiovascular dis-
Blood Tests ease, is becoming an increasingly recognized disorder with
Urine Tests an age-adjusted prevalence of 23.7%.2 Using 2000 census
Diabetes Management data, it is estimated that about 47 million U.S. residents
Dietary Management have the metabolic syndrome.
Exercise
Oral Antidiabetic Agents
Insulin
Pancreas or Islet Cell Transplantation
Hormonal Control of Blood Glucose
Acute Complications After completing this section of the chapter, you should be able to
Diabetic Ketoacidosis meet the following objectives:
Hyperosmolar Hyperglycemic State
Hypoglycemia Characterize the actions of insulin with reference to
Counterregulatory Mechanisms and the Somogyi glucose, fat, and protein metabolism
Effect and Dawn Phenomenon Explain what is meant by counterregulatory hormones and
Chronic Complications describe the actions of glucagon, epinephrine, growth
Theories of Pathogenesis hormone, and the adrenal cortical hormones in
Neuropathies regulation of blood glucose levels
Nephropathies
Retinopathies The body uses glucose, fatty acids, and other substrates
Macrovascular Complications as fuel to satisfy its energy needs. Although the respiratory
Diabetic Foot Ulcers and circulatory systems combine efforts to furnish the body
Infections with the oxygen needed for metabolic purposes, it is the
liver, in concert with the endocrine pancreas, that controls
the bodys fuel supply (Fig. 43-1).
987
988 UNIT X Endocrine Function

food is absorbed into the blood, and by inhibiting insulin

in insulin glucagon and gluconeogenesis
and glucagon, it is thought to extend the use of absorbed
nutrients by the tissues.3

BLOOD GLUCOSE
blood glucose
Body tissues obtain glucose from the blood. In nondiabetic
individuals, fasting blood glucose levels are tightly regu-
lated between 80 and 90 mg/dL. After a meal, blood glu-
insulin release
glucagon cose levels rise, and insulin is secreted in response to this
from beta cells
rise in glucose. Approximately two thirds of the glucose
that is ingested with a meal is removed from the blood and
stored in the liver as glycogen. Between meals, the liver re-
removal of leases glucose as a means of maintaining blood glucose
hepatic glucose
glucose from blood within its normal range.
production
Glucose is an optional fuel for tissues such as muscle,
adipose tissue, and the liver, which largely use fatty acids
and other fuel substrates for energy. Glucose that is not
blood glucose needed for energy is stored as glycogen or converted to fat.
When tissues such as those in the liver and skeletal muscle
FIGURE 43-1 Hormonal and hepatic regulation of blood glucose. become saturated with glycogen, the additional glucose
is converted into fatty acids and then stored as triglyc-
erides in fat cells. When blood glucose levels fall below
The pancreas is made up of two major tissue types: the normal, as they do between meals, glycogen is broken
acini and the islets of Langerhans (Fig. 43-2). The acini se- down by a process called glycogenolysis, and glucose is re-
crete digestive juices into the duodenum, and the islets of leased. Glycogen stored in the liver can be released into the
Langerhans secrete hormones into the blood. Each islet is bloodstream. Although skeletal muscle has glycogen stores,
composed of beta cells that secrete insulin and amylin, it lacks the enzyme glucose-6-phosphatase that allows glu-
alpha cells that secrete glucagon, and delta cells that se- cose to be broken down sufciently to pass through the cell
crete somatostatin. Insulin lowers the blood glucose con- membrane and enter the bloodstream, limiting its useful-
centration by facilitating the movement of glucose into ness to the muscle cell. In addition to mobilizing its glyco-
body tissues. Glucagon maintains blood glucose by increas- gen stores, the liver synthesizes glucose from amino acids,
ing the release of glucose from the liver into the blood. glycerol, and lactic acid in a process called gluconeogenesis.
Somatostatin inhibits the release of insulin and glucagon. Glucose metabolism is discussed more fully in Chapter 11.
Somatostatin also decreases gastrointestinal activity after In contrast to other body tissues such as the liver and
ingestion of food. By decreasing gastrointestinal activity, skeletal muscle, which use fatty acids and other substrates
somatostatin is thought to extend the time during which for fuel, the brain and nervous system rely almost exclu-
sively on glucose for their energy needs. Because the brain
can neither synthesize nor store more than a few minutes
supply of glucose, normal cerebral function requires a con-
Pancreatic acini
tinuous supply from the circulation. Severe and prolonged
hypoglycemia can cause brain death, and even moderate
hypoglycemia can result in substantial brain dysfunction.
Alpha cell The body maintains a system of counterregulatory mecha-
Beta cell nisms to counteract hypoglycemia-producing situations
and ensure brain function and survival. The physiologic
Delta cell
mechanisms that prevent or correct hypoglycemia in-
clude the actions of the counterregulatory hormones:
glucagon, the catecholamines, growth hormone, and the
glucocorticoids.
Islet of
Langerhans
GLUCOSE-REGULATING HORMONES
Red blood Insulin
cells Although several hormones are known to increase blood
glucose levels, insulin is the only hormone known to have
a direct effect in lowering blood glucose levels. The actions
FIGURE 43-2 Islet of Langerhans in the pancreas. (Guyton A.C., Hall J.E. of insulin are threefold: (1) it promotes glucose uptake by
[1996]. Textbook of medical physiology [9th ed., p. 972]. Philadelphia: target cells and provides for glucose storage as glycogen,
W.B. Saunders) (2) it prevents fat and glycogen breakdown, and (3) it
 CHAPTER 43 Diabetes Mellitus and the Metabolic Syndrome 989

TABLE 43-1 Actions of Insulin and Glucagon on Glucose, Fat, and Protein Metabolism

Insulin Glucagon

Glucose
Glucose transport Increases glucose transport into skeletal
muscle and adipose tissue
Glycogen synthesis Increases glycogen synthesis Promotes glycogen breakdown
Gluconeogenesis Decreases gluconeogenesis Increases gluconeogenesis
Fats
Triglyceride synthesis Increases triglyceride synthesis
Triglyceride transport Increases fatty acid transport into adipose Enhances lipolysis in adipose tissue, liberating fatty
into adipose tissue cells acids and glycerol for use in gluconeogenesis
Activation of adipose Inhibits adipose cell lipase Activates adipose cell lipase
cell lipase Activates lipoprotein lipase in capillary walls
Proteins
Amino acid transport Increases active transport of amino acids Increases transport of amino acids into hepatic
into cells cells
Protein synthesis Increases protein synthesis by increasing Increases breakdown of proteins into amino acids
transcription of messenger RNA and accel- for use in gluconeogenesis
erating protein synthesis by ribosomal RNA
Protein breakdown Decreases protein breakdown by enhancing Increases conversion of amino acids into glucose
the use of glucose and fatty acids as fuel precursors

inhibits gluconeogenesis and increases protein synthesis
(Table 43-1). Insulin acts to promote fat storage by increas-
ing the transport of glucose into fat cells. It also facilitates
triglyceride synthesis from glucose in fat cells and inhibits
the intracellular breakdown of stored triglycerides. Insulin
also inhibits protein breakdown and increases protein syn-
thesis by increasing the active transport of amino acids into
body cells; and it inhibits gluconeogenesis, or the building
of glucose from new sources, mainly amino acids. When
sufcient glucose and insulin are present, protein break-
down is minimal because the body is able to use glucose
and fatty acids as a fuel source. In children and adolescents,
insulin is needed for normal growth and development.
Insulin is produced by the pancreatic beta cells in the
islets of Langerhans. The active form of the hormone is com-
posed of two polypeptide chainsan A chain and a B chain
(Fig. 43-3). Active insulin is formed in the beta cells from a
larger molecule called proinsulin. In converting proinsulin to
insulin, enzymes in the beta cell cleave proinsulin at specic
sites to form two separate substances: active insulin and a

Connecting peptide

GLY
ILE
VAL
NH2
GLU
PHE
S
GLN
VAL S COOH
CYS ASN
ASN CYS A-chain CYS THR
GLN
S THRSER TYR LYS
HIS ASN Proinsulin
LEU S ILE GLU PRO
CYS SER LEU S
CYS LEU TYR GLN THR
GLY TYR
SER PHE
HIS S PHE
LEU GLY
VAL
FIGURE 43-3 Structure of proinsulin. GLU ALA GLU ARG
LEU TYR LEU VAL CYS GLY
With removal of the connecting pep-
tide (C-peptide), proinsulin is con-
verted to insulin. B-chain
990 UNIT X Endocrine Function

biologically inactive C-peptide (connecting peptide) chain

that joined the A and B chains before they were separated.
Active insulin and the inactive C-peptide chain are pack-
aged into secretory granules and released simultaneously
from the beta cell. The C-peptide chains can be measured
clinically, and this measurement can be used to study beta
cell activity. Amylin is an 37-amino acid peptide that is co-
secreted with insulin from the pancreatic beta cells in re-
sponse to glucose and other beta-cell stimulators.4 Studies
indicate that amylin acts as a neuroendocrine hormone,
with several effects that complement the actions of insulin
in regulating postprandial blood glucose levels. These in-
clude a suppression of glucagon secretion and a slowing of
the rate at which glucose is delivered to the small intestine
FIGURE 43-5 Biphasic insulin response to a constant glucose stimu-
for absorption. lus. The peak of the rst phase in humans is 3 to 5 minutes; the sec-
The release of insulin from the pancreatic beta cells is ond phase begins at 2 minutes and continues to increase slowly for
regulated by blood glucose levels, increasing as blood glu- at least 60 minutes or until the stimulus stops. (From Ward W.K.,
cose levels rise and decreasing when blood glucose levels Beard J.C., Halter J.B., Pfeifer M.A., Porte D. Jr. [1984]. Pathology of
decline. Blood glucose enters the beta cell by means of the insulin secretion in non-insulin-dependent diabetes mellitus. Dia-
glucose transporter, is phosphorylated by an enzyme called betes Care 7, 491502. Reprinted with permission from The Ameri-
glucokinase, and is metabolized to form the adenosine tri- can Diabetes Association. Copyright 1984 American Diabetes
phosphate (ATP) needed to close the potassium channels Association)
and depolarize the cell. Depolarization, in turn, results in
opening of the calcium channels and insulin secretion4
(Fig. 43-4). Secretion of insulin occurs in an oscillatory or mately 50% is used or degraded. Insulin, which is rapidly
pulsatile fashion. After exposure to glucose, which is a nu- bound to peripheral tissues or destroyed by the liver or kid-
trient secretagogue, a rst-phase release of stored preformed neys, has a half-life of approximately 15 minutes once it is
insulin occurs, followed by a second-phase release of newly released into the general circulation. To initiate its effects
synthesized insulin (Fig. 43-5). Diabetes may result from on target tissues, insulin binds to a membrane receptor.
dysregulation or deciency in any of the steps involved in The insulin receptor is a combination of four subunitsa
this process (e.g., impaired function of the glucose trans- pair of larger subunits that extend outside the cell mem-
porters, intracellular metabolic defects, glucokinase de- brane and are involved in insulin binding, and a smaller
ciency). Serum insulin levels begin to rise within minutes pair of subunits that are predominantly inside the cell
after a meal, reach a peak in approximately 3 to 5 minutes, membrane and contain a kinase enzyme that becomes ac-
and then return to baseline levels within 2 to 3 hours. tivated during insulin binding (Fig. 43-6). Activation of
Insulin secreted by the beta cells enters the portal cir- the kinase enzyme results in autophosphorylation of the
culation and travels directly to the liver, where approxi- subunit itself. Phosphorylation of the subunit in turn

FIGURE 43-4 One model of control of release

of insulin by the pancreatic beta cells and
the action of the sulfonylurea agents. In the
resting beta cell with low ATP levels, potas-
sium diffuses through the ATP-gated chan-
nels maintaining the resting membrane
potential. As blood glucose rises and is trans-
ported into the beta cell via the glucose
transporter, ATP rises causing the potassium
channels to close and depolarization to occur.
Depolarization results in opening of the
voltage-gated calcium channels, which re-
sults in insulin secretion. (Modified from
Karam J.H. [1992]. Type II diabetes and syn-
drome X. Endocrine and Metabolic Clinics of
North America 21, 339)
 CHAPTER 43 Diabetes Mellitus and the Metabolic Syndrome 991

Glucose
Insulin
Insulin Amino acids
binding site S S
Extracellular
S S S S

Cell
membrane

Glucose Amino acid

transporter transport Intracellular
(GLUT-4)
Tyrosine
Signaling kinase
proteins

Enzyme activation/deactivation

Glucose Glycogen Fat Protein Growth and

transport synthesis synthesis synthesis gene expression

FIGURE 43-6 Insulin receptor. Insulin binds to the subunits of the insulin receptor, which increases glu-
cose transport and causes autophosphorylation of the subunit of the receptor, which induces tyrosine
kinase activity. Tyrosine phosphorylation, in turn, activates a cascade of intracellular signaling proteins
that mediate the effects of insulin on glucose, fat, and protein metabolism.

activates some enzymes and inactivates others, thereby di-
recting the desired intracellular effect of insulin on glucose,
fat, and protein metabolism.
Because cell membranes are impermeable to glucose,
they require a special carrier, called a glucose transporter, to
move glucose from the blood into the cell. These trans-
porters move glucose across the cell membrane at a faster
rate than would occur by diffusion alone. Considerable re-
search has revealed a family of glucose transporters termed
GLUT-1, GLUT-2, and so forth.4 GLUT-4 is the insulin-
dependent glucose transporter for skeletal muscle and adi-
pose tissue. It is sequestered inside the membrane of these
cells and thus is unable to function as a glucose transporter
until a signal from insulin causes it to move from its in-
active site into the cell membrane, where it facilitates glu-
cose entry. GLUT-2 is the major transporter of glucose into
beta cells and liver cells. It has a low afnity for glucose and
acts as a transporter only when plasma glucose levels are
relatively high, such as after a meal. GLUT-1 is present in
all tissues. It does not require the actions of insulin and is
important in transport of glucose into the nervous system.
Glucagon
Glucagon, a polypeptide molecule produced by the alpha
cells of the islets of Langerhans, maintains blood glucose
between meals and during periods of fasting. Like insulin,
glucagon travels through the portal vein to the liver, where
it exerts its main action. Unlike insulin, glucagon produces
an increase in blood glucose. The most dramatic effect of
glucagon is its ability to initiate glycogenolysis or the break-
down of liver glycogen as a means of raising blood glucose,
usually within a matter of minutes. Glucagon also increases
the transport of amino acids into the liver and stimulates
their conversion into glucose, a process called gluconeoge-
nesis. Because liver glycogen stores are limited, gluconeo-
genesis is important in maintaining blood glucose levels
over time (see Table 43-1). Other actions of glucagon occur
only when the hormone is present in high concentrations,
usually well above those normally present in the blood. At
high concentrations, glucagon activates adipose cell lipase,
making fatty acids available for use as energy.2 At very high
concentrations, glucagon can increase the strength of the
heart, increase blood flow to some tissues, including the
kidneys, enhance bile secretion, and inhibit gastric acid
secretion.
As with insulin, glucagon secretion is regulated by
blood glucose. A decrease in blood glucose concentration
to a hypoglycemic level produces an immediate increase in
glucagon secretion, and an increase in blood glucose to
hyperglycemic levels produces a decrease in glucagon se-
cretion. High concentrations of amino acids, as occur after
a protein meal, also can stimulate glucagon secretion. In
this way, glucagon increases the conversion of amino acids
to glucose as a means of maintaining the bodys glucose
levels. Glucagon levels also increase during strenuous ex-
ercise as a means of preventing a decrease in blood glucose.
Other Hormones
Other hormones that can affect blood glucose include the
catecholamines, growth hormone, and the glucocorticoids.
These hormones, along with glucagon, are sometimes
called counterregulatory hormones because they counter-
act the storage functions of insulin in regulating blood glu-
cose levels during periods of fasting, exercise, and other
992 UNIT X Endocrine Function
situations that either limit glucose intake or deplete glu-
cose stores.
Catecholamines. The catecholamines, epinephrine and nor-
epinephrine, help to maintain blood glucose levels during
periods of stress. Epinephrine inhibits insulin release and
promotes glycogenolysis by stimulating the conversion of
muscle and liver glycogen to glucose. Muscle glycogen
cannot be released into the blood; nevertheless, the mobi-
lization of these stores for muscle use conserves blood
glucose for use by other tissues such as the brain and the
nervous system. During periods of exercise and other types
of stress, epinephrine inhibits insulin release from the beta
cells and thereby decreases the movement of glucose into
muscle cells. The catecholamines also increase lipase ac-
tivity and thereby increase mobilization of fatty acids; this
process conserves glucose. The blood glucoseelevating ef-
fect of epinephrine is an important homeostatic mecha-
nism during periods of hypoglycemia.
Growth Hormone. Growth hormone has many metabo-
lic effects. It increases protein synthesis in all cells of the
body, mobilizes fatty acids from adipose tissue, and anta-
gonizes the effects of insulin. Growth hormone decreases
cellular uptake and use of glucose, thereby increasing the
level of blood glucose. The increased blood glucose level
stimulates further insulin secretion by the beta cells. The
secretion of growth hormone normally is inhibited by in-
sulin and increased levels of blood glucose. During peri-
ods of fasting, when both blood glucose levels and insulin
secretion fall, growth hormone levels increase. Exercise,
such as running and cycling, and various stresses, includ-
ing anesthesia, fever, and trauma, increase growth hor-
mone levels.
Chronic hypersecretion of growth hormone, as oc-
curs in acromegaly (see Chapter 42), can lead to glucose
intolerance and the development of diabetes mellitus. In
people who already have diabetes, moderate elevations in
growth hormone levels that occur during periods of stress
and periods of growth in children can produce the entire
spectrum of metabolic abnormalities associated with poor
regulation, despite optimized insulin treatment.
Glucocorticoid Hormones. The glucocorticoid hormones,
which are synthesized in the adrenal cortex along with
other corticosteroid hormones, are critical to survival dur-
ing periods of fasting and starvation. They stimulate gluco-
neogenesis by the liver, sometimes producing a 6- to 10-fold
increase in hepatic glucose production. These hormones
also moderately decrease tissue use of glucose. In predis-
posed persons, the prolonged elevation of glucocorticoid
hormones can lead to hyperglycemia and the develop-
ment of diabetes mellitus. In people with diabetes, even
transient increases in cortisol can complicate control.
There are several steroid hormones with glucocorticoid
activity; the most important of these is cortisol, which ac-
counts for approximately 95% of all glucocorticoid activity
(see Chapter 42). Cortisol levels increase during periods
of stress, such as that produced by infection, pain, trauma,
surgery, prolonged and strenuous exercise, and acute anxi-
ety. Hypoglycemia is a potent stimulus for cortisol secretion.
In summary, energy metabolism is controlled by a number of
hormones, including insulin, glucagon, epinephrine, growth
hormone, and the glucocorticoids. Of these hormones, only in-
sulin has the effect of lowering the blood glucose level. In-
sulins blood glucoselowering action results from its ability to
increase the transport of glucose into body cells and to de-
crease hepatic production and release of glucose into the
bloodstream. Other hormonesglucagon, epinephrine, growth
hormone, and the glucocorticoidsmaintain or increase blood
glucose concentrations and are referred to as counterregulatory
hormones. Glucagon and epinephrine promote glycogenolysis.
Glucagon and the glucocorticoids increase gluconeogenesis.
Growth hormone decreases the peripheral use of glucose. In-
sulin has the effect of decreasing lipolysis and the use of fats
as a fuel source; glucagon and epinephrine increase fat use.
Diabetes Mellitus
After completing this section of the chapter, you should be able to
meet the following objectives:
Compare the distinguishing features of type 1 and type 2
diabetes mellitus, list causes of other specic types of
diabetes, and cite the criteria for gestational diabetes
Dene prediabetes
Relate the physiologic functions of insulin to the manifes-
tations of diabetes mellitus
Dene the metabolic syndrome and describe its
associations
Discuss the role of diet and exercise in the management
of diabetes mellitus
Characterize the actions of oral hypoglycemic agents in
terms of the lowering of blood glucose
Describe the clinical manifestations of diabetic keto-
acidosis and their physiologic signicance
Describe the clinical condition resulting from the hyper-
osmolar hyperglycemic state
Name and describe the types (according to duration of
action) of insulin
Relate the actions of the oral hypoglycemic agents to
alterations in glucose metabolism that occur in persons
with type 2 diabetes
Describe the clinical manifestations of insulin-induced
hypoglycemia and state how these may differ in elderly
people
Describe alterations in physiologic function that
accompany diabetic peripheral neuropathy,
retinopathy, and nephropathy
Describe the causes of foot ulcers in people with diabetes
mellitus
Explain the relation between diabetes mellitus and
infection
The term diabetes is derived from a Greek word mean-
ing going through and mellitus from the Latin word for
honey or sweet. Reports of the disorder can be traced
 CHAPTER 43 Diabetes Mellitus and the Metabolic Syndrome 993

back to the rst century AD, when Aretaeus the Cappado-
cian described the disorder as a chronic afiction charac-
terized by intense thirst and voluminous, honey-sweet
urine: the melting down of esh into urine. It was the
discovery of insulin by Banting and Best in 1922 that trans-
formed the once-fatal disease into a manageable chronic
health problem.5
Diabetes is a disorder of carbohydrate, protein, and fat
metabolism resulting from an imbalance between insulin
availability and insulin need. It can represent an absolute
insulin deciency, impaired release of insulin by the pan-
creatic beta cells, inadequate or defective insulin receptors,
or the production of inactive insulin or insulin that is de-
stroyed before it can carry out its action. A person with un-
controlled diabetes is unable to transport glucose into fat
and muscle cells; as a result, the body cells are starved, and
the breakdown of fat and protein is increased.
CLASSIFICATION AND ETIOLOGY
Although diabetes mellitus clearly is a disorder of insulin
availability, it probably is not a single disease. A revised
system for the classication of diabetes was developed in
1997 by the Expert Committee on the Diagnosis and Clas-
sication of Diabetes Mellitus.6 The intent of this revision,
which replaces the 1979 classication system, was to move
away from focusing on the type of pharmacologic treat-
ment used in management of diabetes to one based on
disease etiology. The revised system continues to include
type 1 and type 2 diabetes, but uses Arabic rather than
Roman numerals and eliminates the use of insulin-
dependent and noninsulin-dependent diabetes mellitus
(Table 43-2). Type 2 diabetes currently accounts for about
90% to 95% of the cases of diabetes. Included in the classi-
cation system are the categories of gestational diabetes

TABLE 43-2 Etiologic Classication of Diabetes Mellitus

Type Subtypes Etiology of Glucose Intolerance

I. Type 1* Beta cell destruction usually leading to absolute

II. Type 2*
III. Other specic types
IV. Gestational diabetes
mellitus (GDM)
insulin deciency
A. Immune mediated
B. Idiopathic
May range from predominantly insulin
resistance with relative insulin deciency to
a predominantly secretory defect with
insulin resistance
A. Genetic defects in beta cell function,
e.g., glucokinase
B. Genetic defects in insulin action, e.g., lepre-
chaunism, Rabson-Mendenhall syndrome
C. Diseases of exocrine pancreas, e.g., pancrea-
titis, neoplasms, cystic brosis
D. Endocrine disorders, e.g., acromegaly,
Cushings syndrome
E. Drug or chemical induced, e.g., Vacor,
glucocorticosteroids, thiazide diuretics,
interferon-alfa
F. Infections, e.g., congenital rubella,
cytomegalovirus
G. Uncommon forms of immune-mediated
diabetes, e.g., stiff man syndrome
H. Other genetic syndromes sometimes
associated with diabetes, e.g., Down
syndrome, Klinefelters syndrome,
Turners syndrome
Any degree of glucose intolerance with onset
or rst recognition during pregnancy
Autoimmune destruction of beta cells
Unknown
Regulates insulin secretion due to defect in
glucokinase generation
Pediatric syndromes that have mutations in
insulin receptors
Loss or destruction of insulin-producing
beta cells
Diabetogenic effects of excess hormone
levels
Toxic destruction of beta cells
Insulin resistance
Impaired insulin secretion
Production of islet cell antibodies
Beta cell injury followed by autoimmune
response
Autoimmune disorder of central nervous
system with immune-mediated beta cell
destruction
Disorders of glucose tolerance related to
defects associated with chromosomal
abnormalities
Combination of insulin resistance and
impaired insulin secretion

*Patients with any form of diabetes may require insulin treatment at some stage of the disease. Such use of insulin,
does not, of itself, classify the patient.
(Adapted from The Expert Committee on the Diagnosis and Classication of Diabetes Mellitus. [2004]. Report of the
Expert Committee on the Diagnosis and Classication of Diabetes Mellitus. Diabetes Care 27, 55510. Reprinted with
permission from the American Diabetes Association. Copyright 2004 American Diabetes Association.)
994 UNIT X Endocrine Function
Expert Committee on the Diagnosis and Classication of Diabetes Mellitus
TABLE 43-3
Using Fasting Plasma Glucose (FPG) and Oral Glucose Tolerance Test (OGTT)
Test Normoglycemic Impaired FPG (IFG)*
FPG <100 mg/dL 100125 mg/dL
(5.6 mmol/L) (5.66.9 mmol/L)
2-h OGTT <140 mg/dL
(7.8 mmol/L)
Other
*IFG and IGT are prediabetic states and can occur in isolation or together in a given subject.
In the absence of unequivocal hyperglycemia with acute metabolic decompensation, these criteria should be
conrmed by repeat testing on a separate day.
Fasting is dened as no caloric intake for at least 8 hours.
OGTT with 2-h measurement of venous plasma or serum glucose following a 75-g carbohydrate load.
(Developed from data in American Diabetes Association. [2004]. Diagnosis and classication of diabetes mellitus.
Diabetes Care 27[Suppl. 1], S510.)
mellitus (i.e., diabetes that develops during pregnancy)
and other specic types of diabetes, many of which occur
secondary to other conditions (e.g., Cushings syndrome,
hematochromatosis, pancreatitis, acromegaly).
The revised classication system also includes a system
for diagnosing diabetes according to stages of glucose in-
tolerance6 (Table 43-3). The revised criteria have retained
the former category of impaired glucose tolerance (IGT) and
have added a new category of impaired fasting plasma glucose
(IFG). The categories of IFG and IGT refer to metabolic
stages intermediate between normal glucose homeostasis
and diabetes, and are labeled together as prediabetes. A fast-
ing plasma glucose (FPG) of less than 100 mg/dL or a
2-hour oral glucose tolerance test (OGTT) result of less than
140 mg/dL is considered normal. IFG is dened as FPG of
100 mg/dL to 125 mg/dL. IGT reects abnormal plasma glu-
cose measurements (140 mg/dL but <200 mg/dL) 2 hours
after an oral glucose load.6 IFG and IGT (i.e., prediabetes) is
associated with increased risk for atherosclerotic heart dis-
ease and increased risk for progression to type 2 diabetes.
Approximately 5% of people with IFG and IGT progress to
diabetes each year. Calorie restriction and weight reduction
are important in overweight people with prediabetes.7 Per-
sons with an FPG of 126 mg/dL or higher or 2-hour
OGTT of 200 mg/L or higher are considered to have provi-
sional diabetes.6 The criteria in Chart 43-1 are used to con-
rm the diagnosis of diabetes in persons with provisional
diabetes.
Type 1 Diabetes Mellitus
Type 1 diabetes mellitus is characterized by destruction
of the pancreatic beta cells.8 Type 1 diabetes is subdivided
into two types: type 1A, immune-mediated diabetes, and
type 1B, idiopathic diabetes. In the United States and
Europe, approximately 10% of people with diabetes melli-
tus have type 1 diabetes, with 95% of them having type 1A,
immune-mediated diabetes.
Type 1A diabetes is characterized by autoimmune de-
struction of beta cells. This type of diabetes, formerly called
juvenile diabetes, occurs more commonly in young persons
Impaired GT (IGT)* Diabetes Mellitus
126 mg/dL (7.0 mmol/L)
140199 mg/dL 200 mg/dL (11.1 mmol/L)
(7.811.1 mmol/L)
Symptoms of diabetes mellitus and
casual plasma glucose 200 mg/dL
but can occur at any age. Type 1 diabetes is a catabolic dis-
order characterized by an absolute lack of insulin, an ele-
vation in blood glucose, and a breakdown of body fats and
proteins. The absolute lack of insulin in people with type 1
diabetes mellitus means that they are particularly prone to
the development of ketoacidosis. One of the actions of in-
sulin is the inhibition of lipolysis (i.e., fat breakdown) and
release of free fatty acids (FFAs) from fat cells. In the ab-
sence of insulin, ketosis develops when these fatty acids are
released from fat cells and converted to ketones in the liver.
Because of the loss of the rst-phase insulin (preformed
insulin) response, all people with type 1A diabetes require
CHART 43-1
Criteria for Diagnosis of Diabetes Mellitus
1. Symptoms of diabetes plus casual plasma glucose
concentration >200 mg/dL (11.1 mmol/L). Casual
is dened as any time of the day without regard to
time since last meal. The classic symptoms of
diabetes include polyuria, polydipsia, and
unexplained weight loss.
or
2. Fasting plasma glucose 126 mg/dL (7.0 mmol/L).
Fasting is dened as no caloric intake for at least 8 h.
or
3. 2-h postload glucose 200 mg/dL (11.1 mmol/L)
during oral glucose tolerance test (OGTT). The test
should be performed as described by the World
Health Organization, using a glucose load contain-
ing the equivalent of 75 g anhydrous glucose
dissolved in water.
In the absence of unequivocal hyperglycemia, these criteria
should be conrmed by repeat testing on a different day. The
third measure (OGTT) is not recommended for routine use.
(Developed from data in American Diabetes Association.
[2004]. Diagnosis and classication of diabetes mellitus.
Diabetes Care 27[Suppl. 1], S510.)

DIABETES MELLITUS
Diabetes mellitus is a disorder of carbohydrate, fat, and
protein metabolism brought about by impaired beta cell
synthesis or release of insulin, or the inability of tissues
to use glucose.
Type 1 diabetes results from loss of beta cell function and
an absolute insulin deciency.
Type 2 diabetes results from impaired ability of the tissues
to use insulin (insulin resistance) accompanied by a relative
lack of insulin or impaired release of insulin in relation to
blood glucose levels (beta cell dysfunction).
exogenous insulin replacement to reverse the catabolic
state, control blood glucose levels, and prevent ketosis.
The rate of beta cell destruction is quite variable, being rapid
in some individuals and slow in others. The rapidly pro-
gressive form commonly is observed in children, but also
may occur in adults. The slowly progressive form usually
occurs in adults and is sometimes referred to as latent auto-
immune diabetes in adults (LADA). LADA may constitute up
to 10% of adults who are currently classied as having
type 2 diabetes.
It has been suggested that type 1A, immune-mediated
diabetes results from a genetic predisposition (i.e., diabeto-
genic genes), a hypothetical triggering event that involves
an environmental agent that incites an immune response,
and immunologically mediated beta cell destruction. Much
evidence has focused on the inherited major histocom-
patibility complex (MHC) genes that encode three human
leukocyte antigens (HLA-DP, HLA-DQ, and HLA-DR) found
on the surface of body cells (see Chapter 19). Susceptibil-
ity to type 1 diabetes also has been associated with HLA-
DR3 and HLA-DR4.4 It appears that what is inherited as
part of the HLA genotype in people with type 1 diabetes is
a susceptibility to an abnormal immune response that af-
fects the beta cells. On the other hand, resistance to the
development of type 1 diabetes has been traced to other
HLA subtypes: DR11, DR15, and DQB1. In addition to the
major susceptibility gene for type 1 diabetes in the MHC
region on chromosome 6, an insulin gene regulating beta
cell replication and function has been identied on chro-
mosome 11.
Type 1 diabetesassociated autoantibodies may exist
for years before the onset of hyperglycemia. There are
two major types of autoantibodies: insulin autoantibodies
(IAAs), and islet cell autoantibodies and antibodies di-
rected at other islet autoantigens, including glutamic acid
decarboxylase (GAD) and the protein tyrosine phosphatase
IA-2.9 Testing for antibodies to GAD or IA-2 and for IAAs
using sensitive radiobinding assays can identify more than
85% of cases of new or future type 1 diabetes with 98% spe-
cicity.10 The appearance of IAAs may precede that of anti-
bodies to GAD or IA-2, and IAAs may be the only anti-
bodies detected at diagnosis in young children. Therefore,
it is recommended that determination of IAAs be included
CHAPTER 43 Diabetes Mellitus and the Metabolic Syndrome 995
in primary testing of children younger than 10 years of age
to maximize sensitivity. Strategies for full evaluation of
the risk for developing future type 1 diabetes should in-
clude determination of at least three of the four best-
established markers, IAAs, islet cell autoantibodies, and
antibodies to GAD and IA-2, as well as a test of the rst-
phase insulin response. These people also may have other
autoimmune disorders such as Graves disease, rheumatoid
arthritis, and Addisons disease.
The fact that type 1 diabetes is thought to result from
an interaction between genetic and environmental factors
has led to research into methods directed at prevention
and early control of the disease. These methods include
the identication of genetically susceptible persons and
early intervention in newly diagnosed persons with type 1
diabetes. After the diagnosis of type 1 diabetes, there often
is a short period of beta cell regeneration, during which
symptoms of diabetes disappear and insulin injections are
not needed. This is sometimes called the honeymoon period.
Immune interventions (immunomodulation) designed to
interrupt the destruction of beta cells before development
of type 1 diabetes are being investigated in various trials,
including the Diabetes Prevention Trial-1 (DPT-1). Unfor-
tunately, none of the interventions studied to date to pre-
vent complete and irreversible beta cell failure have shown
any clinical utility. Effects of modulation of various envi-
ronmental inuences such as infant diet and breast-feeding
remains unclear.11
The term idiopathic type 1B diabetes is used to describe
those cases of beta cell destruction in which no evidence of
autoimmunity is present. Only a small number of people
with type 1 diabetes fall into this category; most are of
African or Asian descent. Type 1B diabetes is strongly in-
herited. People with the disorder have episodic ketoacido-
sis due to varying degrees of insulin deciency with periods
of absolute insulin deciency that may come and go.
Type 2 Diabetes Mellitus and
the Metabolic Syndrome
Type 2 diabetes mellitus is a heterogeneous condition
that describes the presence of hyperglycemia in associa-
tion with relative insulin deficiency. In contrast to type 1
diabetes in which absolute insulin deficiency is present,
type 2 diabetes can be associated with high, normal, or
low insulin levels. However, in the presence of insulin re-
sistance, the insulin cannot function effectively, and
hyperglycemia can result. Type 2 diabetes is therefore a
disorder of both insulin levels (beta cell dysfunction) and
insulin function (insulin resistance).12 Type 2 diabetes
(unlike type 1) is not associated with HLA markers or
autoantibodies.
Most people with type 2 diabetes are older and over-
weight; however, type 2 diabetes is becoming a more com-
mon occurrence in obese adolescents.13,14 The metabolic
abnormalities that contribute to hyperglycemia in people
with type 2 diabetes include (1) impaired beta cell function
and insulin secretion, (2) peripheral insulin resistance, and
(3) increased hepatic glucose production.12
Insulin resistance initially produces an increase in beta
cell secretion of insulin (resulting in hyperinsulinemia)
996 UNIT X Endocrine Function
as the body attempts to maintain a normoglycemic state.
In time, however, the insulin response declines because
of increasing beta cell dysfunction. This results initially
in elevated postprandial blood glucose levels. Eventually,
fasting blood glucose levels also rise until frank type 2 di-
abetes occurs. During the evolutionary phase, an indi-
vidual with type 2 diabetes may eventually develop ab-
solute insulin deciency because of progressive beta cell
failure. As with persons with type 1 diabetes, these persons
require insulin therapy to survive. Because most persons
with type 2 diabetes do not have an absolute insulin de-
ciency, they are less prone to develop ketoacidosis as com-
pared with people with type 1 diabetes (the presence of cir-
culating insulin in most type 2 diabetics suppresses ketone
body formation).
Beta Cell Dysfunction. Specic causes of beta cell dysfunc-
tion in patients with prediabetes and type 2 diabetes may
include: (1) an initial decrease in the beta cell mass (this
may be related to genetic factors responsible for beta cell dif-
ferentiation and function, and environmental factors such
as the presence of maternal diabetes during pregnancy or in
utero factors such as the presence of intrauterine growth re-
tardation), (2) increased beta cell apoptosis/decreased re-
generation, (3) long-standing insulin resistance leading to
beta cell exhaustion, (4) chronic hyperglycemia can induce
beta cell desensitization termed glucotoxicity, (5) chronic ele-
vation of free fatty acids can cause toxicity to beta cells
termed lipotoxicity, and (6) amyloid deposition in the beta
cell can cause dysfunction.12 According to one study, beta
cell function was reduced 50% at diagnosis of type 2 dia-
betes, and its progressive decrease (by approximately 4% per
year) profoundly inuenced the subsequent response to
treatment (meaning that combination treatment with sev-
eral agents is usually the norm to maintain glycemic goals).
Insulin Resistance and the Metabolic Syndrome. There
is increasing evidence to suggest that insulin resistance
not only contributes to the hyperglycemia in persons with
type 2 diabetes, but may also play a role in other meta-
bolic abnormalities. These include high levels of plasma
triglycerides and low levels of high-density lipoproteins
(HDLs), hypertension, systemic inammation (as detected
by C-reactive protein [CRP] and other mediators), ab-
normal fibrinolysis, abnormal function of the vascular
endothelium, and macrovascular disease (coronary artery,
cerebrovascular, and peripheral arterial disease). This con-
stellation of abnormalities often is referred to as the in-
sulin resistance syndrome, syndrome X, or the preferred term,
metabolic syndrome.13 In clinical practice, the Third Report
of the National Cholesterol Education Program Expert
Panel on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults (NCEP ATP III) denition of
metabolic syndrome is widely used15 (Chart 43-2). Insulin
resistance and increased risk for developing type 2 diabetes
are also seen in women with polycystic ovary syndrome16
(see Chapter 47).
A major factor in persons with the metabolic syndrome
that leads to type 2 diabetes is central obesity. Approxi-
mately 80% of persons with type 2 diabetes are overweight.
Obese people have increased resistance to the action of in-
CHART 43-2
NCEP ATP III Criteria for a Diagnosis of Metabolic Syndrome*
Three or more of the following:
Abdominal obesity: waist circumference >35 inches
in women or >40 inches in men
Triglycerides 150 mg/dL
High-density lipoproteins (HDL) <50 mg/dL in
women or <40 mg/dL in men
Blood pressure >130/85 mm Hg
Fasting plasma glucose >110 mg/dL
*Developed from: Grundy S.M., Panel Chair. (2001). Third
Report of the National Cholesterol Education Program (NCEP)
Expert Panel on Detection, Evaluation, and Treatment of
High Blood Cholesterol in Adults (Adult Treatment Panel III).
(NIH Publication No. 01-3670.) Bethesda, MD: National
Institutes of Health.
In view of the recent changes in the denition of abnormal
glucose levels (American Diabetes Association. [2004].
Diagnosis and classication of diabetes mellitus. Diabetes Care
27[Suppl. 1], S510), an FPG value >100 mg/dL should now be
used in the diagnosis of the metabolic syndrome.
sulin and impaired suppression of glucose production by
the liver, resulting in both hyperglycemia and hyperinsu-
linemia.12 The type of obesity is an important considera-
tion in the development of type 2 diabetes. It has been
found that people with upper body obesity (central obe-
sity) are at greater risk for developing type 2 diabetes and
metabolic disturbances than persons with lower body obe-
sity (see Chapter 11). The increased insulin resistance has
been attributed to increased visceral (intraabdominal) obe-
sity detected on computed tomography scan.17 Waist cir-
cumference, which is a measure of central obesity, has
been shown to correlate well with insulin resistance. The
new terminology that is emerging for persons with obesity
and type 2 diabetes is diabesity. Therefore, a diagnosis of
the metabolic syndrome using the NCEP ATP III criteria
(see Chart 43-2) should be considered for persons with IFG
or type 2 diabetes. For management, weight loss with ini-
tial 5% to 10% of body weight should be incorporated into
their treatment plan as well as addressing the diabetes and
other related metabolic abnormalities. Over time, insulin
resistance may improve with weight loss, to the extent that
many people with type 2 diabetes can be managed with a
weight-reduction program and exercise.7
It has been theorized that the insulin resistance and in-
creased glucose production in obese people with type 2 di-
abetes may stem from an increased concentration of free
fatty acids (FFAs).12 Visceral obesity is especially important
because it is accompanied by increases in fasting and post-
prandial FFA concentrations. This has several consequences:
(1) acutely, FFAs act at the level of the beta cell to stimu-
late insulin secretion, which, with excessive and chronic
stimulation, causes beta cell failure (lipotoxicity); (2) they
act at the level of the peripheral tissues to cause insulin re-
sistance and glucose underutilization by inhibiting glu-
cose uptake and glycogen storage through a reduction in
 CHAPTER 43 Diabetes Mellitus and the Metabolic Syndrome 997

muscle glycogen synthetase activity; (3) the accumulation
of FFAs and triglycerides reduce hepatic insulin sensitivity,
leading to increased hepatic glucose production and hyper-
glycemia, especially fasting plasma glucose levels. Thus, an
increase in FFA that occurs in obese individuals (especially
visceral obesity) with a genetic predisposition to type 2 di-
abetes may eventually lead to beta cell dysfunction/failure,
increased insulin resistance, and hepatic glucose produc-
tion (Fig. 43-7). A further consequence is the diversion of
excess FFAs to nonadipose tissues, including liver, skeletal
muscle, heart, and pancreatic beta cells.12 The uptake of
FFAs from the portal blood can lead to hepatic triglyc-
eride accumulation and nonalcoholic fatty liver disease
(see Chapter 40).
A proposed link to the insulin resistance associated
with obesity is an adipose cell secretion (adipocytokine)
called adiponectin.18 Adiponectin is secreted by adipose
tissue and circulates in the blood. It has been shown that
decreased levels of adiponectin coincide with insulin re-
sistance in animal models and patients with obesity and
type 2 diabetes. Moreover, there is evidence that the ex-
pression of adiponectin mRNA might be partially regulated
by peroxisome proliferatoractivated receptor-, a nuclear
receptor that leads to the regulation of genes controlling
FFA levels and glucose metabolism (discussed under the thi-
azolidinedione oral antidiabetic agents). In skeletal muscle,
adiponectin has been shown to decrease tissue triglyceride
content by increasing the utilization of fatty acids as a fuel
source. Because its level is low in the metabolic syndrome,
the replenishment of adiponectin may be considered as an
alternative treatment of insulin resistance in the future.18,19
The fact that lifestyle plays an important role in the
pathogenesis of type 2 diabetes has led to an increased em-
phasis on prevention. The ndings of the Diabetes Preven-
tion Program (DPP), a research project involving 27 centers
in the United States, found that diet and exercise dramat-
ically delay the onset of type 2 diabetes.20 Participants ran-
domly assigned to an intensive lifestyle modication pro-
gram (low-fat diet and exercising 150 minutes a week) with
a 7% weight loss, reduced their risk for developing type 2
diabetes by 58%. The study also found that participants as-
signed to treatment with the oral diabetic drug metformin
reduced their risk for developing diabetes by 31%.20
Other Specic Types
The category of other specic types of diabetes, formerly
known as secondary diabetes, describes diabetes that is asso-
ciated with certain other conditions and syndromes. Such
diabetes can occur with pancreatic disease or the removal
of pancreatic tissue and with endocrine diseases, such as
acromegaly, Cushings syndrome, or pheochromocytoma.
Endocrine disorders that produce hyperglycemia do so by
increasing the hepatic production of glucose or decreasing
the cellular use of glucose. Several specic types of diabetes
are associated with monogenetic defects in beta cell func-
tion. These specic types of diabetes, which resemble type 2
diabetes but occur at an earlier age (usually before 25 years
of age), are referred to as maturity-onset diabetes of the young
(MODY).4
Environmental agents that have been associated
with altered pancreatic beta cell function include viruses
(e.g., mumps, congenital rubella, coxsackievirus) and chemi-
cal toxins. Among the suspected chemical toxins are the
nitrosamines, which sometimes are found in smoked and
cured meats. The nitrosamines are related to streptozocin,
which is used to induce diabetes in experimental animals,
and to the rat poison Vacor, which can produce diabetes
when ingested by humans.

Genetic
Environmental
predisposition
factors

Insulin Obesity
Deranged insulin resistance
release

Decreased glucose
uptake

Hyperglycemia

Increased
hepatic glucose Type 2
FIGURE 43-7 Pathogenesis of type 2 diabetes output diabetes
mellitus.
998 UNIT X Endocrine Function
Several diureticsthiazides and loop diureticselevate
blood glucose. These diuretics increase potassium loss,
which is thought to impair insulin release. Other drugs
known to cause hyperglycemia are diazoxide, glucocorti-
coids, levodopa, oral contraceptives, sympathomimetics,
phenothiazines, phenytoin, and total parenteral nutri-
tion (i.e., hyperalimentation). Drug-related increases in
blood glucose usually are reversed after the drug has been
discontinued.
The advent of potent antiretroviral therapy (especially
protease inhibitors) for the treatment of human immuno-
deciency virus (HIV) and acquired immunodeciency
syndrome (AIDS) has signicantly improved survival. How-
ever, these patients are now developing metabolic de-
rangements similar to the features seen in the metabolic
syndrome (insulin resistance, high levels of plasma tri-
glycerides, low levels of high-density lipoproteins [HDLs],
hypertension, obesity, systemic inammation [as detected
by C-reactive protein (CRP) and other mediators], abnor-
mal brinolysis, abnormal endothelial dysfunction, and
macrovascular disease).21 In addition, changes in fat dis-
tribution (peripheral lipoatrophy and visceral obesity),
sometimes referred to as lipodystrophy, often occur (see
Chapter 22). These people should be aggressively treated
to prevent cardiovascular complications resulting from the
abnormal risk factors.21
Gestational Diabetes
Gestational diabetes mellitus (GDM) refers to any degree
of glucose intolerance that is detected rst during preg-
nancy. It occurs to various degrees in 1% to 14% of all
pregnancies, depending on the population and diagnostic
tests used.22 It most frequently affects women with a fam-
ily history of diabetes; with glycosuria; with a history of
stillbirth or spontaneous abortion, fetal anomalies in a pre-
vious pregnancy, or a previous large- or heavy-for-date baby;
and who are obese, of advanced maternal age, or have had
ve or more pregnancies.
All pregnant women should undergo risk assessment
for diabetes during their rst prenatal visit. Those with sig-
nicant risk should undergo plasma glucose testing as soon
as feasible. If they are found not found to have GDM at the
initial screening, they should be retested between 24 and
28 weeks of gestation. Women with average risk should be
tested at 24 to 28 weeks of gestation. Women with an FPG
of more than 126 mg/dL or casual glucose of more than
200 mg/dL meet the threshold for diabetes, if conrmed
on a subsequent day, and do not need to undergo oral glu-
cose tolerance testing.22 Women with high or average GDM
risk who do not demonstrate this degree of hyperglycemia
on FPG testing should undergo further screening using the
oral glucose tolerance test. This screening test consists of
50 g of glucose given without regard to the last meal and
followed in 1 hour by a venous blood sample for glucose
concentration. If the plasma glucose level is greater than
140 mg/dL, then a 100-g 3-hour glucose tolerance test is
indicated to establish the diagnosis of GDM22 (Table 43-4).
On the other hand, women who are younger than 25 years
of age, were of normal body weight before pregnancy, have
TABLE 43-4 Diagnosis of Gestational Diabetes Mellitus
With a 100-g Glucose Load
100-g Glucose Load mg/dL (mmol/L)
Fasting 95 (5.3)
1 hour 180 (10.0)
2 hour 155 (8.6)
3 hour 140 (7.8)
Two or more of the venous plasma concentrations must be met or
exceeded for a positive diagnosis. The test should be done in the morning
after an overnight fast of between 8 and 14 h and after at least 3 days of
unrestricted diet (>150 g carbohydrate/day) and unlimited physical
activity. The subject should remain seated and should not smoke
throughout the test. (Developed from data in American Diabetes
Association. [2004]. Diagnosis and classication of diabetes mellitus.
Diabetes Care 27[Suppl 1], S510.)
no family history of diabetes or poor obstetric outcome,
and are not members of a high-risk ethnic or racial group
(e.g., Hispanic, Native American, Asian, African American)
may not need to be screened.
Diagnosis and careful medical management are es-
sential because women with GDM are at higher risk for
complications of pregnancy, mortality, and fetal abnor-
malities.4 Fetal abnormalities include macrosomia (i.e., large
body size), hypoglycemia, hypocalcemia, polycythemia,
and hyperbilirubinemia.
Treatment of GDM includes close observation of
mother and fetus because even mild hyperglycemia has
been shown to be detrimental to the fetus.22 Maternal fast-
ing and postprandial blood glucose levels should be mea-
sured regularly. Fetal surveillance depends on the degree of
risk for the fetus. The frequency of growth measurements
and determinations of fetal distress depends on available
technology and gestational age. All women with GDM re-
quire nutritional guidance because nutrition is the corner-
stone of therapy. The nutrition plan should provide the
necessary nutrients for maternal and fetal health, result in
normoglycemia and proper weight gain, and prevent keto-
sis.4 If dietary management alone does not achieve a fasting
blood glucose level no greater than 105 mg/dL or a 2-hour
postprandial blood glucose no greater than 120 mg/dL, the
Third International Workshop on GDM recommends ther-
apy with human insulin.22 Oral antidiabetic agents may be
teratogenic and are not recommended in pregnancy. Self-
monitoring of blood glucose levels is essential.
Women with GDM are at increased risk for develop-
ing diabetes 5 to 10 years after delivery. Women in whom
GDM is diagnosed should be followed after delivery to de-
tect diabetes early in its course. These women should be
evaluated during their rst postpartum visit with a 2-hour
oral glucose tolerance test with a 75-g glucose load.
CLINICAL MANIFESTATIONS
Diabetes mellitus may have a rapid or an insidious onset.
In type 1 diabetes, signs and symptoms often arise sud-
denly. Type 2 diabetes usually develops more insidiously;

its presence may be detected during a routine medical ex-
amination or when a patient seeks medical care for other
reasons.
The most commonly identied signs and symptoms
of diabetes are referred to as the three polys: (1) polyuria
(i.e., excessive urination), (2) polydipsia (i.e., excessive
thirst), and (3) polyphagia (i.e., excessive hunger). These
three symptoms are closely related to the hyperglycemia
and glycosuria of diabetes. Glucose is a small, osmotically
active molecule. When blood glucose levels are sufciently
elevated, the amount of glucose ltered by the glomeruli
of the kidney exceeds the amount that can be reabsorbed
by the renal tubules; this results in glycosuria accompa-
nied by large losses of water in the urine. Thirst results
from the intracellular dehydration that occurs as blood
glucose levels rise and water is pulled out of body cells, in-
cluding those in the thirst center. Cellular dehydration
also causes dryness of the mouth. This early symptom may
be easily overlooked in people with type 2 diabetes, par-
ticularly in those who have had a gradual increase in blood
glucose levels. Polyphagia usually is not present in people
with type 2 diabetes. In type 1 diabetes, it probably results
from cellular starvation and the depletion of cellular stores
of carbohydrates, fats, and proteins.
Weight loss despite normal or increased appetite is a
common occurrence in people with uncontrolled type 1
diabetes. The cause of weight loss is twofold. First, loss of
body uids results from osmotic diuresis. Vomiting may
exaggerate the uid loss in ketoacidosis. Second, body tis-
sue is lost because the lack of insulin forces the body to use
its fat stores and cellular proteins as sources of energy. In
terms of weight loss, there often is a marked difference be-
tween type 2 diabetes and type 1 diabetes. Weight loss is a
frequent phenomenon in people with uncontrolled type 1
diabetes, whereas many people with uncomplicated type 2
diabetes have problems with obesity.
Other signs and symptoms of hyperglycemia include
recurrent blurred vision, fatigue, paresthesias, and skin in-
fections. In type 2 diabetes, these often are the symptoms
that prompt a person to seek medical treatment. Blurred vi-
sion develops as the lens and retina are exposed to hyper-
osmolar uids. Lowered plasma volume produces weakness
and fatigue. Paresthesias reect a temporary dysfunction
of the peripheral sensory nerves. Chronic skin infections
are common in people with type 2 diabetes. Hyperglyce-
mia and glycosuria favor the growth of yeast organisms.
Pruritus and vulvovaginitis resulting from candidal infec-
tions are common initial complaints in women with dia-
betes. Balanitis secondary to candidal infections can occur
in men.
DIAGNOSTIC TESTS
The diagnosis of diabetes mellitus in nonpregnant adults
is based on fasting plasma glucose levels, casual plasma
glucose tests, or the results of a glucose challenge test (see
Table 43-3). Testing for diabetes should be considered in
all individuals 45 years of age and older. Testing should be
considered at a younger age in people who are obese, have
a rst-degree relative with diabetes, are members of a high-
CHAPTER 43 Diabetes Mellitus and the Metabolic Syndrome 999
risk group, have delivered an infant weighing more than
9 pounds or have been diagnosed with GDM, have hyper-
tension or hyperlipidemia, or have met the criteria for IGT
or IFG (i.e., prediabetes) on previous testing.23
Blood Tests
Blood glucose measurements are used in both the diagno-
sis and management of diabetes. Diagnostic tests include
the fasting plasma glucose, casual plasma glucose, and glu-
cose tolerance test. Laboratory and capillary or nger
stick glucose tests are used for glucose management in
people with diagnosed diabetes. Glycosylated hemoglobin
(A1C, previously termed HbA1c) provides a measure of glu-
cose control over time. Table 43-5 shows the correlation
between mean plasma glucose level and A1C levels for
people with diabetes.24
Fasting Blood Glucose Test. The fasting plasma glucose has
been suggested as the preferred diagnostic test because of
ease of administration, convenience, patient acceptability,
and cost.23 Glucose levels are measured after food has been
withheld for at least 8 hours. An FPG level below 100 mg/dL
is considered normal (see Table 43-3). A level between
100 mg/dL and 126 mg/dL is signicant and is dened as
impaired fasting glucose. If the FPG level is 126 mg/dL or
higher on two occasions, diabetes is diagnosed.
Casual Blood Glucose Test. A casual plasma glucose is one
that is done without regard to the time of the last meal. A
casual plasma glucose concentration that is unequivocally
elevated (200 mg/dL) in the presence of classic symptoms
of diabetes such as polydipsia, polyphagia, polyuria, and
blurred vision is diagnostic of diabetes mellitus at any age.
Glucose Tolerance Test. The oral glucose tolerance test is
an important screening test for diabetes. The test measures
the bodys ability to store glucose by removing it from the
blood. In men and women, the test measures the plasma
glucose response to 75 g of concentrated glucose solution
at selected intervals, usually 1 hour and 2 hours. In preg-
nant women, a glucose load of 100 g is given (see the Ges-
tational Diabetes section) with an additional 3-hour plasma
glucose determination. In people with normal glucose tol-
erance, blood glucose levels return to normal within 2 to
3 hours after ingestion of a glucose load, in which case, it
can be assumed that sufcient insulin is present to allow
TABLE 43-5 Correlation Between Hemoglobin A1C Level
and Mean Plasma Glucose Levels
Hemoglobin AIC (%) Mean Plasma Glucose mg/dL (mmol/L)
6 135 (7.5)
7 170 (9.5)
8 205 (11.5)
9 240 (13.5)
10 275 (13.5)
11 310 (17.5)
12 345 (19.5)
1000 UNIT X Endocrine Function
glucose to leave the blood and enter body cells. Because a
person with diabetes lacks the ability to respond to an in-
crease in blood glucose by releasing adequate insulin to
facilitate storage, blood glucose levels rise above those ob-
served in normal people and remain elevated for longer
periods (see Table 43-3).
Capillary Blood Tests and Self-Monitoring of Capillary
Blood Glucose Levels. Technologic advances have provided
the means for monitoring blood glucose levels by using a
drop of capillary blood. This procedure has provided health
professionals with a rapid and economical means for mon-
itoring blood glucose and has given people with diabetes
a way of maintaining near-normal blood glucose levels
through self-monitoring of blood glucose. These methods
use a drop of capillary blood obtained by pricking the n-
ger or forearm with a special needle or small lancet. Small
trigger devices make use of the lancet virtually painless.
The drop of capillary blood is placed on or absorbed by a
reagent strip, and glucose levels are determined electroni-
cally using a glucose meter.
Laboratory tests that use plasma for measurement of
blood glucose give results that are 10% to 15% higher than
the nger stick method, which uses whole blood.25 Many
blood glucose monitors approved for home use and some
test strips now calibrate blood glucose readings to plasma
values. It is important that people with diabetes know
whether their monitors or glucose strips provide whole
blood or plasma test results.
Glycated Hemoglobin Testing. Glycated hemoglobin, also
referred to as glycohemoglobin, glycosylated hemoglobin,
HbA1c, or A1C (the preferred term), is a term used to de-
scribe hemoglobin into which glucose has been incorpo-
rated. Hemoglobin normally does not contain glucose when
it is released from the bone marrow. During its 120-day life
span in the red blood cell, hemoglobin normally becomes
glycated to form hemoglobins A1a and A1b (2% to 4%) and
A1c (termed A1C, 4% to 6%). In uncontrolled diabetes or
diabetes with hyperglycemia, there is an increase in the
level of A1C. Based on the Diabetes Control and Compli-
cations Trial (DCCT) and United Kingdom Prospective Di-
abetic Study (UKPDS), it is recommended that persons
with diabetes lower their A1C to 7.0% or even achieve a
normal glycemic level of less than 6.0%.25 Because glucose
entry into the red blood cell is not insulin dependent, the
rate at which glucose becomes attached to the hemoglo-
bin molecule depends on blood glucose. Glycosylation is
essentially irreversible, and the level of A1C present in the
blood provides an index of blood glucose levels over the
previous 6 to 12 weeks.
Urine Tests
The ease, accuracy, and convenience of self-administered
blood glucose monitoring techniques have made urine test-
ing for glucose obsolete for most people with diabetes.
These tests only reect urine glucose levels and are inu-
enced by such factors as the renal threshold for glucose,
uid intake and urine concentration, urine testing method-
ologies, and some drugs. Because of these factors, the ADA
recommends that all people who use insulin should self-
monitor their blood glucose, not urine glucose. Unlike glu-
cose tests, urine ketone determinations remain an impor-
tant part of monitoring diabetic control, particularly in
people with type 1 diabetes who are at risk for developing
ketoacidosis and in pregnant diabetic women to check the
adequacy of nutrition and glucose control.25
DIABETES MANAGEMENT
The desired outcomes of glycemic control in both type 1
and type 2 diabetes is normalization of blood glucose as a
means of preventing short- and long-term complications.
Treatment plans involve nutrition therapy, exercise, and
antidiabetic agents. People with type 1 diabetes require in-
sulin therapy from the time of diagnosis. Weight loss and
dietary management may be sufcient to control blood
glucose levels in people with type 2 diabetes. However,
they require follow-up care because insulin secretion from
the beta cells may decrease or insulin resistance may per-
sist, in which case oral antidiabetic agents are prescribed.
Among the methods used to achieve these goals are edu-
cation in self-management and problem solving. Individ-
ual treatment goals should take into account the persons
age and other disease conditions, the persons capacity to
understand and carry out the treatment regime, and socio-
economic factors that might inuence compliance with
the treatment plan. Optimal control of type 2 diabetes is
associated with prevention or delay of chronic diabetes
complications.26
Dietary Management
Dietary management usually is prescribed to meet the spe-
cic needs of each person with diabetes. Goals and prin-
ciples of diet therapy differ between type 1 and type 2 dia-
betes, as well as for lean and obese people. Integral to
diabetes management is a prescribed plan for nutrition
therapy.27 Therapy goals include maintenance of near-
normal blood glucose levels, achievement of optimal lipid
levels, adequate calories to maintain and attain reason-
able weights, prevention and treatment of chronic dia-
betes complications, and improvement of overall health
through optimal nutrition.
For a person with type 1 diabetes, the usual food in-
take is assessed and used as a basis for adjusting insulin
therapy to t with the persons lifestyle. Eating consistent
amounts and types of food at specic and routine times is
encouraged. Home blood glucose monitoring is used to
fine-tune the plan. Newer forms of therapy, such as multi-
ple daily insulin injections and the use of an insulin pump,
provide many options. Most people with type 2 diabetes
are overweight. Nutrition therapy goals focus on achiev-
ing glucose, lipid, and blood pressure goals, and weight
loss if indicated. Mild to moderate weight loss (5% to 10%
of total body weight) has been shown to improve diabetes
control, even if desirable weight is not achieved.
A coordinated team effort, including the person with
diabetes, is needed to individualize the nutrition plan. The
diabetic diet has undergone marked changes over the
years, particularly in the recommendations for distribu-

tion of calories among carbohydrates, proteins, and fats.
There no longer is a specic diabetic or ADA diet but rather
a dietary prescription based on nutrition assessment and
treatment goals. Information is assessed regarding meta-
bolic parameters and medical history of factors such as
renal impairment and gastrointestinal autonomic neuro-
pathy. Evaluating the effectiveness of the meal plan re-
quires monitoring metabolic parameters such as blood
glucose, A1C, lipids, blood pressure, body weight, and
quality of life. Self-management education is essential to
facilitate understanding of the associations among food,
exercise, medication, and blood glucose.
The registered dietitian plays an essential role in the
diabetes care team and is able to select from a variety of
methods such as carbohydrate counting, food exchanges,
healthy food choices, glycemic index, and total available
glucose to tailor the meal plan to meet individual needs.
Simpler recommendations have been associated with im-
proved client understanding and dietary adherence. Car-
bohydrate counting uses product label information that is
easily available to people with diabetes.28 Regardless of
food source, total grams of carbohydrate are counted, plac-
ing an emphasis on the nutrient that most affects blood
glucose control.
Nutrition therapy also is tailored to control of other
dietary components. Because diabetes is a risk factor for
cardiovascular disease, it is recommended that less than
10% of daily calories should be obtained from saturated fat
and that dietary cholesterol be limited to 300 mg or less.
Periodic fasting lipid panels may identify concomitant
lipid disorders. If lipid disorders are identied, appropriate
modications according to the Third Report of the Na-
tional Cholesterol Education Program (NECP ATP III) on
detection, evaluation, and treatment of high blood choles-
terol should be followed.15 For example, with a low-density
lipoprotein cholesterol elevation, a diet with less than 7%
of total calories from saturated fat, with 25% to 35% of
daily calories obtained from fat, and with a cholesterol in-
take of less than 200 mg/day is recommended. For people
with diabetic nephropathy, some studies suggest lowering
the intake of protein to 10% of daily calories. Recommen-
dations for dietary sodium are the same as for the general
population: 2400 to 3000 mg/day as a baseline; less than
2400 mg/day if mild to moderate hypertension is present;
and less than 2000 if severe hypertension or nephropathy
exists. The ADA provides literature with more detailed in-
formation on diet therapy and patient education. Included
is the method of calculating individual meal plans. Regis-
tered dietitians are valuable resources to the nurse, physi-
cian, and person with diabetes and should be included in
nutritional planning.
Exercise
The benets of exercise include cardiovascular tness and
psychological well-being. For many people with type 2 di-
abetes, the benets of exercise include a decrease in body
fat, better weight control, and improvement in insulin sen-
sitivity.7,20,29 Exercise is so important in diabetes manage-
ment that a planned program of regular exercise usually is
considered an integral part of the therapeutic regimen for
CHAPTER 43 Diabetes Mellitus and the Metabolic Syndrome 1001
every person with diabetes. In general, sporadic exercise
has only transient benets; a regular exercise or training
program is the most benecial. It is better for cardiovascu-
lar conditioning and can maintain a muscle-to-fat ratio
that enhances peripheral insulin receptivity.
In people with insulin-treated diabetes, the benecial
effects of exercise are accompanied by an increased risk for
hypoglycemia. Although muscle uptake of glucose in-
creases signicantly, the ability to maintain blood glucose
levels is hampered by failure to suppress the absorption of
injected insulin and activate the counterregulatory mech-
anisms that maintain blood glucose. Not only is there an
inability to suppress insulin levels, but insulin absorption
also may increase. This increased absorption is more pro-
nounced when insulin is injected into the subcutaneous
tissue of the exercised muscle, but it occurs even when in-
sulin is injected into other body areas. Even after exercise
ceases, insulins lowering effect on blood glucose contin-
ues. In some people with type 1 diabetes, the symptoms of
hypoglycemia occur many hours after cessation of exer-
cise. This may occur because subsequent insulin doses (in
people using multiple daily insulin injections) are not ad-
justed to accommodate the exercise-induced decrease in
blood glucose. The cause of hypoglycemia in people who
do not administer a subsequent insulin dose is unclear. It
may be related to the fact that the liver and skeletal mus-
cles increase their uptake of glucose after exercise as a
means of replenishing their glycogen stores, or that the
liver and skeletal muscles are more sensitive to insulin dur-
ing this time. People with insulin-treated diabetes should
be aware that delayed hypoglycemia can occur after exer-
cise and that they may need to alter their diabetes med-
ication dose, their carbohydrate intake, or both.
Although of benet to people with diabetes, exercise
must be weighed on the riskbenet scale. Before begin-
ning an exercise program, persons with diabetes should
undergo an appropriate evaluation for macrovascular and
microvascular disease.29 The goal of exercise is safe partic-
ipation in activities consistent with an individuals life-
style. As with nutrition guidelines, exercise recommenda-
tions need to individualized. Considerations include the
potential for hypoglycemia, hyperglycemia, ketosis, cardio-
vascular ischemia, and dysrhythmias (particularly silent
ischemic heart disease); exacerbation of proliferative reti-
nopathy; and lower extremity injury. For those with chronic
diabetes, the complications of vigorous exercise can be
harmful and can cause eye hemorrhage and other prob-
lems. For people with type 1 diabetes who exercise during
periods of poor control (i.e., when blood glucose is ele-
vated, exogenous insulin levels are low, and ketonemia ex-
ists), blood glucose and ketone rise to even higher levels
because the stress of exercise is superimposed on preexisting
insulin deciency and increased counterregulatory hor-
mone activity.
Oral Antidiabetic Agents
There are two categories of antidiabetic agents: oral med-
ications and insulin. Because people with type 1 diabetes
are decient in insulin, they are in need of exogenous in-
sulin replacement therapy from the start. People with type 2
1002 UNIT X Endocrine Function
diabetes have increased hepatic glucose production; de-
creased peripheral utilization of glucose; decreased utiliza-
tion of ingested carbohydrates; and over time, impaired
insulin secretion from the pancreas (Fig. 43-8). The oral an-
tidiabetic agents used in the treatment of type 2 diabetes at-
tack each one of these areas and sometimes more.3032 In
order to optimize the benecial effects from each agent
and improve compliance, the new approach in the pharma-
ceutical armamentarium is to have combination drugs such
as rosiglitazone and metformin or a sulfonylurea and met-
formin. If good glycemic control cannot be achieved with
a combination of oral agents, insulin can be used with the
oral agents or by itself.
Oral antidiabetic agents approved by the U.S. Food
and Drug Administration (FDA) fall into four categories:
beta cell stimulator agents (sulfonylureas, repaglinide, and
nateglinide), biguanides, -glucosidase inhibitors, and thia-
zolidinediones (TZDs)3032 (see Fig. 43-8).
Sulfonylureas. The sulfonylureas were discovered acci-
dentally in 1942, when scientists noticed that one of the
Impaired insulin secretion
Type 2
Diabetes Mellitus
Increased basal hepatic
glucose production
Hepatic glucose
Glucose absorption
output
-glucoside inhibitors
Biguanides Type 2
Diabetes
Mellitus
Thiazolidinediones
Beta cell
stimulators
Insulin
secretion
sulfonamide drugs being developed at the time caused
hypoglycemia. These drugs reduce blood glucose by stim-
ulating the release of insulin from beta cells in the pan-
creas and increasing the sensitivity of peripheral tissues
to insulin. These agents are effective only when some
residual beta cell function remains. Sulfonylurea receptors
in beta cells of the pancreas are linked to potassium
adenosine triphosphate (ATP) channels; when the drug
attaches to the receptors, these channels close, and a cou-
pled reaction leads to an influx of calcium. The influx of
calcium triggers secretion of insulin from the beta cells
(see Fig. 43-4).
The sulfonylureas are used in the treatment of type 2
diabetes and cannot be substituted for insulin in people
with type 1 diabetes, who have an absolute insulin de-
ciency. Slight modications in the basic structure of the
members of this drug group produce agents that have sim-
ilar qualitative actions but markedly different potencies.
The sulfonylureas traditionally are grouped into rst- and
second-generation agents (Table 43-6). These agents differ
Carbohydrate absorption
Decreased insulin-stimulated
glucose uptake
Thiazolidinediones
Biguanides
Peripheral glucose
uptake
FIGURE 43-8 (Top) Mechanisms of ele-
Major
vated blood glucose in type 2 diabetes.
effect
(Bottom) Action sites of oral hypo-
Minor glycemic agents and mechanisms of
effect lowering blood glucose in type 2 dia-
betes mellitus.
 CHAPTER 43 Diabetes Mellitus and the Metabolic Syndrome 1003

TABLE 43-6 Oral Antidiabetic Agents*

Daily Dosage Duration of

Pharmacologic Agent (mg) action (h) Dosing Schedule Mechanism of Action

Beta cell stimulators Stimulates release of

Sulfonylureas (rst generation) insulin from beta cells
Chlorpropamide (generic) 100500 60 1 time/day in the pancreas
Sulfonylureas (second generation)
Glipizide (Glucotrol) 2.540 624 12 times/day 30 min
Glyburide (DiaBeta, Micronase) before meal
Glimepiride (Amaryl) 1.2520 1624 12 times/day with meal
Nonsulfonylureas 18 1824 1 time/day with rst meal
Repaglinide (Prandin) 0.516 5 1530 min before meal
Nateglinide (Starlix) 60360 34 130 min before meal
Biguanide Decreases production
Metformin (Glucophage, 5002000 712 13 times/day with food and release of glucose
Glucophage XR) by the liver
Alpha glucosidase inhibitors Delays the breakdown
Acarbose (Precose) 25300 46 13 times/day rst bite food and absorption of
Miglitol (Glyset) 25300 46 13 times/day with food carbohydrates from
the intestine
Thiazolidinediones Sensitizes body cells to
Rosiglitazone (Avandia) 48 1624 12 times/day with or the action of insulin
without food
Pioglitazone (Actos) 1545 1624 1 time/day without food

*List may not be inclusive.

in dosage and duration of action. The second-generation
drugs (glyburide, glipizide, glimepiride) are considerably
more potent than the rst-generation drugs (tolbutamide,
acetohexamide, tolazamide, chlorpropamide). The second-
generation agents are used more widely than the first-
generation agents.
Because the sulfonylureas increase insulin levels and
the rate at which glucose is removed from the blood, it is
important to recognize that they can cause hypoglycemic
reactions. This problem is more common in elderly people
with impaired hepatic and renal function who are taking
the longer-acting sulfonylureas.
Repaglinide and Nateglinide. Repaglinide (Prandin) and
nateglinide (Starlix) are nonsulfonylurea beta cell stimu-
lators that require the presence of glucose for their main
action. These agents exert their action by closing the
ATP-dependent potassium channel in the beta cells (see
Fig. 43-4). Insulin release is glucose dependent and dimin-
ishes at low glucose levels. These agents, which are rap-
idly absorbed from the gastrointestinal tract, are taken
shortly before meals (repaglinide 15 to 30 minutes and
nateglinide 15 to 30 minutes). Both repaglinide and
nateglinide can produce hypoglycemia; thus, proper timing
of meals in relation to drug administration is important.
Biguanides. The biguanides are older oral antidiabetic
drugs. Metformin (Glucophage) is the most signicant
agent in this group. Phenformin, the earlier form of the
drug, was used extensively in the 1960s but was removed
from the U.S. market in 1977 because of the occurrence of
lactic acidosis in people treated with it. After more than a
decade of use in Europe as well as Canada and other coun-
tries, metformin was approved by the FDA in 1995. Unlike
its precursor, phenformin, metformin rarely results in lac-
tic acidosis (0.03 cases per 1000 patients). Metformin in-
hibits hepatic glucose production and increases the sensi-
tivity of peripheral tissues to the actions of insulin. Because
metformin does not stimulate insulin secretion, it does
not produce hypoglycemia as a side effect. Secondary ben-
ets of metformin therapy include weight loss and im-
proved lipid proles. Whereas the primary action of the
sulfonylurea drugs is to increase insulin secretion, met-
formin exerts its benecial effects on glycemic control
through increased peripheral use of glucose and mainly by
decreasing hepatic glucose production. To decrease the
risk for lactic acidosis, metformin is contraindicated in
people with elevated serum creatinine levels (a test of renal
function), clinical and laboratory evidence of hepatic dis-
ease, and any condition associated with hypoxemia or de-
hydration. Metformin sometimes is combined with other
oral agents such as a sulfonylurea or with insulin to im-
prove blood glucose control.3032
-Glucosidase Inhibitors. In patients with type 2 diabetes,
sulfonylureas, biguanides, or both may have benecial
effects on fasting plasma glucose levels. However, post-
prandial hyperglycemia persists in more than 60% of these
patients and probably accounts for sustained increases in
A1C levels. An alternative approach to the problem of post-
prandial hyperglycemia is the use of drugs such as acarbose
1004 UNIT X Endocrine Function
(Precose) and miglitol (Glyset), inhibitors of -glucosidase,
which is a small intestine brush border enzyme that breaks
down complex carbohydrates. By delaying the breakdown
of complex carbohydrates, the -glucosidase inhibitors
delay the absorption of carbohydrates from the gut and
blunt the postprandial increase in plasma glucose and in-
sulin levels. Although not a problem with monotherapy or
combination therapy with a biguanide, hypoglycemia may
occur with concurrent sulfonylurea treatment. If hypo-
glycemia does occur, it should be treated with glucose (dex-
trose) and not sucrose (table sugar), whose breakdown may
be blocked by the action of the -glucosidase inhibitors.
Thiazolidinediones. The TZDs (or glitazones) are the only
class of drugs that directly target insulin resistance, a funda-
mental defect in the pathophysiology of type 2 diabetes.
The TZDs improve glycemic control by increasing insulin
sensitivity in the insulin-responsive tissuesliver, skeletal
muscle, and fatallowing the tissues to respond to endo-
genous insulin more efciently without increased output
from already dysfunctional beta cells.12,32 A secondary effect
is the suppression of hepatic glucose production. Rosiglita-
zone (Avandia) and pioglitazone (Actos) were approved by
the FDA in 1999. Another TZD, troglitazone, was approved
in 1997, but because of hepatic safety concerns, it is no
longer available, having been withdrawn worldwide in
March 2000. Subsequent postmarketing analysis of both
rosiglitazone and pioglitazone has shown no indication of
similar liver dysfunction. Rosiglitazone and pioglitazone
both are approved for use as monotherapy and in combi-
nation therapy. Because of the previous problem with liver
toxicity in this class of drugs, liver enzymes should be mea-
sured according to the current guidelines.
The mechanism of action of the TZDs is complex
and not fully understood. The action of the TZDs is asso-
ciated with binding to a nuclear receptor, the peroxisome
proliferatoractivated receptor- (PPAR-; Fig. 43-9).32 Bind-
ing of the TZDs to the PPAR- receptor begins a cascade of
events that lead to regulation of genes involved in lipid
and glucose metabolism. These include insulin-responsive
genes such as the GLUT-4, lipoprotein lipase, and resistin
genes. The result is an increase in the number of GLUT-4
Thiazolidinediones
Enhanced response
to insulin
Proteins
Nuclear
receptors
DNA
mRNA
Transcription
FIGURE 43-9 Action of the thiazolidinediones on activation of the
PPAR receptor that regulates gene transcription of proteins that
regulate glucose uptake and reduce fatty acid release.
transporters and increased insulin-mediated uptake of glu-
cose in the peripheral tissues. Newly described proteins
produced by adipocytes, called adiponectin and resistin, may
be a part of the missing link in explaining insulin resis-
tance in persons with type 2 diabetes. Resistin suppresses
insulins ability to stimulate glucose uptake by adipose
cells. The TZDs seem to decrease insulin resistance, in part,
by suppressing the production of resistin by adipocytes.33
Additional effects of TZDs are numerous, and include cor-
rection of many of the abnormal metabolic features asso-
ciated with type 2 diabetes. This includes a decrease in FFA
and triglycerides, microalbuminuria, blood pressure, in-
ammatory mediators (e.g., brinogen and C-reactive pro-
tein), and procoagulation factors.32 The TZDs also have the
potential for preventing beta cell exhaustion by reducing
FFAs and blood glucose levels.
Amylin. A synthetic version of the human hormone amylin
(pramlintide acetate [Symlin]) has recently been devel-
oped for use in the treatment of insulin-dependent dia-
betes and is now in clinical trials.34 It is the rst in a new
class of amylin-receptor agonists. Amylin, which is normally
co-secreted with insulin, is thought to suppress glucagon
secretion, slow gastric emptying, and reduce the range of
after-meal variations in blood glucose levels. The drug,
which is administered by injection, is not a substitute for
insulin but is complementary to its action.
Insulin
Type 1 diabetes mellitus always requires treatment with in-
sulin, and many people with type 2 diabetes eventually re-
quire insulin therapy. Insulin is destroyed in the gastro-
intestinal tract and must be administered by injection.
Insulin preparations are categorized according to onset,
peak, and duration of action. An inhaled form of insulin
is in the clinical trial stage.
During the past several decades, many pharmaceutical
companies have entered the insulin-manufacturing mar-
ket. After much research, human insulin has become avail-
able, providing an alternative to previous forms of insulin
that were obtained from bovine and porcine sources. The
manufacture of human insulin uses recombinant DNA
technology. Beef insulin differs from human insulin by
three amino acids, and pork insulin differs by only one
amino acid. Many people with diabetes develop antibodies
to beef and pork insulin. Improvements in the purication
techniques for insulin extracted from animal pancreases
have made it possible to reduce or eliminate many of the
contaminants that could incite antibody formation. How-
ever, synthetic human insulin is widely available and gen-
erally used. A change from pork or beef to human insulin
should be carefully monitored because hypoglycemia can
occur owing to increased receptivity to the human insulin.
There are three principal types of insulin: short acting,
intermediate acting, and long acting (Table 43-7). The
short-acting insulins fall into two categories: short acting
and ultra-short acting. Insulin injection (Regular) is a
short-acting soluble crystalline insulin whose effects begin
within 30 minutes after subcutaneous injection and gen-
erally last for 5 to 8 hours. The ultrashort-acting insulins
(insulin lispro [Humalog] and insulin aspart [NovoLog])

TABLE 43-7 Activity Prole of Human Insulin Preparations in the United States*
Type (Human Insulin) Onset
Lispro insulin solution (Humalog) 515 min
Insulin aspart injection (Novalog) 515 min
Insulin injection (Regular Insulin) 0.51.0 h
Isophane insulin suspension (NPH) 2.04.0 h
or insulin zinc suspension (Lente)
70/30 (70% NPH/30% regular) premixed 0.51.0 h
75/25 (75% NPH/25% Humalog) premixed 15 min
Extended insulin zinc suspension (Ultralente) 4.08.0 h
Insulin glargine (Lantus) 4.08.0 h
*List may not be inclusive.
Lantus insulin should never be mixed with or administered using the same syringe used to administer any other
type of insulin.
are produced by recombinant technology with an amino
acid substitution. These insulins have a more rapid onset,
peak, and shorter duration of action than short-acting Reg-
ular insulin. The ultrashort-acting insulins, which are used
in combination with an intermediate- or long-acting in-
sulin, are usually administered immediately before a meal.
Intermediate-acting insulins (NPH and Lente) have a slower
onset and duration of action. Because the intermediate-
acting insulins require several hours to reach therapeutic
levels, their use in type 1 diabetes requires supplementation
with an ultrashort- or short-acting insulin. The long-acting
Ultralente insulin has an even longer onset and duration
of action than the intermediate-acting insulins. As with
intermediate-acting insulins, it is used in combination
with the shorter-acting insulins. Glargine (Lantus) is a new
long-acting human insulin analog. It has a slower, more
prolonged absorption than NPH insulin and provides a rel-
atively constant concentration over 24 hours. Glargine is
usually taken as a single dose and is used in combination
with preprandial injections of a short-acting insulin. All
forms of insulin have the potential of producing hypogly-
cemia or insulin reaction as a side effect (discussed later).
Two intensive treatment regimensmultiple daily in-
jection (MDI) and continuous subcutaneous infusion of
insulin (CSII)closely simulate the normal pattern of in-
sulin secretion by the body. With each method, a basal in-
sulin level is maintained, and bolus doses of short-acting
insulin are delivered before meals.
The MDI treatment regimen uses long-acting or
intermediate-acting insulin administered once or twice
daily to maintain the basal insulin level. Boluses of short-
acting insulin are used before meals. The development of
convenient injection devices (e.g., pen injector) has made
it easier for people with diabetes to comply with the mul-
tiple doses of short-acting insulin that are administered
before meals.
With the CSII (insulin pump) method, the basal insulin
requirements are met by continuous infusion of subcuta-
neous insulin, the rate of which can be varied to accom-
modate diurnal variations. The CSII technique involves the
insertion of a small needle or plastic catheter into the sub-
cutaneous tissue of the abdomen. Tubing from the catheter
CHAPTER 43 Diabetes Mellitus and the Metabolic Syndrome 1005
Peak (hrs) Duration (hrs)
11.5 3.04.0
11.5 3.04.0
2.04.0 5.08.0
4.010.0 18.024.0
Peak 1 @ 3.0 and peak 2 @ 4.010.0 1018.0
Peak 1 @ 0.51.5 and peak 2 @ 5.06.0 22.0
812.0 (may have second peak) 18.036.0
No peak Up to 24
is connected to a syringe set into a small infusion pump
worn on a belt or in a jacket pocket. The computer-operated
pump then delivers one or more set basal amounts of in-
sulin. In addition to the basal amount delivered by the
pump, a bolus amount of insulin may be delivered when
needed (e.g., before a meal) by pushing a button.
Self-monitoring of blood glucose levels is a necessity
when using the CSII method of management. Each basal
and bolus dose is determined individually and programmed
into the infusion pump computer. Although the pumps
safety has been proved, strict attention must be paid to
signs of hypoglycemia. However, investigations have found
CSII therapy to be associated with a marked and sustained
reduction in the rate of severe hypoglycemia. Ketotic epi-
sodes caused by pump failure, catheter clogging, and infec-
tions at the needle site also are possible complications.
Candidate selection is crucial to the successful use of
the insulin pump. Only people who are highly motivated
to do frequent blood glucose tests and make daily insulin
adjustments are candidates for this method of treatment.34
Use of an insulin pump requires an intensive therapy pro-
gram that is best implemented with the support of a dia-
betes health care team. The diabetologist, nurse educator,
and dietitian are key team members; a social worker or
psychologist and exercise physiologist are helpful addi-
tions to the team.
Pancreas or Islet Cell Transplantation
Pancreas or islet cell transplantation is not a lifesaving
procedure. It does, however, afford the potential for sig-
nicantly improving the quality of life. The most serious
problems are the requirement for immunosuppression
and the need for diagnosis and treatment of rejection. In-
vestigators are looking for methods of transplanting islet
cells and protecting the cells from destruction without the
use of immunosuppressive drugs.
ACUTE COMPLICATIONS
The three major acute complications of diabetes are dia-
betic ketoacidosis, hyperosmolar hyperglycemic state, and
hypoglycemia.
1006 UNIT X Endocrine Function
Diabetic Ketoacidosis
Diabetic ketoacidosis (DKA) occurs when ketone produc-
tion by the liver exceeds cellular use and renal excretion.
DKA most commonly occurs in a person with type 1 dia-
betes, in whom the lack of insulin leads to mobilization of
fatty acids from adipose tissue because of the unsuppressed
adipose cell lipase activity that breaks down triglycerides
into fatty acids and glycerol. The increase in fatty acid lev-
els leads to ketone production by the liver (Fig. 43-10). It
can occur at the onset of the disease, often before the dis-
ease has been diagnosed. For example, a mother may bring
a child into the clinic or emergency department with re-
ports of lethargy, vomiting, and abdominal pain, unaware
that the child has diabetes. Stress increases the release of
gluconeogenic hormones and predisposes the person to
the development of ketoacidosis. DKA often is preceded by
physical or emotional stress, such as infection, pregnancy,
or extreme anxiety. In clinical practice, ketoacidosis also
occurs with the omission or inadequate use of insulin.
The three major metabolic derangements in DKA
are hyperglycemia, ketosis, and metabolic acidosis. The
definitive diagnosis of DKA consists of hyperglycemia
(blood glucose levels >250 mg/dL), low serum bicarbon-
ate (<15 mEq/L), and low pH (<7.3), with ketonemia (pos-
itive at 12 dilution) and moderate ketonuria.37 Hyper-
glycemia leads to osmotic diuresis, dehydration, and a
critical loss of electrolytes. Hyperosmolality of extracellu-
Insulin deficiency
(and glucagon excess)
Decreased glucose uptake
Protein breakdown Glycogen
Amino acids Gluconeogenesis Ketones
Glucose
Metabolic
acidosis
Hyperglycemia
Osmotic CNS depression
diuresis
Coma
Water,
electrolyte loss
Dehydration
Circulatory failure
lar uids from hyperglycemia leads to a shift of water and
potassium from the intracellular to the extracellular com-
partment. Extracellular sodium concentration frequently
is low or normal despite enteric water losses because of the
intracellularextracellular uid shift. This dilutional effect
is referred to as pseudohyponatremia. Serum potassium lev-
els may be normal or elevated, despite total potassium de-
pletion resulting from protracted polyuria and vomiting.
Metabolic acidosis is caused by the excess ketoacids that
require buffering by bicarbonate ions; this leads to a marked
decrease in serum bicarbonate levels.
Compared with an insulin reaction, DKA usually is
slower in onset, and recovery is more prolonged. The per-
son typically has a history of 1 or 2 days of polyuria, poly-
dipsia, nausea, vomiting, and marked fatigue, with eventual
stupor that can progress to coma. Abdominal pain and
tenderness may be experienced without abdominal dis-
ease. The breath has a characteristic fruity smell because of
the presence of the volatile ketoacids. Hypotension and
tachycardia may be present because of a decrease in blood
volume. A number of the signs and symptoms that occur
in DKA are related to compensatory mechanisms. The heart
rate increases as the body compensates for a decrease in
blood volume, and the rate and depth of respiration in-
crease (i.e., Kussmauls respiration) as the body attempts to
prevent further decreases in pH. Metabolic acidosis is dis-
cussed further in Chapter 34.
Lipolysis
Glycerol
FFA
FIGURE 43-10 Mechanisms of diabetic ketoaci-
dosis. Diabetic ketoacidosis is associated with
very low insulin levels and extremely high lev-
els of glucagon, catecholamines, and other
counterregulatory hormones. Increased levels
of glucagon and the catecholamines (red arrows)
lead to mobilization of substrates (blue arrows)
for gluconeogenesis and ketogenesis by the
liver (green arrows). Gluconeogenesis in excess
of that needed to supply glucose for the brain
and other glucose-dependent tissues produces
a rise in blood glucose levels. Mobilization of
free fatty acids (FFA) from triglyceride stores in
adipose tissue leads to accelerated ketone pro-
duction and ketosis.

The goals in treating DKA are to improve circulatory
volume and tissue perfusion, decrease serum glucose, cor-
rect the acidosis, and correct electrolyte imbalances.
These objectives usually are accomplished through the
administration of insulin and intravenous uid and elec-
trolyte replacement solutions. Because insulin resistance
accompanies severe acidosis, low-dose insulin therapy is
used. An initial loading dose of regular insulin often is
given intravenously, followed by continuous low-dose
infusion. Frequent laboratory tests are used to monitor
blood glucose and serum electrolyte levels and to guide
fluid and electrolyte replacement. It is important to re-
place uid and electrolytes and correct pH while bringing
the blood glucose concentration to a normal level. Too
rapid a drop in blood glucose may cause hypoglycemic
symptoms and cerebral edema. A sudden change in the
osmolality of extracellular fluid occurs when blood glu-
cose is lowered too rapidly, and this can cause cerebral
edema. Serum potassium levels often fall as acidosis is cor-
rected and extracellular potassium moves into the intra-
cellular compartment; at this time, it may be necessary to
add potassium to the intravenous infusion. Identication
and treatment of the underlying cause, such as infection,
also are important. With the better understanding of the
pathogenesis of DKA and more uniform agreement on di-
agnosis and treatment, the mortality rate has been reduced
to less than 5%.
Hyperosmolar Hyperglycemic State
The hyperosmolar hyperglycemic state (HHS) is charac-
terized by hyperglycemia (blood glucose >600 mg/dL),
hyperosmolarity (plasma osmolarity >310 mOsm/L) and
dehydration, the absence of ketoacidosis, and depression
of the sensorium.37 HHS may occur in various conditions,
including type 2 diabetes, acute pancreatitis, severe in-
fection, myocardial infarction, and treatment with oral or
parenteral nutrition solutions. It is seen most frequently in
people with type 2 diabetes. Two factors appear to contrib-
ute to the hyperglycemia that precipitates the condition:
an increased resistance to the effects of insulin and an ex-
cessive carbohydrate intake.
In hyperosmolar states, the increased serum osmolar-
ity has the effect of pulling water out of body cells, includ-
ing brain cells. The condition may be complicated by
thromboembolic events arising because of the high serum
osmolality. The most prominent manifestations are de-
hydration, neurologic signs and symptoms, and excessive
thirst. The neurologic signs include grand mal seizures,
hemiparesis, Babinskis reexes, aphasia, muscle fascicula-
tions, hyperthermia, hemianopia, nystagmus, and visual
hallucinations. The onset of HHS often is insidious, and
because it occurs most frequently in older people, it may
be mistaken for a stroke.
The treatment of HHS requires judicious medical ob-
servation and care because water moves back into brain
cells during treatment, posing a threat of cerebral edema.
Extensive potassium losses that also have occurred during
the diuretic phase of the disorder require correction. Be-
cause of the problems encountered in the treatment and
the serious nature of the disease conditions that cause
CHAPTER 43 Diabetes Mellitus and the Metabolic Syndrome 1007
HHS, the prognosis for this disorder is less favorable than
that for ketoacidosis.
Hypoglycemia
Hypoglycemia, or an insulin reaction, occurs from a relative
excess of insulin in the blood and is characterized by below-
normal blood glucose levels.38 It occurs most commonly in
people treated with insulin injections, but prolonged hypo-
glycemia also can result from some oral hypoglycemic
agents.
Hypoglycemia usually has a rapid onset and progres-
sion of symptoms. The signs and symptoms of hypo-
glycemia can be divided into two categories: those caused
by altered cerebral function and those related to activation
of the autonomic nervous system. Because the brain relies
on blood glucose as its main energy source, hypoglycemia
produces behaviors related to altered cerebral function.
Headache, difculty in problem solving, disturbed or altered
behavior, coma, and seizures may occur. At the onset of
the hypoglycemic episode, activation of the parasympa-
thetic nervous system often causes hunger. The initial
parasympathetic response is followed by activation of the
sympathetic nervous system; this causes anxiety, tachycar-
dia, sweating, and constriction of the skin vessels (i.e., the
skin is cool and clammy).
There is wide variation in the manifestation of signs
and symptoms; not every person with diabetes manifests
all or even most of the symptoms. The signs and symptoms
of hypoglycemia are more variable in children and in el-
derly people. Elderly people may not display the typical
autonomic responses associated with hypoglycemia but
frequently develop signs of impaired function of the cen-
tral nervous system, including mental confusion. Some
people develop hypoglycemic unawareness. Unawareness
of hypoglycemia should be suspected in people who do not
report symptoms when their blood glucose concentrations
are less than 50 to 60 mg/dL. This occurs most commonly
in people who have a longer duration of diabetes and A1C
levels within the normal range.38 Some medications, such
as -adrenergicblocking drugs, interfere with the sympa-
thetic response normally seen in hypoglycemia.
Many factors precipitate an insulin reaction in a per-
son with type 1 diabetes, including error in insulin dose,
failure to eat, increased exercise, decreased insulin need
after removal of a stress situation, medication changes,
and a change in insulin site. Alcohol decreases liver gluco-
neogenesis, and people with diabetes need to be cautioned
about its potential for causing hypoglycemia, especially if
it is consumed in large amounts or on an empty stomach.
The most effective treatment of an insulin reaction is
the immediate administration of 15 to 20 g of glucose in
concentrated carbohydrate source, which can be repeated
as necessary. Monosaccharides such as glucose, which can
be absorbed directly into the bloodstream, work best for
this purpose. Complex carbohydrates can be administered
after the acute reaction has been controlled to sustain
blood glucose levels. It is important not to overtreat hypo-
glycemia and cause hyperglycemia.
Alternative methods for increasing blood glucose
may be required when the person having the reaction is
1008 UNIT X Endocrine Function
unconscious or unable to swallow. A small amount of glu-
cose gel (available in most pharmacies) may be inserted
into the buccal pouch when glucagon is unavailable. Glu-
cagon may be given intramuscularly or subcutaneously.
Glucagon acts by hepatic glycogenolysis to raise blood
sugar. The liver contains only a limited amount of glyco-
gen (approximately 75 g); glucagon is ineffective in people
whose glycogen stores have been depleted. Some people
report becoming nauseated after glucagon administration,
which also could be in response to the severe hypoglyce-
mia. In situations of severe or life-threatening hypoglyce-
mia, it may be necessary to administer glucose (20 to 50 mL
of a 50% solution) intravenously.
COUNTERREGULATORY MECHANISMS
AND THE SOMOGYI EFFECT
AND DAWN PHENOMENON
The Somogyi effect describes a cycle of insulin-induced
posthypoglycemic episodes. In 1924, Joslin and associates
noticed that hypoglycemia was associated with alternate
episodes of hyperglycemia.39 It was not until 1959 that So-
mogyi presented the results of his 20 years of studies,
which conrmed the observation that hypoglycemia
begets hyperglycemia. In people with diabetes, insulin-
induced hypoglycemia produces a compensatory increase
in blood levels of catecholamines, glucagon, cortisol, and
growth hormone. These counterregulatory hormones cause
blood glucose to become elevated and produce some degree
of insulin resistance. The cycle begins when the increase in
blood glucose and insulin resistance is treated with larger
insulin doses. The hypoglycemic episode often occurs dur-
ing the night or at a time when it is not recognized, ren-
dering the diagnosis of the phenomenon more difcult.
Research suggests that even rather mild insulin-
associated hypoglycemia, which may be asymptomatic,
can cause hyperglycemia in those with type 1 diabetes
through the recruitment of counterregulatory mechanisms,
although the insulin action does not wane. A concomitant
waning of the effect of insulin (i.e., end of the duration of
action), when it occurs, exacerbates posthypoglycemic
hyperglycemia and accelerates its development. These
ndings may explain the labile nature of the disease in
some people with diabetes. Measures to prevent hypo-
glycemia and the subsequent activation of counterregula-
tory mechanisms include a redistribution of dietary car-
bohydrates and an alteration in insulin dose or time of
administration.40
The dawn phenomenon is characterized by increased
levels of fasting blood glucose or insulin requirements, or
both, between 5:00 and 9:00 AM without antecedent hypo-
glycemia. It occurs in people with type 1 or type 2 dia-
betes. It has been suggested that a change in the normal
circadian rhythm for glucose tolerance, which usually is
higher during the later part of the morning, is altered in
people with diabetes.41 Growth hormone has been sug-
gested as a possible factor. When the dawn phenomenon
occurs alone, it may produce only mild hyperglycemia,
but when it is combined with the Somogyi effect, it may
produce profound hyperglycemia.
CHRONIC COMPLICATIONS
The chronic complications of diabetes include disorders of
the microvasculature (i.e., neuropathies, nephropathies, and
retinopathies), macrovascular complications, and foot ul-
cers. The microvascular complications occur in the insulin-
independent tissues of the bodytissues that do not re-
quire insulin for glucose entry into the cell. This probably
means that intracellular glucose concentrations in many of
these tissues approach or equal those in the blood. The
level of chronic glycemia is the best-established concomi-
tant factor associated with diabetic complications.42 The
Diabetes Control and Complications Trial (DCCT), which
was conducted with 1441 people with type 1 diabetes, has
demonstrated that the incidence of retinopathy, nephrop-
athy, and neuropathy can be reduced by intensive diabetic
treatment.43 Similar results have been demonstrated by the
UKPDS in people with type 2 diabetes.25,44
Theories of Pathogenesis
The interest among researchers in explaining the causes and
development of chronic lesions in a person with diabetes
has led to a number of theories. Several of these theories
have been summarized to prepare the reader for under-
standing specic chronic complications.
Polyol Pathway. A polyol is an organic compound that
contains three or more hydroxyl (OH) groups. The polyol
pathway refers to the intracellular mechanisms responsible
for changing the number of hydroxyl units on a glucose
molecule. In the sorbitol pathway, glucose is transformed
rst to sorbitol and then to fructose. This process is activated
CHRONIC COMPLICATIONS OF DIABETES
The chronic complications of diabetes result from elevated
blood glucose levels and associated impairment of lipid
and other metabolic pathways.
Diabetic nephropathy, which is a leading cause of end-
stage renal disease, is associated with the increased work
demands and microalbuminuria imposed by poorly con-
trolled blood glucose levels.
Diabetic retinopathy, which is a leading cause of blindness,
is closely linked to elevations in blood glucose and hyper-
lipidemia seen in persons with uncontrolled diabetes.
Diabetic peripheral neuropathies, which affect both the
somatic and autonomic nervous systems, result from the
demyelinating effect of long-term uncontrolled diabetes.
Macrovascular disorders such as coronary heart disease,
stroke, and peripheral vascular disease reect the com-
bined effects of unregulated blood glucose levels,
elevated blood pressure, and hyperlipidemia.
The chronic complications of diabetes are best prevented
by measures aimed at tight control of blood glucose levels,
maintenance of normal lipid levels, and control of
hypertension.

by the enzyme aldose reductase.42 Although glucose is con-
verted readily to sorbitol, the rate at which sorbitol can be
converted to fructose and then metabolized is limited. Sor-
bitol is osmotically active, and it has been hypothesized that
the presence of excess intracellular amounts may alter cell
function in those tissues that use this pathway (e.g., lens,
kidneys, nerves, blood vessels). In the lens, for example, the
osmotic effects of sorbitol cause swelling and opacity. In-
creased sorbitol also is associated with a decrease in myo-
inositol and reduced adenosine triphosphatase activity. The
reduction of these compounds may be responsible for the
peripheral neuropathies caused by Schwann cell damage.
Aldose reductase inhibitors are in development to try to re-
duce complications resulting from this pathway; however,
to date, none has been successful for a variety of reasons.42
Formation of Advanced Glycation End Products. Glyco-
proteins, or what could be called glucose proteins, are nor-
mal components of the basement membrane in smaller
blood vessels and capillaries. These glycoproteins are also
termed advanced glycation end products (AGEs). It has been
suggested that the increased intracellular concentration of
glucose associated with uncontrolled blood glucose levels
in diabetes favors the formation of AGEs. These abnormal
glycoproteins are thought to produce structural defects in
the basement membrane of the microcirculation and to
contribute to eye, kidney, and vascular complications.
Some of the altered cellular functions resulting from AGEs
are due to binding to specic receptors for AGEs (RAGEs).42
Problems With Tissue Oxygenation. Proponents of the
tissue oxygenation theories suggest that many of the
chronic complications of diabetes arise because of a decrease
in oxygen delivery in the small vessels of the microcircula-
tion. Among the factors believed to contribute to this
inadequate oxygen delivery is a defect in red blood cell
function that interferes with the release of oxygen from
the hemoglobin molecule. In support of this theory is the
nding of a two- to threefold increase in A1C in some
people with diabetes. In A1C, a glycoprotein is substituted
for valine in the chain, causing a high afnity for oxygen.
The concentration of the red blood cell glycolytic inter-
mediate, 2,3-diphosphoglycerate (2,3-DPG), declines dur-
ing the acidotic and recovery phases of DKA; 2,3-DPG
reduces hemoglobins afnity for oxygen. An increase in
A1C and a decrease in 2,3-DPG increase the hemoglobins
afnity for oxygen, and less oxygen is released for tissue use.
Protein Kinase C. Diacylglycerol (DAG) and protein ki-
nase C (PKC) are critical intracellular signaling molecules
that can regulate many vascular functions, including per-
meability, vasodilator release, endothelial activation, and
growth factor signaling.42 Levels of DAG and PKC are ele-
vated in diabetes. Activation of PKC in blood vessels of the
retina, kidney, and nerves can produce vascular damage.
A PKC inhibitor is currently in clinical trials for diabetic
retinopathy and neuropathy.42
Neuropathies
Although the incidence of peripheral neuropathies is high
among people with diabetes, it is difcult to document ex-
CHAPTER 43 Diabetes Mellitus and the Metabolic Syndrome 1009
actly how many people are affected by these disorders be-
cause of the diversity in clinical manifestations and be-
cause the condition often is far advanced before it is
recognized. Results of the DCCT study show that intensive
therapy can reduce the incidence of clinical neuropathy
by 60% compared with conventional therapy.43
Two types of pathologic changes have been observed
in connection with diabetic peripheral neuropathies. The
rst is a thickening of the walls of the nutrient vessels that
supply the nerve, leading to the assumption that vessel
ischemia plays a major role in the development of these
neural changes. The second nding is a segmental de-
myelinization process that affects the Schwann cell. This
demyelinization process is accompanied by a slowing of
nerve conduction.
It appears that the diabetic peripheral neuropathies
are not a single entity. The clinical manifestations of these
disorders vary with the location of the lesion. Although
there are several methods for classifying the diabetic pe-
ripheral neuropathies, a simplified system divides them
into the somatic and autonomic nervous system neu-
ropathies (Chart 43-3).
Somatic Neuropathy. A distal symmetric polyneuropathy,
in which loss of function occurs in a stocking-glove pat-
tern, is the most common form of peripheral neuropathy.
Somatic sensory involvement usually occurs rst and usu-
ally is bilateral, symmetric, and associated with diminished
CHART 43-3
Classication of Diabetic Peripheral Neuropathies
Somatic
Polyneuropathies (bilateral sensory)
Paresthesias, including numbness and tingling
Impaired pain, temperature, light touch, two-point
discrimination, and vibratory sensation
Decreased ankle and knee-jerk reexes
Mononeuropathies
Involvement of a mixed nerve trunk that includes
loss of sensation, pain, and motor weakness
Amyotrophy
Associated with muscle weakness, wasting, and severe
pain of muscles in the pelvic girdle and thigh
Autonomic
Impaired vasomotor function
Postural hypotension
Impaired gastrointestinal function
Gastric atony
Diarrhea, often postprandial and nocturnal
Impaired genitourinary function
Paralytic bladder
Incomplete voiding
Erectile dysfunction
Retrograde ejaculation
Cranial nerve involvement
Extraocular nerve paralysis
Impaired pupillary responses
Impaired special senses
1010 UNIT X Endocrine Function
perception of vibration, pain, and temperature, particu-
larly to the lower extremities. In addition to the discom-
forts associated with the loss of sensory or motor function,
lesions in the peripheral nervous system predispose a per-
son with diabetes to other complications. The loss of feel-
ing, touch, and position sense increases the risk for falling.
Impairment of temperature and pain sensation increases
the risk for serious burns and injuries to the feet.
Painful diabetic neuropathy involves the somatosen-
sory neurons that carry pain impulse. This disorder, which
causes hypersensitivity to light touch and occasionally se-
vere burning pain, particularly at night, can become
physically and emotionally disabling.45
Autonomic Neuropathy. The autonomic neuropathies in-
volve disorders of sympathetic and parasympathetic ner-
vous system function, There may be disorders of vasomotor
function, decreased cardiac responses, impaired motility of
the gastrointestinal tract, inability to empty the bladder,
and sexual dysfunction.45 Defects in vasomotor reexes can
lead to dizziness and syncope when the person moves from
the supine to the standing position (see Chapter 25). In-
complete emptying of the bladder predisposes to urinary
stasis and bladder infection and increases the risk for renal
complications.
In the male, disruption of sensory and autonomic ner-
vous system function may cause sexual dysfunction (see
Chapter 45). Diabetes is the leading physiologic cause of
erectile dysfunction, and it occurs in both type 1 and type 2
diabetes. Of the 7.8 million men with diabetes in the United
States, 30% to 60% have erectile dysfunction.46
Disorders of Gastrointestinal Motility. Gastrointestinal
motility disorders are common in persons with long-
standing diabetes. Although the pathogenesis of these dis-
orders is poorly understood, neuropathy and metabolic
abnormalities secondary to hyperglycemia are thought to
play an important role.47 The symptoms vary in severity
and include constipation, diarrhea and fecal incontinence,
nausea and vomiting, and upper abdominal discomfort
referred as dyspepsia. The presence and severity of these
symptoms do not correlate well with the disturbances of
gastrointestinal motility.
Gastroparesis (delayed emptying of stomach) is com-
monly seen in persons with diabetes.47 The disorder is
characterized by complaints of epigastric discomfort, nau-
sea, postprandial vomiting, bloating, and early satiety. Ab-
normal gastric emptying also jeopardizes the regulation of
the blood glucose level. Diagnostic measures include the
use of endoscopy or a barium radiography to exclude me-
chanical obstruction due to peptic ulcer disease or cancer.
Gastric emptying tests using a radionuclide-labeled solid
meal such as chicken liver can be used to conrm the pres-
ence of gastroparesis. Management includes the use of pro-
kinetic agents (e.g., metoclopramide, erythromycin) as
well as antiemetic agents. Gastric pacing is a clinical re-
search tool proposed as an alternative for severe, refractory
gastroparesis.48 Strict control of blood glucose is important
because hyperglycemia may slow gastric emptying, even
in the absence of diabetic neuropathy.
Diarrhea is another common symptom seen mostly in
persons with poorly controlled type 1 diabetes and auto-
nomic neuropathy.49 The pathogenesis is thought to be
multifactorial. Diabetic diarrhea is typically intermittent,
watery, painless, and nocturnal and may be associated
with fecal incontinence. Management includes the use of
antidiarrheal agents (loperamide, diphenoxylate). Cloni-
dine (an 2-adrenergic agonist)50 and octreotide (a long-
acting somatostatin analog)51 have been used with some
success in persons with rapid transit. Antibiotics are used
for those with small bowel bacterial overgrowth secondary
to slow transit. As with gastroparesis, strict control of blood
glucose is important.
Nephropathies
Diabetic nephropathy is the leading cause of end-stage
renal disease (ESRD), accounting for 40% of new cases.1 In
the United States, 40% of all people who seek renal re-
placement therapy (see Chapter 36) have diabetes.52 The
complication affects people with both type 1 and type 2
diabetes. According to the reports of the U.S. Renal Data
System, the increase in ESRD since the early 1980s has
been predominantly among people with type 2 diabetes.53
The term diabetic nephropathy is used to describe the
combination of lesions that often occur concurrently in
the diabetic kidney. The most common kidney lesions in
people with diabetes are those that affect the glomeruli.
Various glomerular changes may occur in people with di-
abetic nephropathy, including capillary basement mem-
brane thickening, diffuse glomerular sclerosis, and nodular
glomerulosclerosis (see Chapter 35). Changes in the capil-
lary basement membrane take the form of thickening of
basement membranes along the length of the glomeruli.
Diffuse glomerulosclerosis consists of thickening of the
basement membrane and the mesangial matrix. Nodular
glomerulosclerosis, also called intercapillary glomeruloscle-
rosis or Kimmelstiel-Wilson disease, is a form of glomerulo-
sclerosis that involves the development of nodular lesions
in the glomerular capillaries of the kidneys, causing im-
paired blood ow with progressive loss of kidney function
and, eventually, renal failure. Nodular glomerulosclerosis
is thought to occur only in people with diabetes. Changes
in the basement membrane in diffuse glomerulosclerosis
and Kimmelstiel-Wilson syndrome allow plasma proteins
to escape in the urine, causing proteinuria and the devel-
opment of hypoproteinemia, edema, and others signs of
impaired kidney function.
Not all people with diabetes develop clinically sig-
nificant nephropathy; for this reason, attention is focus-
ing on risk factors for the development of this com-
plication. Among the suggested risk factors are genetic
and familial predisposition, elevated blood pressure, poor
glycemic control, smoking, hyperlipidemia, and micro-
albumuria.52,54,55 Diabetic nephropathy occurs in family
clusters, suggesting a familial predisposition, although
this does not exclude the possibility of environmental
factors shared by siblings. The risk for development of
ESRD also is greater among Native Americans, Hispanics
(especially Mexican Americans), and African Americans.52,54
Kidney enlargement, nephron hypertrophy, and hyper-

ltration occur early in the disease, suggesting increased
work of the kidneys in reabsorbing excessive amounts
of glucose. One of the first manifestations of diabetic
nephropathy is an increase in urinary albumin excretion
(i.e., microalbuminuria), which is easily assessed by labo-
ratory methods. Microalbuminuria is dened as a urine
protein loss between 30 and 300 mg/day; or between 30
and 300 g/mg creatinine on albumin-to-creatinine ratio
(A/C ratio) from a spot urine collection.52 It is recommended
that the A/C ratio be the preferred screen for microalbu-
minuria.52 The risk for microalbuminuria increases abruptly
with A1C levels above 8.1%55 (Fig. 43-11). Both systolic
and diastolic hypertension accelerates the progression of
diabetic nephropathy. Even moderate lowering of blood
pressure can decrease the risk for ESRD.52,53,56 Smoking in-
creases the risk for ESRD in both diabetic and nondiabetic
people. People with type 2 diabetes who smoke have a
greater risk for microalbuminuria, and their rate of progres-
sion to ESRD is approximately twice as rapid as in those who
do not smoke.54
Measures to prevent diabetic nephropathy or its pro-
gression in persons with diabetes include achievement of
glycemic control; maintenance of blood pressure less than
130/80 mm Hg, or less than 125/75 mm Hg in the pres-
ence of signicant proteinuria; prevention or reduction in
the level of proteinuria (using angiotensin-converting en-
zyme [ACE] inhibitors or angiotensin-receptor blockers
[ARBs], or protein restriction in selected patients); treat-
ment of hyperlipidemia; and smoking cessation in people
who smoke.52,54,56,57
FIGURE 43-11 Relationship between mean hemoglobin A1 and the
risk for microalbuminuria in patients with type 2 diabetes mellitus.
(Krolewski A.S., Laffel L.M.B., Krolewski M., et al. [1995]. Glycosy-
lated hemoglobin and the risk for microalbuminuria in patients with
insulin-dependent diabetes mellitus. New England Journal of Medicine
332(19), 12511255)
CHAPTER 43 Diabetes Mellitus and the Metabolic Syndrome 1011
Retinopathies
Diabetes is the leading cause of acquired blindness in the
United States. Although people with diabetes are at in-
creased risk for development of cataracts and glaucoma,
retinopathy is the most common pattern of eye disease.
Diabetic retinopathy is estimated to be the most frequent
cause of newly diagnosed blindness among Americans be-
tween the ages of 20 and 74 years.58 Diabetic retinopathy
is characterized by abnormal retinal vascular permeability,
microaneurysm formation, neovascularization and associ-
ated hemorrhage, scarring, and retinal detachment58,59 (see
Chapter 54). Twenty years after the onset of diabetes, nearly
all people with type 1 diabetes and more than 60% of
people with type 2 diabetes have some degree of retinop-
athy. Pregnancy, puberty, and cataract surgery can accel-
erate these changes.58,59
Although there has been no extensive research on risk
factors associated with diabetic retinopathy, they appear to
be similar to those for other complications. Among the sug-
gested risk factors associated with diabetic retinopathy are
poor glycemic control, elevated blood pressure, and hyper-
lipidemia. The strongest case for control of blood glucose
comes from the UKPDS study, which demonstrated a re-
duction in retinopathy with improved glucose control.25
Because of the risk for retinopathy, it is important that
people with diabetes have regular dilated eye examinations.
They should have an initial examination for retinopathy
shortly after the diagnosis of diabetes is made. The recom-
mendation for follow-up examinations is based on the type
of examination that was done and the ndings of that ex-
amination. People with persistently elevated glucose levels
or proteinuria should be examined yearly.58 Women who
are planning a pregnancy should be counseled on the risk
for development or progression of diabetic retinopathy.
Women with diabetes who become pregnant should be fol-
lowed closely throughout pregnancy. This does not apply
to women who develop GDM because such women are not
at risk for development of diabetic retinopathy.
People with macular edema, moderate to severe non-
proliferative retinopathy, or any proliferative retinopathy
should receive the care of an ophthalmologist. Methods
used in the treatment of diabetic retinopathy include the
destruction and scarring of the proliferative lesions with
laser photocoagulation. The Diabetic Retinopathy Study
provides evidence that photocoagulation may delay or
prevent visual loss in more than 50% of eyes with prolif-
erative retinopathy.
Macrovascular Complications
Diabetes mellitus is a major risk factor for coronary artery
disease, cerebrovascular disease, and peripheral vascular dis-
ease (see Chapter 24). The prevalence of these macro-
vascular complications is increased twofold to fourfold in
people with diabetes. Approximately 50% to 75% of all
type 2 diabetics will die of a macrovascular problem.
Multiple risk factors for macrovascular disease, includ-
ing obesity, hypertension, hyperglycemia, hyperinsuline-
mia, hyperlipidemia, altered platelet function, endothelial
dysfunction, systemic inammation (as evidenced by in-
creased CRP), and elevated brinogen levels, frequently are
1012 UNIT X Endocrine Function

found in people with diabetes. There appear to be differ-

ences between type 1 and type 2 diabetes in terms of dura-
tion of disease and the development of macrovascular dis-
ease. In people with type 2 diabetes, macrovascular disease
may be present at the time of diagnosis. Indeed, approx-
imately 50% of type 2 diabetics have some form of com-
plication at presentation (either microvascular or macro-
vascular). In type 1 diabetes, the attained age and the
duration of diabetes appear to correlate with the degree of
macrovascular disease. The reason for these discrepancies
has been attributed to the associated cardiovascular risk
factors that are part of the metabolic syndrome.60
Aggressive management of cardiovascular risk factors
should include smoking cessation, control of hypertension,
lipid lowering, diabetes control, and antiplatelet agents
(aspirin, clopidogrel, or both) if not contraindicated23 (see
Chapter 24). If treatment is warranted for peripheral vas-
cular disease, the peroneal arteries between the knees and FIGURE 43-12 Neuropathic ulcers occur on pressure points in areas
ankles commonly are involved in diabetics, making revas- with diminished sensation in diabetic polyneuropathy. Pain is ab-
sent (and therefore the ulcer may go unnoticed). (Bates B.B. [1995].
cularization difcult.
A guide to physical examination and history taking [6th ed.]. Philadelphia:
J.B. Lippincott)
Diabetic Foot Ulcers
Foot problems are common among people with diabetes
and may become severe enough to cause ulceration, in-
fection, and, eventually, a need for amputation. Foot prob- sensory status (Fig. 43-13). The monolament is held in the
lems have been reported as the most common complica- hand or attached to a handle at one end. When the un-
tion leading to hospitalization among people with diabetes. attached or unsupported end of the monolament is pressed
In a controlled study of 854 outpatients with diabetes fol- against the skin until it buckles or bends slightly, it deliv-
lowed in a general medical clinic, foot problems accounted ers 10 g of pressure at the point of contact.61 The test con-
for 16% of hospital admissions over a 2-year period and sists of having the person being tested report at which of
23% of total hospital days.61 In people with diabetes, lesions two moments he or she is being touched by the monola-
of the feet represent the effects of neuropathy and vascular ment. For example, the examiner will call out one and
insufciency. Approximately 60% to 70% of people with di- then two and briey touch the monolament to the site
abetic foot ulcers have neuropathy without vascular dis- at one of the two test times. Between 4 and 10 sites per foot
ease, 15% to 20% have vascular disease, and 15% to 20% are touched. An incorrect response at even one site indi-
have neuropathy and vascular disease.61 cates increased risk for neuropathy and foot complications.
Distal symmetric neuropathy is a major risk factor for Because of the constant risk for foot problems, it is im-
foot ulcers. People with sensory neuropathies have im- portant that people with diabetes wear shoes that have
paired pain sensation and often are unaware of the con- been tted correctly and inspect their feet daily, looking
stant trauma to the feet caused by poorly tting shoes, for blisters, open sores, and fungal infection (e.g., athletes
improper weight bearing, hard objects or pebbles in the
shoes, or infections such as athletes foot. Neuropathy pre-
vents people from detecting pain; they are unable to ad-
just their gait to avoid walking on an area of the foot where
pressure is causing trauma and necrosis. Motor neurop-
athy with weakness of the intrinsic muscles of the foot
may result in foot deformities, which lead to focal areas
of high pressure. When the abnormal focus of pressure is
coupled with loss of sensation, a foot ulcer can occur.
Common sites of trauma are the back of the heel, the plan-
tar metatarsal area, or the great toe, where weight is borne
during walking (Fig. 43-12).
All persons with diabetes should receive a full foot ex-
amination at least once a year. This examination should in-
clude assessment of protective sensation, foot structure and
biomechanics, vascular status, and skin integrity.3,61 Evalu-
ation of neurologic function should include a somato-
sensory test using either the Semmes-Weinstein mono-
lament or vibratory sensation. The Semmes-Weinstein FIGURE 43-13 Use of a monolament in testing for impaired sensa-
monolament is a simple, inexpensive device for testing tion in the foot of a person with diabetes.
 CHAPTER 43
foot) between the toes. If their eyesight is poor, a family
member should do this for them. In the event a lesion is
detected, prompt medical attention is needed to prevent
serious complications. Specially designed shoes have been
demonstrated to be effective in preventing relapses in
people with previous ulcerations.61 Smoking should be
avoided because it causes vasoconstriction and contributes
to vascular disease. Because cold produces vasoconstric-
tion, appropriate foot coverings should be used to keep the
feet warm and dry. Toenails should be cut straight across
to prevent ingrown toenails. The toenails often are thick-
ened and deformed, requiring the services of a podiatrist.
Persons with diabetes mellitus develop more extensive
and rapidly progressive peripheral vascular disease than do
nondiabetic individuals. Cardiovascular risk factors should
be addressed in patients with diabetic ulcers and peripheral
vascular disease. Ulcers, which are resistant to standard
therapy, may respond to the application of growth factors.
Growth factors provide a means by which cells communi-
cate with each other and can have profound effects on cell
proliferation, migration, and extracellular matrix synthe-
sis. Becaplermin, a topical preparation of recombinant
human platelet-derived growth factor (PDGF), is used in
treatment of neuropathic lower extremity ulcers.
INFECTIONS
Although not specically an acute or a chronic compli-
cation, infections are a common concern of people with
diabetes. Certain types of infections occur with increased
frequency in people with diabetes: soft tissue infections of
the extremities, osteomyelitis, urinary tract infections and
pyelonephritis, candidal infections of the skin and mucous
surfaces, dental caries and periodontal disease, and tuber-
culosis.62 Controversy exists about whether infections are
more common in people with diabetes or whether infec-
tions seem more prevalent because they often are more
serious in people with diabetes.
Suboptimal response to infection in a person with di-
abetes is caused by the presence of chronic complications,
such as vascular disease and neuropathies, and by the pres-
ence of hyperglycemia and altered neutrophil function.
Sensory decits may cause a person with diabetes to ignore
minor trauma and infection, and vascular disease may im-
pair circulation and delivery of blood cells and other sub-
stances needed to produce an adequate inammatory
response and effect healing. Pyelonephritis and urinary
tract infections are relatively common in persons with di-
abetes, and it has been suggested that these infections may
bear some relation to the presence of a neurogenic bladder
or nephrosclerotic changes in the kidneys. Hyperglycemia
and glycosuria may inuence the growth of microorgan-
isms and increase the severity of the infection. Diabetes
and elevated blood glucose levels also may impair host de-
fenses such as the function of neutrophils and immune
cells. Polymorphonuclear leukocyte function, particularly
adherence, chemotaxis, and phagocytosis, are depressed
in persons with diabetes, particularly those with poor gly-
cemic control.
Diabetes Mellitus and the Metabolic Syndrome 1013
In summary, diabetes mellitus is a disorder of carbohydrate,
protein, and fat metabolism resulting from an imbalance be-
tween insulin availability and insulin need. The disease can be
classied as type 1 diabetes, in which there is destruction of
beta cells and an absolute insulin deciency, or type 2 diabetes,
in which there is a lack of insulin availability or effectiveness
(i.e., beta cell dysfunction or insulin resistance). Type 1 diabetes
can be further subdivided into type 1A immune-mediated dia-
betes, which is thought to be caused by autoimmune mecha-
nisms, and type 1B idiopathic diabetes, for which the cause is
unknown. Other specic types of diabetes include secondary
forms of carbohydrate intolerance, which occur secondary to
some other condition, such as pancreatic disorders, that de-
stroys beta cells, or endocrine diseases such as Cushings syn-
drome, which cause increased production of glucose by the
liver and decreased use of glucose by the tissues. GDM devel-
ops during pregnancy, and although glucose tolerance often re-
turns to normal after childbirth, it indicates an increased risk for
development of diabetes. A prediabetes state also exists and is
composed of IFG, IGT, or both. The metabolic syndrome repre-
sents a constellation of metabolic abnormalities characterized
by obesity, insulin resistance, high triglycerides levels and low
HDL levels, hypertension and cardiovascular disease, insulin re-
sistance, and increased risk for development of type 2 diabetes.
The diagnosis of diabetes mellitus is based on clinical signs
of the disease, fasting blood glucose levels, casual plasma glu-
cose measurements, and results of the glucose tolerance test.
Self-monitoring provides a means of maintaining near-normal
blood glucose levels through frequent testing of blood glucose
and adjustment of insulin dosage. Glycosylation involves the
irreversible attachment of glucose to the hemoglobin mole-
cule; the measurement of A1C provides an index of blood glu-
cose levels over several months.
The treatment of diabetes includes diet, exercise, and, in
many cases, the use of an antidiabetic agent. Dietary manage-
ment focuses on maintaining a well-balanced diet, controlling
calories to achieve and maintain an optimum weight, and reg-
ulating the distribution of carbohydrates, proteins, and fats.
Two types of antidiabetic agents are used in the management
of diabetes: injectable insulin and oral diabetic drugs. Type 1,
and sometimes type 2, diabetes requires treatment with in-
jectable insulin. Oral diabetic drugs include the beta cell stimu-
lating agents, biguanides, -glucosidase inhibitors, and TZDs.
These drugs require a functioning pancreas and may be used
in the treatment of type 2 diabetes. The benets of exercise
include cardiovascular tness and psychological well-being.
Many people with type 2 diabetes benet from a decrease in
body fat, better weight control, and an improvement in insulin
sensitivity. In people with type 1 diabetes, the benets of exer-
cise are accompanied by a risk for hypoglycemia.
The metabolic disturbances associated with diabetes affect
almost every body system. The acute complications of diabetes
include DKA, HHS, and hypoglycemia. The chronic complica-
tions of diabetes affect the microvascular system (including
the retina, kidneys, and peripheral nervous system) and the
macrovascular system (coronary, cerebrovascular, and periph-
eral arteries). The diabetic foot is usually a combination of both
microvascular and macrovascular dysfunction. Infection is also
a frequent cofactor in the diabetic foot.
1014 UNIT X Endocrine Function
REVIEW EXERCISES
A 6-year-old boy is admitted to the emergency room
with nausea, vomiting, and abdominal pain. He is
very lethargic; his skin is warm, dry, and flushed; his
pulse is rapid; and he has a sweet smell to his breath.
His parents relate that he has been very thirsty during
the past several weeks, his appetite has been poor, and
he has been urinating frequently. His initial plasma
glucose is 420 mg/dL, and a urine test for ketones is
strongly positive.
A. What is the most likely cause of this boys elevated
blood glucose and ketonuria? Explain his presenting
signs and symptoms in terms of the elevated blood
glucose and metabolic acidosis.
B. What type of treatment will this boy require?
A 53-year-old accountant presents for his routine yearly
examination; his history indicates that he was found to
have a fasting glucose of 120 mg/dL on two prior occa-
sions. Currently, he is asymptomatic. He has no other
medical problems and does not use any medications.
He neither smokes nor drinks alcohol. His father had
type 2 diabetes at age 60 years. His physical examina-
tion reveals a blood pressure of 125/80 mm Hg, BMI
(body mass index) of 32 kg/m2, and waist circumference
of 45 inches. Laboratory study results are as follows:
CBC, TSH, and ALT are within normal limits. The lipid
panel shows an HDL of 30 mg/dL, LDL of 136 mg/dL,
and triglycerides of 290 mg/dL (normal <165 mg/dL).
A. What is this mans probable diagnosis?
B. Based on this mans blood glucose level and the ADA
diabetes classication system, what diabetic status
would you place this man in? Does he need a 75-g
oral glucose tolerance test (OGTT) for further assess-
ment of his IFG?
C. His OGTT test results reveals a 2 hr glucose value of
175 mg/dL. What is the diagnosis? What type of
treatment would be appropriate for this man?
Acknowledgments
We would like to thank Tan Attila, MD, for his contributions re-
garding diabetic gastroparesis and nonalcoholic fatty liver
disease.
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