Professional Documents
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___________________________________________________________________________________Table of Contents
TABLE OF CONTENTS
INTRODUCTION.................................................................................................................................................................... 1
CHAPTER 1: DEFINING DIABETES ..................................................................................................................................... 3
Introduction ....................................................................................................................................................................... 3
Learning Objectives .......................................................................................................................................................... 3
Definition of Diabetes Mellitus........................................................................................................................................... 5
Insulin Regulates Blood Glucose Levels ....................................................................................................................... 5
Type 2 Diabetes Is a Metabolic Disease ....................................................................................................................... 8
Long-term Complications of Type 2 Diabetes ............................................................................................................... 9
Classification of Diabetes................................................................................................................................................ 10
Type 1 Diabetes .......................................................................................................................................................... 12
Type 2 Diabetes .......................................................................................................................................................... 13
Gestational Diabetes................................................................................................................................................... 14
Populations at Risk for Developing Type 2 Diabetes ...................................................................................................... 15
Impaired Fasting Glucose and Impaired Glucose Tolerance ...................................................................................... 15
A1C ............................................................................................................................................................................. 15
Summary..................................................................................................................................................................... 16
Epidemiology................................................................................................................................................................... 17
Financial Impact of Diabetes........................................................................................................................................... 19
Risk Factors .................................................................................................................................................................... 20
Metabolic Syndrome ................................................................................................................................................... 22
Living With Type 2 Diabetes............................................................................................................................................ 22
Summary......................................................................................................................................................................... 24
SELF-ASSESSMENT QUESTIONS .................................................................................................................................... 26
Self-Assessment QuestionsAnswers........................................................................................................................... 30
___________________________________________________________________________________Table of Contents
_______________________________________________________________________________________ Introduction
INTRODUCTION
The growing incidence of diabetes in the United States represents a major public health
challenge. Data from the US Centers for Disease Control and Prevention (CDC) show
that in 2010, 25.6 million individuals aged 20 years or older living in the United States,
or 11.3%, had diagnosed or undiagnosed diabetes. However, the prevalence of diabetes
in the US is projected to increase significantly over the next few decades. In fact, it has
been estimated that by 2050 up to 33% of the population could be living with diabetes.
Projected increases are due to an aging US population, and to increases in minority
populations who have increased risk for the development of diabetes. Additionally,
individuals with diabetes are living longer and contributing to the prevalence for longer
periods of time
Diabetes mellitus is recognized primarily in 2 forms: type 1 diabetes and type 2 diabetes.
These forms of diabetes have some features in common, although they result from
different causes. This learning system focuses on type 2 diabetes, which is the most
common type of diabetes mellitus.
Diabetes is a metabolic disease in which the bodys basic metabolic processes for using
and storing energy are defective. The bodys main source of energy is the simple sugar,
glucose. In diabetes, blood glucose levels are abnormally high because the metabolism
of carbohydrates, the nutrients that are the main source of sugars for the body, is
impaired. However, metabolism of lipids and proteins, 2 other key groups of nutrients,
is also abnormal in diabetes. These defects in carbohydrate, lipid, and protein metabolism
over time can contribute to a host of severe and chronic consequences in the
cardiovascular system, eyes, kidneys, and nerves.
This module, Exploring Diabetes, is designed to provide you with the information
you need to understand what diabetes is, who is affected by it, and the underlying
metabolic defects and complications that can be associated with diabetes, focusing
on type 2 diabetes.
Chapter 1 presents an overview of what diabetes is, how it is classified, and its
prevalence and risk factors
Chapter 2 describes the core defects in type 2 diabetes
Chapter 3 discusses how carbohydrates, lipids, and proteins are normally metabolized
and what happens to these metabolic processes in people with type 2 diabetes
Chapter 4 discusses the long-term complications of type 2 diabetes
Throughout the text, medical terms are defined in the margin, and progress check
questions, provided to help you review what you have learned, are located at the end
of each chapter. The module concludes with a summary, a glossary of medical terms,
and a bibliography.
LEARNING OBJECTIVES
epidemiology
(ep-i-dee-mee-OL-uh-jee):
the branch of medicine that deals with
the study of the causes, distribution,
and control of disease in populations
The actions of insulin and glucagon have opposite effects that help to maintain glucose
homeostasis (see Figure 2).
1. Insulin: when blood glucose levels are high, the beta-cells of the pancreas secrete
more insulin; insulin facilitates the transport of glucose into muscle, fat, and liver cells,
which decreases blood glucose levels
2. Glucagon: when blood glucose levels are low, the alpha-cells of the pancreas secrete
glucagon; glucagon causes the liver to make more glucose, which increases blood
glucose levels
incretin (in-KREE-tin): class of
insulinotropic substances that are
released in the gastrointestinal tract
in response to food ingestion
As is discussed in later chapters of this module, the release of insulin and glucagon is in
part regulated by the action of incretin hormones, which are released by the intestines in
response to ingestion of food.
Adapted from: Shier D, Butler J, Lewis R. Holes Human Anatomy & Physiology. 13th edition. New York, NY:
McGraw-Hill Education; 2013.
hyperglycemia
(hahy-per-glahy-SEE-mee-uh):
abnormally high blood glucose levels
polyuria (pol-ee-YOOR-ee-uh):
excessive urination
polydipsia (pol-ee-DIP-see-uh):
excessive thirst
Thirst and increased fluid intake (polydipsia; poly = many, dipsia = drink)
Because the resulting fluid loss leads to dehydration, which drives increased thirst
Weight loss, weakness, and fatigue
Because the body begins to use proteins and fats for energy, which can result in
the breakdown of muscle and other tissues
polyphagia (pol-ee-FEY-jee-uh):
excessive eating
morbidity (mawr-BID-i-tee):
sickness or disease
mortality (mawr-TAL-i-tee):
death rate
CLASSIFICATION OF DIABETES
Because of the number of people affected by diabetes and its serious consequences,
many clinicians, researchers, and organizations are focused on discovering its causes
and how it can be best managed and treated. Key organizations include:
American Diabetes Association (ADA), which publishes a variety of clinical materials,
including yearly updates to its diagnostic criteria and standards of care
American Association of Clinical Endocrinologists (AACE), which publishes a variety
of clinical materials, including position statements and guidelines
US government organizations that have developed diabetes awareness and prevention
programs include the Centers for Disease Control and Prevention (CDC) and the National
Institutes of Health (NIH). Other US organizations, including Veterans Affairs/Department
of Defense and the American College of Physicians have released diabetes-related
guidelines.
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The classification systems used by the ADA and the AACE are similar. As described
in greater detail on the following pages, the main types of diabetes identified in these
classification systems are:
Type 1 diabetes
Type 2 diabetes
Gestational diabetes
Diabetes is differentiated from associated conditions on the basis of plasma glucose
levels. The tests for plasma glucose levels can be performed in several ways:
A test known as the A1C can be used to diagnose diabetes. A1C levels reflect the
average blood glucose levels for the past 2 to 3 months. An A1C 6.5% is the
recommended cutpoint (or threshold) diagnostic of diabetes. As discussed in greater
detail in Module 2: Diagnosis of Type 2 Diabetes and Module 3: Management of Type
2 Diabetes, A1C can be used to not only diagnose diabetes but also provide guidance
on how well a diabetes treatment is working
Casual plasma glucose is measured at any time, without regard to meals (also called
random glucose); a casual plasma glucose 200 mg/dL, in conjunction with symptoms
of hyperglycemia or hyperglycemic crisis, is considered diagnostic of diabetes
Fasting plasma glucose, or FPG, is measured when the patient has no caloric
intake (i.e., has fasted) for at least 8 hours; an FPG 126 mg/dL is considered
diagnostic of diabetes
Postprandial (post = after, prandial = eating) blood glucose, or PPG, is often
measured 2 hours after a meal or after the patient drinks a solution that contains
a high glucose concentration, termed an oral glucose tolerance test (OGTT);
a 2-hour plasma glucose 200 mg/dL is considered diagnostic of diabetes
postprandial
(pohst-PRAN-dee-uhl): after a meal
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Type 1 Diabetes
autoimmune disorder
(aw-toh-i-MYOON dis-AWR-der):
a disorder in which the body
mistakenly recognizes its own
tissues as foreign and attacks
and destroys them
ketoacidosis (KEE-toh-as-uh-DOHsis): acidosis that is caused by an
excess of ketone bodies; it occurs
in individuals who do not produce
enough insulin to maintain normal
fat metabolism
Type 1 diabetes is an autoimmune disorder in which the beta-cells of the pancreas are
destroyed. Beta-cell destruction eventually results in a complete inability to produce
insulin. When insulin is not available, muscle, fat, and liver cells are unable to absorb the
glucose they need, and glucose accumulates in the blood. Left untreated, blood glucose
levels increase significantly, leading to chronic hyperglycemia and potentially fatal acute
conditions, such as diabetic ketoacidosis. Individuals with type 1 diabetes must receive
daily insulin through injections or an insulin pump in order to survive.
Type 1 diabetes is responsible for approximately 5% to10% of all cases of diabetes.
The peak incidence of type 1 diabetes is in childhood and adolescence. Of individuals
who develop diabetes after age 30, it is estimated that only 5% to 10% have type 1
diabetes. It should be noted that determining which type of diabetes a patient has can
be difficult, as many patients do not fit easily into a specific category.
Most cases of type 1 diabetes are thought to be the result of an autoimmune process.
In fact, most patients with type 1 diabetes (85% to 90%) have antibodies to beta-cells,
insulin, or other cell substances that are markers of immune destruction. There is a small
subset of patients, more common among individuals of African or Asian descent, who
have type 1 diabetes and show no evidence of autoimmunity, but are prone to
ketoacidosis.
The signs and symptoms of type 1 diabetes are due to the pathophysiologic abnormalities
that occur when insulin is not present. These signs and symptoms, which may occur
suddenly, are listed in the following table.
Polyuria
Polydipsia
Polyphagia
Unintended weight loss
In addition to these acute symptoms, patients with type 1 diabetes are at risk of developing
long-term complications, which in fact are responsible for the majority of the morbidity and
mortality associated with diabetes. These long-term complications are discussed in
Chapter 4.
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Type 2 Diabetes
Type 2 diabetes is by far the most common form of diabetes mellitus, accounting for
approximately 90% to 95% of all cases of diabetes. Most individuals who are diagnosed
with type 2 diabetes are 40 years of age or older. However, type 2 diabetes is increasingly
being diagnosed in younger individuals, including children and adolescents, particularly
those who are obese. Type 2 diabetes develops gradually, and often goes undiagnosed
until complications develop. It is estimated that 25% of individuals with diabetes in the US
may be undiagnosed.
The three main defects responsible for the development of type 2 diabetes include:
Insulin resistance in peripheral tissues (mostly muscles and fat, but also the liver)
Impaired insulin secretion resulting from declining beta-cell function
Excess hepatic glucose production due to increased glucagon secretion and
insulin insufficiency; insulin resistance also contributes to increased hepatic
glucose production
In the face of insulin resistance, the beta-cells compensate by producing a greater
amount of insulin to keep blood glucose levels normal. This means that in type 2 diabetes,
there is a relative deficiency of insulin in contrast to the absolute deficiency of insulin
in type 1 diabetes. As type 2 diabetes progresses, the beta-cells continue to fail,
and eventually cannot compensate any longer, and blood glucose levels rise as a
consequence of beta-cell failure. More information on the pathogenesis of type 2
diabetes is presented in Chapter 2.
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Patients with type 2 diabetes can have all the symptoms seen in patients with type 1
diabetes, such as polyuria, polydipsia, polyphagia, etc. However, because the
development of type 2 diabetes is often gradual, patients may be asymptomatic for many
years. That is, many patients have type 2 diabetes for several years before they are
diagnosed with the disease. These asymptomatic patients are at risk for development
of the cardiovascular, retinal, kidney, and nerve complications associated with diabetes.
In fact, many patients already have some of these long-term complications when they are
diagnosed with type 2 diabetes. The following table lists presenting symptoms of patients
with type 2 diabetes.
microalbuminuria
(MAHY-kroh-al-byoo-muh-NYOORee-uh): the leakage of a small
amount of albumin into the urine,
defined as 20 mcg/min to
200 mcg/min
macroalbuminuria
(MAK-roh-al-byoo-muh-NYOOR-eeuh): the leakage of large amounts of
albumin into the urine; defined as
>200 mcg/min
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Polyuria
Polydipsia
Polyphagia
Frequent infections
Slow-healing cuts and bruises
Tingling, numbness, burning sensations in the hands/feet
Recurring skin, gum, or bladder infections
Blurred vision
Microalbuminuria or macroalbuminuria
Gestational Diabetes
Gestational diabetes is a disorder in which glucose levels become elevated during
pregnancy; the glucose levels usually return to normal after delivery. However, the
risk of developing type 2 diabetes later in life is substantially increased.
Another term used to describe IFG and IGT is prediabetes. It is now appreciated that a
risk of developing diabetes exists even in individuals with glucose levels within the normal
range, although this risk becomes greater as A1C levels approach the threshold for
diagnosis of diabetes (6.5%).
A1C
Both the ADA and the AACE provide for the use of A1C to determine if patients are at
high risk for the development of diabetes. However, the two organizations have different
recommendations governing the use of A1C to determine if a patient is at increased risk
for the development of diabetes.
The ADA guidelines state that patients with A1C between 5.7% and 6.4% should be
considered at increased risk for developing diabetes. The AACE guidelines state an A1C
of 5.5% to 6.4% should be considered a screening test for prediabetes, and recommends
that patients with A1C levels in this range receive further testing with either FPG or OGTT.
Both the ADA and the AACE support the use of A1C levels for the diagnosis of diabetes
in appropriate patients. In this Learning System, we will focus on the ADA guidelines.
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Summary
Table 3 provides the glucose levels that are diagnostic of diabetes and IFG and IGT
according to both the ADA.
Diabetes
Diabetes
5.7% to 6.4%
Diabetes
6.5%
* The risk of developing diabetes in patients is continuous, extending below the lower limit of the
range for identified prediabetes, and becoming disproportionately greater at the higher end of
the range.
Unless there is unequivocal hyperglycemia, a second test should be performed to confirm
a diagnosis of diabetes
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EPIDEMIOLOGY
In 2010, 25.8 million individuals in the United States were living with diabetes. Of those
living with diabetes:
25.6 million (diagnosed and undiagnosed) (11.3%) were aged 20 or older
18.8 million individuals were diagnosed with the disease
7 million individuals were undiagnosed
Diabetes can result in significant long-term complications such as cardiovascular disease
or renal failure. Diabetes is the seventh leading cause of death in the United States.
The prevalence of diabetes in the US is projected to increase significantly over the next
few decades. It has been estimated that by 2050, up to 33% of the population could be
living with diabetes if recent increases in diabetes continue and diabetes mortality is low.
In Figure 4, you can see that the number of US individuals with diagnosed diabetes has
risen steadily since 1995.
Adapted from: Centers for Disease Control and Prevention. Number (in Millions) of Civilian,
Noninstitutionalized Persons with Diagnosed Diabetes, United States,19802010.
http://www.cdc.gov/print.do?url=http%3A//www.cdc.gov/diabetes/statistics/prev/national/figpersons.htm.
Accessed August 30, 2012.
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The increases projected for 2050 are based on an aging US population and to increases
in minority populations who have increased risk for the development of diabetes.
Additionally, individuals with diabetes are living longer and contributing to the
prevalence for longer periods of time.
Figure 5 shows the estimated prevalence of diabetes in the US, by state. As you can
see, there is a swath through the southeastern United States where the prevalence of
diagnosed diabetes is higher the seen for most other areas of the US. This has been
dubbed the diabetes belt and includes all of Mississippi and parts of 14 other states:
Alabama, Arkansas, Florida, Georgia, Kentucky, Louisiana, North Carolina, Ohio,
Pennsylvania, South Carolina, Tennessee, Texas, Virginia, and West Virginia.
Several factors, some modifiable and some non-modifiable, contribute to the increased
risk for type 2 diabetes in the diabetes belt. Individuals who live in this region are more
likely to be African American and less likely to have a college degree. These are both nonmodifiable risk factors associated with an increased risk for type 2 diabetes.
Compared with other US regions, individuals living in the diabetes belt have higher rates
of obesity and physical inactivity, both modifiable risk factors. It is expected that if the
prevalence of obesity and physical inactivity were decreased within the diabetes belt, the
incidence of diabetes would also be decreased. In time, the disparity between the
incidence of diabetes in the diabetes belt and the rest of the country would be decreased.
Individuals with few risk factors (e.g., young, white, non-obese) who live within the diabetes
belt have an increased risk for developing type 2 diabetes compared with similar individuals
living outside the diabetes belt. This increased risk may result from social, cultural, or
genetic factors that are present in the area of the diabetes belt.
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RISK FACTORS
A number of factors increase the risk that an individual will develop type 2 diabetes.
A powerful risk factor is obesityat least 80% of patients with type 2 diabetes are obese.
Compared with normal weight individuals, obese individuals have a 50% to 100%
increased risk of death from all causes, mostly due to cardiovascular causes. The
mortality risk increases as the degree of obesity increases.
In addition, independent of obesity, the distribution of fat can vary and has medical
implications. For example, some patients have excess weight in the abdominal region.
This excess weight may be carried intra-abdominally, termed visceral fat, or as
subcutaneous abdominal fat. This is sometimes referred to as an apple shape. In
contrast, excess weight in the hip region is part of the subcutaneous (sub = under,
cutaneous = skin) fat. This is sometimes referred to as a pear shape. Many of the
complications associated with obesity, including insulin resistance, diabetes, and
cardiovascular disease, are more strongly linked to excess fat in the abdominal area.
One of the reasons that obesity may be so closely linked with type 2 diabetes is that
obesity itself causes some degree of insulin resistance, which, as we discussed earlier,
is a key characteristic of type 2 diabetes. Studies show that even moderate weight loss
(5% of body weight) is associated with reduced insulin resistance and improvements in
blood glucose measurements.
The following table summarizes information on obesity and other key risk factors for
type 2 diabetes.
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Description
Obesity
Older age
History of gestational
diabetes
Polycystic Ovary
Syndrome (PCOS)
Impaired fasting
glucose/impaired
glucose tolerance/
A1C of 5.7% to 6.4%
Physical inactivity/
sedentary lifestyle
Race/ethnicity
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Metabolic Syndrome
Having any one of the risk factors we have just discussed increases the likelihood that a
person will develop type 2 diabetes. Patients with type 2 diabetes frequently have more
than one of these risk factors. Researchers have identified a cluster of risk factors that
increases risk for cardiovascular disease, termed metabolic syndrome. Patients with type
2 diabetes frequently also have metabolic syndrome. Because individuals with metabolic
syndrome are at risk for developing cardiovascular disease and type 2 diabetes, a large
amount of research is focused on strategies to reduce their risk. Several groups have
published definitions of metabolic syndrome. Under guidelines developed by the National
Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), the metabolic
syndrome is diagnosed if any three of the following five symptoms are present:
Abdominal obesity (waist circumference >40 inches in men, >35 inches in women)
triglyceride (trahy-GLIS-uh-rahyd):
lipid molecule containing 3 fatty acids
bound to glycerol; is the primary fat in
the diet and the primary molecule
used for fuel storage
high-density lipoprotein (HDL)
cholesterol: good cholesterol;
transports excess cholesterol from
tissues to the liver for elimination
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In addition to these very serious complications, patients also face other complications
that, while not usually life-threatening, can impair their quality of life and functioning.
For example, due to decreased blood flow and nerve damage, patients with diabetes
may experience loss of feeling in their feet, which often means they may not notice a
foot injury until an infection occurs. Certain types of nerve damage can also produce
symptoms such as diarrhea and constipation and urinary incontinence. Between 50%
and 75% of men with diabetes develop erectile dysfunction (ED); more than 50% of
male patients who develop ED notice its onset within 10 years of being diagnosed
with diabetes.
Patients may understandably be worried about how these potential complications will
affect their ability to work at their jobs, take care of their families, and socialize. Studies
have shown this is a reasonable worry, for diabetes can significantly impair a variety
of aspects of a persons life, including social functioning and emotional and physical
functioning. It can also result in significant diabetes-related health care expenditures.
Direct costs such as medications used to treat the disease, the supplies for monitoring
blood glucose levels, and an increased need for medical services such as doctor visits
and hospitalization all contribute to the costs associated with diabetes. Indirect costs,
such as missed work, also contribute to the economic burden of diabetes.
In fact, analysis of 2009 claims data from 10 million members of a commercial health plan
showed that the average total annual health care expenditure for an adult plan member
with employer coverage was:
$4400 for an adult who has not been diagnosed with diabetes
$11,700 for an adult who has been diagnosed with diabetes
$7800 for patients with diabetes without complications
$20,700 for patients with complications from their diabetes
CVD, the major cause of morbidity and mortality in patients with diabetes, is also
responsible for the majority of the direct and indirect costs of diabetes.
Depression is common in patients with type 2 diabetes. In patients with diabetes, the
presence of depression has numerous negative effects, including reduced adherence to
diet, exercise, and medication regimens. Depression has been shown to further decrease
quality of life in patients with diabetes. Patients may be more likely to exhibit signs of
depression at initial diagnosis or when their medical status changes.
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SUMMARY
The following table summarizes the information presented in this chapter on the definition of diabetes.
Defining Diabetes
Definition
Diabetes is a common, progressive, and potentially devastating disease that can have severe long-term
implications for patients health and well-being.
In patients who do not have type 2 diabetes, the body is able to maintain plasma glucose levels within a narrow
range through the use of negative feedback loops; this process is known as glucose homeostasis. Glucose
homeostasis requires effective coordination between the liver, the peripheral tissues, and the alpha- and beta-cells
of the pancreas.
Type 2 diabetes is a metabolic disease in which:
The body is unable to use insulin effectively, termed insulin resistance
The body is unable to produce enough (or in some cases, any) insulin, termed insulin deficiency
The liver produces excess glucose due to increased glucagon secretion and insulin insufficiency
Glucose cannot enter muscle, fat, and liver cells to be used as energy, and the concentration of glucose rises
to high levels in the blood (hyperglycemia)
Hyperglycemia can result in serious long-term complications, including cardiovascular disease and damage
to the eyes, kidneys, and nerves
Classification
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In 2010, 25.8 million individuals in the United States were living with diagnosed or undiagnosed diabetes; between
90% and 95% of patients with diabetes have type 2 diabetes
It has been estimated that by 2050, up to 33% of the population could be living with diabetes if recent
increases in diabetes continue and diabetes mortality is low
It has been estimated that health care costs associated with the treatment of diabetes or prediabetes could
be as high as $512 billion by 2021
Risk Factors
Risk factors include: overweight/obesity; family history of type 2 diabetes; history of gestational diabetes or delivery
of a baby weighing >9 lbs; polycystic ovary syndrome; older age; A1C of 5.7% to 6.4% (ADA criteria), IFG, or IGT;
physical inactivity/sedentary lifestyle; and certain race/ethnicity backgrounds
Patients with type 2 diabetes and their families may face significant medical, occupational, social, and economic
quality-of-life issues
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SELF-ASSESSMENT QUESTIONS
There may be more than one correct answer for each question.
1. Match each hormone with its correct description.
A. Insulin ___________
B. Glucagon _________
26
___________________________________________________________________________Self-Assessment Questions
4. Fasting plasma glucose levels greater than or equal to ______ are diagnostic of diabetes.
_____ A. 100 mg/dL (5.6 mmol/L)
_____ B. 126 mg/dL (7.0 mmol/L)
_____ C. 140 mg/dL (7.8 mmol/L)
_____ D. 200 mg/dL (11.1 mmol/L)
5. In 2010, approximately _______ % of the US population aged 20 years or older had diagnosed or undiagnosed
diabetes; by 2050, it is estimated that up to______% of the US population could be living with the disease.
_____ A. 8.6, 18
_____ B. 10.6, 25
_____ C. 11.3, 33
_____ D. 13.4, 45
6. Compared with normal weight individuals, obese individuals have _________________ increased risk of death from
all causes.
_____ A. up to a 25%
_____ B. up to a 50%
_____ C. a 50% to 75%
_____ D. a 50% to 100%
7. A diagnosis of diabetes may have serious effects on an individual and his or her family because:
_____ A. patients with diabetes frequently require care for the rest of their lives.
_____ B. the realization that one has diabetes usually grows gradually over several years.
_____ C. patients with diabetes have significantly increased risk of illnesses like heart attack, stroke,
and kidney failure.
_____ D. diabetes can cause a wide range of less serious but troublesome conditions.
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8. Direct medical costs for a patient with diabetes are approximately ______________ times higher than those for a
patient without the disease.
_____ A. 2.3
_____ B. 2.7
_____ C. 3.5
_____ D. 5.7
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___________________________________________________________________________Self-Assessment Questions
29
SELF-ASSESSMENT QUESTIONSANSWERS
1. A 2, 4, 5, 8 ;
B 1, 3, 6, 7
2. B,
C,
D
3. A
4. B
5. C
6. D
7. A,
C,
D
8. A
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LEARNING OBJECTIVES
Upon completion of this chapter, you should be able to:
1. Identify the core defects characteristic of type 2 diabetes.
2. Describe the progressive nature of beta-cell dysfunction, insulin resistance,
and excess hepatic glucose production that results in type 2 diabetes.
31
32
33
34
35
36
2. Because muscle, fat, and liver cells are resistant to the effects of insulin, the betacells of the pancreas must produce a greater amount of insulin to keep blood glucose
levels normal. Therefore, the amount of insulin in the blood begins to rise, leading to
hyperinsulinemia (hyper = high, insulin = insulin, emia = in the blood). However,
beta-cells begin to slowly fail.
3. Initially, the body responds to the increased amount of insulin and is able to move
an appropriate amount of glucose into the cells; thus, blood glucose levels remain
relatively normal.
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38
TYPE 2 DIABETES
As we have noted, key factors in the pathogenesis of type 2 diabetes are insulin
resistance and beta-cell failure. Figure 10 illustrates these concepts, showing that:
In patients who develop type 2 diabetes, beta-cell dysfunction leads to beta cell
failure. When this occurs, glucose levels remain permanently in the elevated state.
Chronically high levels of glucose in the blood contribute to insulin resistance and
promote the complications of diabetes; this concept is known as glucotoxicity.
Glucotoxicity also negatively affects beta-cell function and survival
A related concept, that high levels of glucose and free fatty acids in the blood act
synergistically to negatively impact beta-cell function and survival, has been termed
glucolipotoxicity
Prior to beta-cell failure and development of type 2 diabetes:
There is a compensatory phase during which insulin resistance develops; to
compensate for the insulin resistance, beta-cell mass and insulin secretion
are increased
glucotoxicity
(GLOO-koh-tok-SIS-i-tee):
the concept that high levels of
glucose can further exacerbate
type 2 diabetes metabolism by
promoting insulin resistance
and beta-cell dysfunction
glucolipotoxicity (GLOO-koh-liPOH-tok-SIS-i-tee): the concept
that high levels of glucose and free
fatty acids can act synergistically
to exacerbate type 2 diabetes
metabolism by promoting insulin
resistance and beta-cell dysfunction
:
stage, however, they remain higher than baseline levels; it is theorized that
decompensation may be caused by combined effects of high glucose and fatty
acid level in the blood
Glucose and free fatty acid (FFA) levels rise during the decompensation and
failure stages
In other words, while insulin resistance first is the most obvious part of the
metabolic dysfunction, it is beta-cell dysfunction that ultimately determines the onset
of type 2 diabetes.
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SUMMARY
The following table summarizes the information in this chapter on the pathogenesis of type 2 diabetes.
Pathogenesis of Type 2 Diabetes
Core Defects
The core defects in type 2 diabetes are:
Insulin resistance
The body is unable to use insulin effectivelythat is, it is resistant to the effects of insulin
Insulin insufficiency
The beta-cells of the pancreas produce an inadequate amount of insulin
Excess hepatic glucose production
Because of release of glucagon and insufficient insulin, the liver continues to produce glucose
Normal Glucose Regulation
People without insulin resistance and without diabetes are able to maintain glucose homeostasis through
a feedback loop involving the pancreatic beta-cells, peripheral tissues, and the liver.
Insulin is effective at facilitating the transport of glucose to muscle, fat, and liver cells
These individuals are able to secrete adequate amounts of insulin to keep blood glucose levels in the
normal range
These individuals have normal glucose levels (euglycemia)
Progression to Type 2 Diabetes
Insulin resistance:
Insulin resistance begins to increase
The beta-cells begin to slowly fail
Circulating insulin levels rise
Glucose levels remain within normal range
IFG (impaired fasting glucose):
Insulin resistance continues to worsen
Insulin levels begin to slowly fall from their previous levels
Plasma glucose levels are above normal, although not at diabetic levels, in part because of excess hepatic
glucose production
Beta-cells continue to fail
Type 2 diabetes:
Beta-cell dysfunction continues to progress and beta-cell failure occurs
Insulin resistance remains
Because of continued release of glucagon and insufficient insulin, the liver produces excess glucose
Glucose levels rise above normal range (hyperglycemia)
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42
___________________________________________________________________________Self-Assessment Questions
SELF-ASSESSMENT QUESTIONS
There may be more than one correct answer for each question.
1. The core defects of type 2 diabetes are:
____
A. Euglycemia
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44
___________________________________________________________________________Self-Assessment Questions
45
SELF-ASSESSMENT QUESTIONSANSWERS
1. A,
B,
C
2. C
3. B
4. B,
C
5. C
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LEARNING OBJECTIVES
Upon completion of this chapter, you should be able to:
1. State the roles of incretin hormones and the DPP-4 enzyme in glucose metabolism.
2. Explain how insulin facilitates the transport of glucose into muscle, liver, and fat cells
by GLUT4 receptors.
3. Describe the defects in the incretin response in type 2 diabetes.
4. Describe the key abnormalities seen in carbohydrate, lipid, and protein metabolism
in type 2 diabetes.
47
48
49
apoptosis (ap-uhp-TOH-sis):
programmed cell death
In pancreatic beta-cells, both GLP-1 and GIP promote the production and secretion of
insulin. Both GIP and GLP-1 have also been shown to increase beta-cell proliferation and
decrease beta-cell apoptosis in some, but not all, animal models. GLP-1 has been shown
to inhibit glucagon secretion from the alpha-cells of the pancreas. (see Table 5).
It is important to note that the actions of GLP-1 and GIP are glucose dependent,
that is, when blood glucose concentrations are low, stimulation of insulin release
by GLP-1 and GIP and suppression of glucagon release by GLP-1 are not observed.
GLP-1
GIP
Yes*
Yes*
Yes*
No
50
51
52
Insulin also has another effect: It prevents the liver from making more glucose. As weve
discussed, hepatic glucose production is also decreased by GLP-1: GLP-1 suppresses
glucagon release from alpha-cells, which, in turn, leads to a decrease in hepatic glucose
production.
The end result is that the blood glucose concentration returns to normal because:
Insulin has facilitated the movement of glucose out of the blood and into muscle,
fat, and liver cells
Insulin (and decreased glucagon) has prevented the liver from making more glucose
53
54
glycogenolysis
(GLAHY-kuh-juh-NOL-uh-sis):
breakdown of glycogen to glucose
gluconeogenesis
(gloo-koh-nee-uh-JEN-uh-sis):
formation of new glucose from
protein or fat
55
When glucagon levels are high, above the maximum concentrations normally found
in the blood, it causes the breakdown of fat tissue, which increases the amount of fatty
acids available for the body to use as energy. (See Figure 15.)
Figure 15. The Role of Muscle and Adipose Tissue in Glucose Metabolism
During the Fasting State
56
Triglycerides: the most common fat in the diet and in the body
Composed of 3 fatty acids and a glycerol molecule
Main role is energy storage: excess glucose, proteins, and other fats are
converted to triglycerides for storage
Both triglycerides and cholesterol are carried in the blood by proteins; the
combination molecule is called a lipoprotein
Key lipoproteins include:
Low-density lipoprotein cholesterol (LDL cholesterol): transports about 75%
of cholesterol in the blood; also known as the bad cholesterol because when
present in high levels, it deposits its cholesterol in arteries, forming plaques
that lead to coronary artery disease
High-density lipoprotein cholesterol (HDL cholesterol): transports excess
cholesterol from body cells to the liver for elimination; also known as the
good cholesterol because it prevents accumulation of cholesterol and is
associated with a reduced risk of coronary artery disease
As weve noted, in type 2 diabetes, peripheral cells must switch from glucose to other
fuels. Fat cells turn to their stored triglycerides for energy production.
57
Triglycerides are broken down into fatty acids and glycerol, releasing free fatty acids
(FFA) and glycerol into the bloodstream
Tissues throughout the body use the free fatty acids for energy production
Ketone bodies are produced when free fatty acids are metabolized
Excess fatty acids also cause the liver to synthesize triglyceride-rich lipoproteins
and cholesterol-rich LDL
Excess cholesterol is taken up by scavenger cells, which then enter the walls of the
of the arteries; over time, cholesterol accumulates in the arteries, forming lipid plaques
lipotoxicity (li-POH-tok-SIS-i-tee):
the concept that high levels of free
fatty acids can further exacerbate
type 2 diabetes metabolism by
promoting insulin resistance and
beta-cell dysfunction
Some evidence suggests that the excess of free fatty acids, a common feature of obesity
observed in type 2 diabetes can further exacerbate beta-cell dysfunction and insulin
resistance in muscle and liver in type 2 diabetes. This concept has been termed
lipotoxicity. A related concept, that high levels of glucose and free fatty acids in the blood
act synergistically to negatively impact beta-cell function and survival, has been termed
glucolipotoxicity.
58
59
Some proteins are enzymes that facilitate the chemical reactions of metabolism
Proteins can also be broken down for energy production when glucose is not available
Proteins are synthesized from molecules called amino acids. Much like beads in a
necklace, amino acids are linked together in long chains called peptides. A complicated
protein molecule can have thousands of amino acids combined by peptide linkages; the
average is about 400 amino acids. Some proteins are formed when one or more peptide
chains are coiled and folded in configurations specific to each protein.
As weve noted, in type 2 diabetes, peripheral cells must find another source of energy
when glucose is not available. When available, the body preferentially uses carbohydrates
or fats for energy. However, once the stores of fats and carbohydrates run out, the body
will stop protein formation and use stored proteins for energy.
As shown in Figure 17:
1. The breakdown of protein (proteolysis) for energy results in the generation of
amino acids
2. Excess amino acids can be used to produce more glucose, thereby contributing
to hyperglycemia
3. In addition, amino acids can be used directly for energy production
catabolism (kuh-TAB-uh-liz-uhm):
a metabolic process in which complex
substances are broken down into
simple compounds
60
4. When insulin is not available, protein storage is virtually stopped. The catabolism of
proteins increases, protein synthesis is halted, and large quantities of amino acids
are entered into the plasma. If diabetes is severe and left untreated, wasting will
occur. Wasting is a loss of body mass and essential tissues, where key organs, which
are made of protein, are broken down or catabolized. If wasting and its underlying
cause are left untreated, death can occur within a few weeks.
61
SUMMARY
The following table summarizes information presented in this chapter on carbohydrate,
lipid, and protein metabolism in type 2 diabetes.
Carbohydrate, Lipid, and Protein Metabolism in Type 2 Diabetes
Normal Carbohydrate Metabolism
The presence of food in the GI tract stimulates release of the incretins GLP-1
and GIP:
GLP-1 and GIP stimulate production and release of insulin by beta-cells
and inhibit beta-cell apoptosis
GLP-1 suppresses release of glucagon by alpha-cells
GLP-1 also promotes satiety*, slows gastric emptying*, and inhibits gastric
acid secretion
The insulin secreted by the beta-cells of the pancreas:
Facilitates the transfer of glucose into muscle, fat, and liver cells
Prevents the liver from making more glucose
Once within the cells, glucose can either be:
Used immediately to produce energy
Transformed to storage molecules
When the limit of glycogen storage capacity is reached, excess glucose
is converted to fat
When glucose levels are low, the body makes more glucose by breaking down
glycogen (glycogenolysis) or synthesizing new glucose (gluconeogenesis) in
the liver
(cont.)
62
Fat cells break down triglycerides to release free fatty acids for energy production
throughout the body
Ketone bodies are produced
Excess fatty acids are converted by the liver to cholesterol, which can be
deposited in artery walls
High levels of free fatty acids may have other toxic effects (lipotoxicity)
Muscle cells use proteins for energy production when glucose is not available
Some amino acids are used to create glucose (gluconeogenesis), worsening
hyperglycemia
Fewer new proteins are created, which results in wasting if untreated
63
SELF-ASSESMENT QUESTIONS
There may be more than one correct answer for each question.
1. Incretins:
_____ A. metabolize carbohydrates.
_____ B. are produced by the liver.
_____ C. are produced by cells in the small intestine.
_____ D. increase insulin production and release.
2. _________ cells require insulin to facilitate the entry of glucose into the cell.
_____ A. Brain
_____ B. Resting muscle
_____ C. Fat
_____ D. Liver
3. Glucose is transported across the cell membrane into the cell by:
_____ A. GLP-1.
_____ B. GIP.
_____ C. DPP-4.
_____ D. GLUT4.
64
___________________________________________________________________________Self-Assessment Questions
4. If more glucose is available than the cells need for energy, extra glucose is converted to:
_____ A. ketone bodies.
_____ B. glycogen.
_____ C. cholesterol.
_____ D. amino acids.
5. Ketone bodies are produced by the breakdown of:
_____ A. triglycerides.
_____ B. glycerol.
_____ C. fatty acids.
_____ D. lipoproteins.
65
SELF-ASSESSMENT QUESTIONSANSWERS
1. C,
D
2. B,
C,
D
3. D
4. B
5. C
66
LEARNING OBJECTIVES
Upon completion of this chapter, you should be able to:
1. List the complications associated with type 2 diabetes and explain how they occur
and their clinical course.
2. Explain the long-term cardiovascular, retinal, kidney, and nerve complications
associated with diabetes.
67
68
atherosclerosis
(ath-uh-roh-skluh-ROH-sis):
progressive process in which smooth
muscle cells proliferate in the walls of
blood vessels and fatty plaques are
deposited on the inside of blood
vessels, obstructing blood flow
69
heterogeneous
(het-er-uh-JEE-nee-uhs):
arising from dissimilar causes
CARDIOVASCULAR DISEASE
Cardiovascular disease is the cause of death for at least 68% of all patients with diabetes
who are over the age of 65, according to data from the US National Institute of Diabetes
and Digestive and Kidney Diseases, the National Institutes of Health, and the National
Diabetes Information Clearinghouse.
People with diabetes are at particularly high risk of developing cardiovascular disease
for several reasons:
The liver synthesizes increased cholesterol in patients with type 2 diabetes, which
provides more cholesterol for the development of fatty plaques
The particular type of LDL cholesterol that is more prevalent in patients with diabetes
small, dense LDL particlesis associated with a greater cardiovascular risk
hypertension
(hahy-per-TEN-shuhn):
elevated blood pressure
High blood pressure, termed hypertension (hyper = high, tension = to stretch), is also
common in patients with type 2 diabetes and can accelerate other complications of
type 2 diabetes, particularly cardiovascular disease and nephropathy
Obesity, which is common in people with type 2 diabetes, is associated with insulin
resistance and metabolic syndrome, and is a risk factor for cardiovascular disease
Common types of macrovascular disease, which are defined in the following table, include:
Coronary artery disease
Cerebrovascular disease
Peripheral vascular disease
70
Description
Coronary artery
disease
Cerebrovascular
disease
Peripheral
vascular disease
RETINOPATHY
The long-term hyperglycemia associated with diabetes can damage the tiny blood vessels
in the retina of the eye, a condition called retinopathy. In the US, diabetic retinopathy is
the leading cause of blindness in adults between 20 and 74 years of age. Individuals with
diabetes are 25 times more likely to become legally blind than those without.
retinopathy (ret-n-OP-uh-thee):
damage to the retina of the eye;
can lead to blindness
Because type 2 diabetes is frequently not diagnosed for many years, retinopathy may be
present at the time of diagnosis. Between 2005 and 2008, 28.5% of patients with diabetes
who were 40 years of age or older had diabetic retinopathy; approximately 4.4% of
patients with retinopathy had advanced disease that could result in severe vision loss.
NEPHROPATHY
The kidneys filter waste products from the blood and retain necessary compounds,
including many proteins. When the kidneys are damaged, toxic waste products can
accumulate in the blood, while valuable compounds are lost in the urine. This condition
damage to the kidneysis termed nephropathy (nephro = kidney, pathy = damage).
nephropathy (nuh-FROP-uh-thee):
kidney damage that can arise
as a complication of chronic
hyperglycemia
71
Diabetic nephropathy affects between 20% and 40% of individuals with diabetes.
Diabetic nephropathy is the leading cause of ESRD and also increases the risk of
cardiovascular disease (CVD). CVD is the leading cause of morbidity and mortality in
patients with diabetes.
The development of diabetic kidney disease is related to chronic hyperglycemia, and like
other microvascular complications of diabetes, the risk of complications increases with the
duration of hyperglycemia. Because patients with type 2 diabetes may be asymptomatic
for a long period of time, diabetic nephropathy may be present at the time of diagnosis.
albumin (al-BYOO-muhn):
the main protein in the blood
Hyperglycemia and hypertension are two modifiable risk factors for diabetic nephropathy.
Intensive diabetes management designed to achieve near-normal glycemic levels has
been shown to delay the onset of microalbuminuria. Microalbuminuria is the excretion of
a modest amount of protein in the urine (30 mg and <300 mg of albumin per day) and
persistent microalbuminuria is a marker for development of diabetic nephropathy in
patients with type 2 diabetes.
Intensive glucose control has also been demonstrated to delay or prevent the
progression from microalbuminuria to macroalbuminuria (300 mg of albumin per day).
Clinical studies have also shown that blood pressure control reduces the development
of diabetic nephropathy.
Diabetic nephropathy proceeds through five stages that are differentiated based upon
changes in the glomerular filtration rate (GFR), albumin excretion, and blood pressure.
While this staging is not a diagnostic classification, it helps to illustrate the natural
progression of diabetic nephropathy (see Table 8).
Urinary Albumin
Excretion
Blood Pressure
1 Hyperfiltration
<30 mg/day
Normal
2 Microalbuminuria
High normalnormal
30299 mg/day
Rising
515 years
3 Overt proteinuria
Normaldecreasing
300 mg/day
Elevated
1020 years
4 Progressive
nephropathy
Decreasing
Increasing
Elevated
1525 years
5 End-stage
renal disease
<15 mL/min
Massive
Elevated
2030 years
Stage
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NEUROPATHY
Neuropathy (neuro = nerve, pathy = disease) is among the most common long-term
complications of diabetes, occurring in 60% to 70% of all patients. Nerve damage is
probably the result of several factors, including how long the patient has had diabetes,
the degree of blood glucose control, dyslipidemia, obesity, and smoking. Another potential
cause is damage to the blood vessels that carry oxygen and nutrients to the nerves.
Diabetic neuropathy is categorized based on its clinical presentation. Classifications
include peripheral, autonomic, proximal, and focal neuropathies. It is likely that
different types of diabetic neuropathies have different factors.
Peripheral Neuropathy
Peripheral neuropathy is the most common type of diabetic neuropathy. The damage to
the nerves of the extremities produces a variety of symptoms, including pain,
strange/unpleasant sensations, decreased sensation, and muscle weakness that starts in
the ends of the extremities. The legs are usually affected more often than the arms.
The decreased sensation in the feet means that patients often do not notice a cut or a
sore, and serious infections can then develop. The impairment in blood flow that can
occur with peripheral vascular diseasea vascular complication of diabetesmakes the
problem worse. Hyperglycemia also provides more nutrients for pathogens, increasing
risk of infection. In many cases, the end result is the development of gangrene or a bone
infection and the need to amputate the affected body part. As noted previously, diabetes
is the most common cause of nontraumatic lower limb amputation.
neuropathy (nyoo-ROP-uh-thee):
nerve damage, primarily peripheral
neuropathy (in which the nerves in
the extremities are affected); loss
of sensation may occur, which may
result in serious infection, gangrene,
and the need for amputation
73
Autonomic Neuropathy
Neuropathy can also affect the nerves that supply the organs of the body. The symptoms
depend on the organ system that is involved. For example, if the nerves supplying the
gastrointestinal system are involved, patients can have symptoms of diarrhea or
constipation. If the nerves supplying the heart are involved, patients may have changes in
heart rate or not experience the warning symptom of pain during a heart attack. Reports
of sudden death have been attributed to diabetic neuropathy. Bladder dysfunction can
occur if the urinary system is involved. In addition, neuropathy contributes to the
development of erectile dysfunction, which occurs in 50% to 75% of men with diabetes.
Other Neuropathies
Proximal neuropathy causes pain in the thighs, hips, or buttocks and results in weakness
in the legs.
Focal neuropathy refers to a sudden weakness of one nerve or a group of nerves, causing
muscle weakness or pain; it can affect any nerve in the body.
SUMMARY
Figure 18 and the following table summarize the development of long-term complications
in type 2 diabetes.
74
Long-term complications are the major contributors to the mortality and morbidity
associated with type 2 diabetes
Long-term complications are generally categorized as:
Macrovascular disease: coronary artery disease, cerebrovascular disease,
and peripheral vascular disease
Microvascular disease: damage to the retina (retinopathy), to the kidney
(nephropathy), and nerves (neuropathy)
Uncontrolled blood glucose, blood pressure, and lipids can significantly increase
long-term complications
Macrovascular Disease
75
76
Retinopathy refers to damage to the tiny blood vessels in the retina and is a
leading cause of blindness in adults
May be present at time of diagnosis with type 2 diabetes
Nephropathy: refers to damage to the kidneys; kidneys filter and purify the blood
Hyperglycemia and hypertension are modifiable risk factors for the
development of diabetic neuropathy
Microalbuminuria is the secretion of modest amounts of protein in the urine;
persistent microalbuminuria is a marker for the development of diabetic
nephropathy in patients with type 2
Maintaining blood pressure and glucose control has been demonstrated to
prevent or delay the progression of diabetic nephropathy
Diabetic nephropathy proceeds through five stages that are differentiated
based on changes in GFR, albumin excretion, and blood pressure
Treatment options for ESRD include dialysis or kidney transplant
Neuropathy refers to damage to the nerves and occurs in 60% to 70% of patients
with diabetes
Neuropathy in the extremities produces loss of sensation, strange/unpleasant
sensations, pain, and muscle weakness
The loss of sensation means that patients may not notice a cut or sore,
particularly in the lower extremities; this can result in the progression to
serious infection, gangrene, and the need for amputation
Neuropathy of the body organs can result in a variety of symptoms depending
on which organs are affected
Symptoms can include diarrhea, constipation, nausea/vomiting
(GI systems), irregular heart rate or absence of pain with cardiac
ischemia, or heart attack, bladder dysfunction, and erectile dysfunction
Other neuropathies include:
Proximal neuropathy, which causes pain in the thighs, hips, or buttocks
and can cause weakness in the legs
Focal neuropathy, which refers to a sudden weakness of one nerve or a
group of nerves, causing muscle weakness or pain
SELF-ASSESSMENT QUESTIONS
There may be more than one correct answer for each question.
1. Diabetes causes cardiovascular disease by:
_____ A. promoting atherosclerosis.
_____ B. thickening the basement membrane lining small blood vessels.
_____ C. causing increased synthesis of cholesterol.
_____ D. increasing the proportion of small, dense LDL particles.
2. Diabetes is a common cause of lower limb amputation because it can cause:
_____ A. impaired blood flow to the extremities.
_____ B. decreased sensation in the feet.
_____ C. decreased nutrients for pathogens.
_____ D. slow healing of trauma.
3. Which of the following is (are) true regarding retinopathy?
_____ A. Individuals with diabetes are 25 times more likely to become legally blind than those without the disease.
_____ B. Only a small percentage of patients with diabetes develop retinopathy.
_____ C. Hyperglycemia damages the tiny blood vessels in the retina.
77
78
79
SELF-ASSESSMENT QUESTIONSANSWERS
1. A,
C,
D
2. A,
B,
D
3. A,
C
4. A,
B
5. B
80
___________________________________________________________________________________Module Summary
MODULE SUMMARY
1) Diabetes is a common, progressive, and potentially devastating disease that
can have severe long-term implications for patients health and well-being.
In patients who do not have type 2 diabetes, the body is able to maintain plasma
glucose levels within a narrow range through the use of negative feedback loops;
this process is known as glucose homeostasis.
Type 2 diabetes is a metabolic disease in which:
As a result, glucose cannot enter muscle, fat, and liver cells to be used as energy,
and the concentration of glucose rises to high levels in the blood (hyperglycemia).
Hyperglycemia can result in serious long-term complications, including cardiovascular
disease and damage to the eyes, kidneys, and nerves.
The major types of diabetes are:
Type 2 diabetes: the body is resistant to the effects of insulin (insulin resistance),
and while it produces some insulin, it is not enough to meet the bodys needs
(insulin insufficiency); compounded by excess hepatic glucose production
Some patients have glucose levels are higher than normal but not high enough
for a diagnosis of diabetes (A1C of 5.7% to 6.4% [ADA criteria], IGT, IFG); these
individuals are at a high risk for later developing type 2 diabetes.
81
In 2010, 25.8 million individuals in the United States were living with diagnosed or
undiagnosed diabetes. The prevalence of diabetes in the US is projected to increase
significantly over the next few decades. It has been estimated that by 2050, up to
33% of the population could be living with diabetes if recent increases in diabetes
continue and diabetes mortality is low.
Risk factors include obesity; family history of type 2 diabetes; history of gestational
diabetes or delivery of a baby weighing >9 lbs; polycystic ovary syndrome; A1C of
5.7% to 6.4% (ADA criteria), IFG, or IGT; aged 40 years; physical
inactivity/sedentary lifestyle; and certain race/ethnicity backgrounds
Patients with type 2 diabetes and their families are faced with significant medical,
financial, occupational, and social quality-of-life issues.
2) The core defects in type 2 diabetes are:
Insulin resistance: the inability to use insulin effectivelythat is, resistance to the
effects of insulin
Are able to secrete adequate amounts of insulin to keep blood glucose levels in
the normal range
82
___________________________________________________________________________________Module Summary
Plasma glucose levels are above normal, although not at diabetic levels, in part
because of excess hepatic glucose production
In type 2 diabetes:
When glucose levels are low, the body makes more glucose by breaking down
glycogen (glycogenolysis) or by synthesizing new glucose (gluconeogenesis)
in the liver.
83
The core defects in diabetes mean that glucose can no longer effectively be
transported into muscle, fat, and liver cells, preventing the uptake and use of glucose
in most cells of the body. This results in increased blood glucose levels and reduced
use of glucose by the cells of the body. Additionally, the body makes more glucose
available by:
Type 2 diabetes also disrupts normal lipid metabolism. Fat cells break down
triglycerides to release free fatty acids for energy production throughout the body
when glucose is not available, creating ketone bodies and excess fatty acids, which
are converted by the liver to cholesterol, some of which is then deposited in
artery walls.
Protein metabolism is also abnormal in type 2 diabetes. Muscle cells shift to use
of proteins for energy production because glucose is limited, while some amino
acids are used to create glucose (gluconeogenesis), worsening hyperglycemia.
New protein formation is suppressed, which results in wasting if left untreated.
4) Long-term complications are the major contributors to the mortality and morbidity
associated with type 2 diabetes. Long-term complications are generally
categorized as:
Uncontrolled blood glucose, blood pressure, and lipids can significantly increase
long-term complications.
84
___________________________________________________________________________________Module Summary
Obesity
Coronary artery disease: affects the arteries of the heart and can lead
to heart attack
Cerebrovascular disease: affects the arteries supplying the brain and can lead
to stroke
Peripheral vascular disease: affects the arteries that supply the extremities
and can lead to amputation
Retinopathy refers to damage to the tiny blood vessels in the retina and is the leading
cause of blindness in adults. It takes years to develop.
Nephropathy refers to damage to the kidneys that impairs their ability to filter and
purify the blood. Diabetic nephropathy affects between 20% and 40% of patients with
diabetes. Like other microvascular complications of diabetes, the development of
nephropathy is associated with the degree and duration of hyperglycemia. Diabetic
nephropathy proceeds through five stages that are differentiated based on changes
in the GFR, albumin excretion, and blood pressure. Those stages are: hyperfiltration,
microalbuminuria, overt proteinuria, progressive nephropathy, and ESRD (end-stage
renal disease).
85
86
__________________________________________________________________________________________Glossary
GLOSSARY
acini (as-uh-nahy): secretory tissue of the exocrine pancreas; produces pancreatic juice
albumin (al-BYOO-muhn): an abundant, water-soluble protein found throughout the body, made by the liver, primarily
to help maintain blood volume
alpha-cell (AL-fuh): cell in the pancreas that produces glucagon
amino acid (uh-MEE-noh): one of the building blocks of proteins; 20 amino acids are used in different combinations
to produce the different proteins
apoptosis (ap-uhp-TOH-sis): programmed cell death
atherosclerosis (ath-uh-roh-skluh-ROH-sis): progressive process in which smooth muscle cells proliferate in
the walls of blood vessels and fatty plaques are deposited on the inside of blood vessels, obstructing blood flow
autoimmune disorder (aw-toh-i-MYOON dis-AWR-der): a disorder in which the body mistakenly recognizes its own
tissues as foreign and attacks and destroys them
autonomic neuropathy (aw-tuh-NOM-ik nyoo-ROP-uh-thee): any neuropathy of the autonomic nervous system,
including digestion, bowels, bladder, and the nerves that serve the heart and control blood pressure
basement membrane: a layer that secures the thin layer of tissue that surrounds organs to the underlying tissue
beta-cell (BEY-tuh): the predominant cell of the islets of Langerhans in the pancreas; secretes insulin
beta-cell failure: decreased secretion of insulin by the beta-cells because they are worn out
capillaries (KAP-uh-layhr-eez): microscopic blood vessels that connect the arterioles and venules and allow for the
exchange of substances between the blood and tissue fluids
carbohydrate (kar-boh-HAHY-dreyt): any of a group of organic compounds that includes sugars, starches, celluloses,
and gums, and serves as a major energy source in the body
catabolism (kuh-TAB-uh-liz-uhm): a metabolic process in which complex substances are broken down into simple
compounds
diabetic ketoacidosis (dahy-uh-BET-ik KEE-toh-as-uh-DOH-sis): buildup of ketone bodies (keto-acids) in the blood
of patients with uncontrolled diabetes, which increases the acidity of the blood
dialysis (dahy-AL-uh-sis): a process that mimics the action of the kidney in filtering the blood; the patients blood
is filtered through the dialysis machine
end-stage renal disease (ESRD): kidney failure
87
endocrine (en-DOH-krin): refers to secretions from ductless organs (such as the islets of Langerhans in the pancreas)
that are released directly into the bloodstream and affect metabolism or other bodily functions
enzyme (EN-zahym): a protein produced by living cells that catalyzes chemical reactions
epidemiology (ep-i-dee-mee-OL-uh-jee): the branch of medicine that deals with the study of the causes, distribution,
and control of disease in populations
exocrine (EK-suh-krin): refers to the discharge of secretions through a duct opening on either an internal or external
surface of the body
fatty acid: any of the saturated or unsaturated organic acids that have a single carboxyl group and usually an even
number of carbon atoms; one component of triglycerides
focal neuropathy (FOH-kuhl nyoo-ROP-uh-thee): neuropathy that results in a sudden weakness of one nerve or a group
of nerves that can cause muscle weakness or pain
free fatty acids: fatty acids that are bound to albumin and are in the blood
gangrene (GANG-green): tissue death due to lack of blood supply to the tissue
glomerular filtration rate (GFR): amount of fluid filtered from the kidney per unit of time; used to measure kidney function
glucagon (GLOO-kuh-gon): hormone secreted by the alpha-cells of the pancreas that increases glucose levels; opposes
the action of insulin
gluconeogenesis (gloo-koh-nee-uh-JEN-uh-sis): formation of new glucose from protein or fat
glucose (GLOO-kohs): a simple sugar occurring widely in most plant and animal tissue; the principal circulating sugar
in the blood and the major energy source of the body
glucolipotoxicity (GLOO-koh-li-POH-tok-SIS-i-tee): the concept that high levels of glucose and free fatty acids can
act synergistically to exacerbate type 2 diabetes metabolism by promoting insulin resistance and beta-cell dysfunction
glucotoxicity (GLOO-koh-tok-SIS-i-tee): the concept that high levels of glucose can further exacerbate type 2 diabetes
metabolism by promoting insulin resistance and beta-cell dysfunction
GLUT4: the transporter molecule that, when signaled by insulin, moves from the cell interior to the cell surface and
transports glucose into the cell
glycerol (GLIS-uh-rawl): a simple carbohydrate that serves as the backbone for triglycerides; linked to 3 fatty acids
to form a triglyceride
glycogen (GLAYH-kuh-jen): molecule that is the main form of carbohydrate storage; occurs primarily in the liver and
muscle tissue; readily converted to glucose as needed by the body to satisfy its energy needs
88
__________________________________________________________________________________________Glossary
89
lipid (LIP-id): fat; found almost exclusively in foods of animal origin and continuously synthesized in the body
lipoprotein (lip-oh-PROH-teen): the combination of lipids and proteins; examples are low-density lipoproteins and highdensity lipoproteins
lipotoxicity (li-POH-tok-SIS-i-tee): the concept that high levels of free fatty acids can further exacerbate diabetes
metabolism by promoting insulin resistance and beta-cell function
macroalbuminuria (MAK-roh-al-byoo-muh-NYOOR-ee-uh): the leakage of large amounts of albumin into the urine;
defined as >200 mcg/min
microalbuminuria (MAHY-kroh-al-byoo-muh-NYOOR-ee-uh): the leakage of a small amount of albumin into the urine,
defined as 20 mcg/min to 200 mcg/min
morbidity (mawr-BID-i-tee): sickness or disease
mortality (mawr-TAL-i-tee): death rate
myocardial infarction (MI) (mahy-uh-KAHR-dee-uhl in-FAHRK-shuhn): death of a portion of the heart muscle as a
result of deprivation of its blood supply (heart attack)
nephropathy (nuh-FROP-uh-thee): kidney damage that can arise as a complication of chronic hyperglycemia
neuropathy (nyoo-ROP-uh-thee): nerve damage, primarily peripheral neuropathy (in which the peripheral nerves in the
extremities are affected); loss of sensation, which may result in serious infection, gangrene, and the need for amputation
pancreas (PAN-kree-uhs): gland in the abdomen near the stomach that secretes insulin and glucagon
peripheral neuropathy (puh-RIF-er-uhl nyoo-ROP-uh-thee): the most common type of diabetic neuropathy; results in
pain or loss of feeling in the extremities
peptide (PEP-tahyd): a chain of amino acids
polydipsia (pol-ee-DIP-see-uh): excessive thirst
polyphagia (pol-ee-FEY-jee-uh): excessive eating
polyuria (pol-ee-YOOR-ee-uh): excessive urination
postprandial (pohst-PRAN-dee-uhl): after a meal
protein (PROH-teen): composed of amino acid building blocks; makes up most body structures, and is involved in
multiple life functions (enzymes)
90
__________________________________________________________________________________________Glossary
proximal neuropathy (PROK-suh-muhl nyoo-ROP-uh-thee): neuropathy that affects the thighs, hips, or buttocks and
that can lead to weakness in the legs
retina: the back portion of the eye that contains the nervous system tissue for receiving and transmitting visual stimuli
retinopathy (ret-n-OP-uh-thee): damage to the retina of the eye; can lead to blindness
stroke: any acute clinical event related to impairment of cerebral circulation that lasts longer than 24 hours
subcutaneous fat (suhb-kyoo-TEY-nee-uhs): the fat layer under the skin
triglyceride (trahy-GLIS-uh-rahyd): lipid molecule containing 3 fatty acids bound to glycerol; is the primary fat in the diet
and the primary molecule used for fuel storage
visceral fat (VIS-er-uhl): also known as abdominal fat; excessive fat surrounding the abdominal organs; people with
visceral fat have an apple shape rather than a pear shape
91
92
________________________________________________________________________________________References
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