Module 1 Understanding Type 2 Diabetes

DIABETES LEARNING SYSTEM
MODULE 1: EXPLORING DIABETES
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Module 1: Exploring Diabetes __________________________________________________________________________
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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
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CHAPTER 2: PATHOGENESIS OF TYPE 2 DIABETES .....................................................................................................31

Introduction ......................................................................................................................................................................31
Learning Objectives .........................................................................................................................................................31
Core Defects in Type 2 Diabetes.....................................................................................................................................33
Normal Glucose Regulation.............................................................................................................................................34
Insulin Resistance Begins................................................................................................................................................36
Impaired Fasting Glucose................................................................................................................................................38
Type 2 Diabetes...............................................................................................................................................................39
Summary .........................................................................................................................................................................41
SELF-ASSESSMENT QUESTIONS.....................................................................................................................................43
Self-Assessment QuestionsAnswers ...........................................................................................................................46
CHAPTER 3: CARBOHYDRATE, LIPID, AND PROTEIN METABOLISM IN TYPE 2 DIABETES .......................................47

Introduction ......................................................................................................................................................................47
Learning Objectives .........................................................................................................................................................47
Overview of Normal Carbohydrate Metabolism ...............................................................................................................49
The Incretin Response.....................................................................................................................................................49
Insulin and Glucose Transport.........................................................................................................................................52
Glucose Use and Storage................................................................................................................................................54
Glucose Production When Glucose Levels Are Low .......................................................................................................55
Carbohydrate Metabolism in Type 2 Diabetes.................................................................................................................56
Lipid Metabolism in Type 2 Diabetes ...............................................................................................................................57
Protein Metabolism in Type 2 Diabetes ...........................................................................................................................60
Summary .........................................................................................................................................................................62
SELF-ASSESMENT QUESTIONS .......................................................................................................................................64

Self-Assessment QuestionsAnswers ...........................................................................................................................66
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___________________________________________________________________________________Table of Contents
CHAPTER 4: LONG-TERM COMPLICATIONS OF TYPE 2 DIABETES............................................................................. 67

Introduction ..................................................................................................................................................................... 67
Learning Objectives ........................................................................................................................................................ 67
Complications of Type 2 Diabetes................................................................................................................................... 69
Cardiovascular Disease .................................................................................................................................................. 70
Retinopathy ..................................................................................................................................................................... 71
Nephropathy.................................................................................................................................................................... 71
Neuropathy...................................................................................................................................................................... 73
Peripheral Neuropathy ................................................................................................................................................ 73
Autonomic Neuropathy................................................................................................................................................ 74
Other Neuropathies..................................................................................................................................................... 74
Summary......................................................................................................................................................................... 74
SELF-ASSESSMENT QUESTIONS .................................................................................................................................... 77

Self-Assessment QuestionsAnswers........................................................................................................................... 80
MODULE SUMMARY .......................................................................................................................................................... 81
GLOSSARY ......................................................................................................................................................................... 87
REFERENCES .................................................................................................................................................................... 93
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_______________________________________________________________________________________ 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 glucose (GLOO-kohs): a simple
sugar occurring widely in most plant
of carbohydrates, the nutrients that are the main source of sugars for the body, is and animal tissue; the principal
impaired. However, metabolism of lipids and proteins, 2 other key groups of nutrients, circulating sugar in the blood and the
major energy source of the body
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 carbohydrate (kar-boh-HAHY-
cardiovascular system, eyes, kidneys, and nerves. dreyt): any of a group of organic
compounds that includes sugars,
starches, celluloses, and gums, and
This module, Exploring Diabetes, is designed to provide you with the information serves as a major energy source in
you need to understand what diabetes is, who is affected by it, and the underlying the body
metabolic defects and complications that can be associated with diabetes, focusing lipid (LIP-id): fat; found almost
on type 2 diabetes. exclusively in foods of animal
origin and continuously synthesized
Chapter 1 presents an overview of what diabetes is, how it is classified, and its in the body
prevalence and risk factors protein (PROH-teen): composed of
amino acid building blocks; makes up
Chapter 2 describes the core defects in type 2 diabetes most body structures, and is involved
in multiple life functions (enzymes)
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.
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__________________________________________________________________________Chapter 1: Defining Diabetes
CHAPTER 1: DEFINING DIABETES

INTRODUCTION
Diabetes is a common, progressive, and potentially devastating disease that can
have severe long-term implications for patients health and well-being. This chapter will
provide a brief overview of diabetes, its classification, and epidemiology. epidemiology
(ep-i-dee-mee-OL-uh-jee):
the branch of medicine that deals with
LEARNING OBJECTIVES the study of the causes, distribution,
and control of disease in populations
Upon completion of this chapter, you should be able to:
1. Define diabetes mellitus in terms of abnormal glucose metabolism and state its
potential long-term complications.
2. List the main types of diabetes as classified by the American Diabetes Association
(ADA) and define the differences of each type.
3. State key statistics on the prevalence of type 2 diabetes.
4. List the risk factors associated with type 2 diabetes.
5. Discuss the emotional/psychologic effects that a diagnosis of diabetes may have.

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DEFINITION OF DIABETES MELLITUS

hypoglycemia (hahy-poh-glahy-
Insulin Regulates Blood Glucose Levels SEE-mee-uh): abnormally low
concentrations of glucose in the
circulating blood
Glucose is the main source of energy for the body. Glucose is derived from the
carbohydrates contained in foods like fruits, vegetables, dairy products, cereals, breads, homeostasis (hoh-mee-uh-STEY-
sis): a tendency to stability in the
and pasta. Because glucose is the only nutrient that can provide the necessary nutrients normal body states of an organism
for certain organs, including the brain and retina, it is important to maintain constant blood that is achieved by a system of
controls activated by a negative
glucose levels. For this reason, physiologic mechanisms that prevent or rapidly correct feedback mechanism
hypoglycemia have evolved.
pancreas (PAN-kree-uhs): gland in
the abdomen near the stomach that
When a person eats, glucose derived from carbohydrates becomes available, and blood secretes insulin and glucagon
glucose levels rise. When a person has not eaten for a while, such as overnight, the
glucose circulating in the blood is depleted, and blood glucose levels can fall. In a person exocrine (EK-suh-krin): refers to the
discharge of secretions through a
without diabetes, the body prevents sustained increases or decreases in blood glucose duct opening on either an internal or
levels, maintaining blood glucose levels between 80 mg/dL and 90 mg/dL (around 4.4 external surface of the body
mmol/L to 5.0 mmol/L). Even after a person eats a meal and blood glucose levels rise, the endocrine (en-DOH-krin): refers to
body soon compensates and brings the blood glucose concentration back into the desired secretions from ductless organs
range. This is known as glucose homeostasis and requires effective coordination of (such as the islets of Langerhans
in the pancreas) that are released
several biologic processes. directly into the bloodstream
and affect metabolism or other
The bodys ability to increase and decrease glucose levels includes secreting 2 hormones bodily functions
called insulin and glucagon, which work in opposition to each other. Both of these acini (as-uh-nahy): secretory tissue
hormones are produced by specialized cells in the pancreas, an organ located in the of the exocrine pancreas; produces
abdomen near the stomach. pancreatic juice
islets of Langerhans (IHY-let LANJ-

The pancreas acts as both an exocrine and an endocrine gland. Exocrine glands er-hahnz): microscopic structures
scattered throughout the pancreas
discharge their secretions through a duct opening. The majority of the pancreas consists that comprise its endocrine functions
of exocrine tissue called acini, which aids in food digestion by secreting a fluid that
contains digestive enzymes into the small intestine. alpha-cell (AL-fuh): cell in the
pancreas that produces glucagon
Scattered throughout the exocrine tissue of the pancreas are pancreatic islets known as capillaries (KAP-uh-lar-eez):
the islets of Langerhans. The islets of Langerhans contain the endocrine tissue of the microscopic blood vessels that
connect the arterioles and venules
pancreas. Approximately 1 million to 2 million islets are found throughout the pancreas. and allow for the exchange of
Each islet is surrounded by capillaries because endocrine secretions are released substances between the blood and
directly into the bloodstream. Two types of pancreatic endocrine cells that can be found in tissue fluids
the islets of Langerhans include (see Figure 1): glucagon (GLOO-kuh-gon):

hormone secreted by the alpha-cells
of the pancreas that increases
Alpha-cells, which secrete glucagon glucose levels; opposes the action
of insulin
Beta-cells, which secrete insulin
beta-cell (BEY-tuh): the predominant
cell of the islets of Langerhans in the
pancreas; secretes insulin
insulin (IN-suh-lin): hormone

secreted by the beta-cells of the
pancreas that is the key regulator of
the metabolism of glucose and the
processes necessary for metabolism
of fats, carbohydrates, and proteins;
opposes the action of glucagon

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Figure 1. The Pancreas
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
As is discussed in later chapters of this module, the release of insulin and glucagon is in
incretin (in-KREE-tin): class of part regulated by the action of incretin hormones, which are released by the intestines in
insulinotropic substances that are
released in the gastrointestinal tract
response to ingestion of food.
in response to food ingestion

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Figure 2. Insulin and Glucagon Regulate Blood Glucose Levels
Adapted from: Shier D, Butler J, Lewis R. Holes Human Anatomy & Physiology. 13th edition. New York, NY:
McGraw-Hill Education; 2013.

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Type 2 Diabetes Is a Metabolic Disease

In type 2 diabetes, there are three defects in the regulation of glucose metabolism that
are consistently displayed:
insulin resistance: a condition The body is unable to use insulin effectively, termed insulin resistance
in which the body cells are less
responsive to (resistant to) The body is unable to produce enough (or in some cases, any) insulin, termed
the actions of insulin
insulin deficiency
The liver produces excess glucose due to increased glucagon secretion and
insulin insufficiency
hyperglycemia Hyperglycemia, or abnormally high blood glucose, is the hallmark of diabetes. Diabetes
(hahy-per-glahy-SEE-mee-uh): is diagnosed by blood tests that measure the level of glucose in the blood. Without
abnormally high blood glucose levels
effective insulin action and/or without sufficient amounts of insulin, glucose cannot enter
muscle, fat, and liver cells, and the concentration of glucose in the blood rises to
abnormally high levels. Hyperglycemia is worsened since the body commonly recognizes
an apparent lack of glucose in muscle, fat, and liver cells and responds by secreting
glucagon. Glucagon causes the liver to produce more glucose, further increasing blood
glucose levels.
Defective glucose homeostasis in type 2 diabetes can result in both immediate and long-
term problems. In the short term, the body will:
Get rid of some excess blood glucose by eliminating it in the urine
Use other sources for energy, such as fats and proteins, which disrupt fat and
protein metabolism
Diabetes can result in symptoms such as:
polyuria (pol-ee-YOOR-ee-uh): Excessive urination (polyuria; poly = many, uria = urine)
excessive urination
As the body removes excess glucose from the body
polydipsia (pol-ee-DIP-see-uh): Thirst and increased fluid intake (polydipsia; poly = many, dipsia = drink)
excessive thirst
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 (polyphagia; poly = many, phagia = eat)
excessive eating
Because glucose is not entering cells that need it for energy, the body is using
and depleting its store of proteins and fat

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Long-term Complications of Type 2 Diabetes

Long-term, high blood glucose levels can lead to both vascular and nonvascular
complications. Nonvascular complications, which are not discussed further in this
module, include cataracts, gum disease, and hearing loss. Vascular complications
of diabetes can be further categorized as:
Macrovascular disease
Damage to large blood vessels; forms of macrovascular disease include

cardiovascular disease, cerebrovascular disease, and peripheral vascular disease
Microvascular disease
Damage to small blood vessels; forms of microvascular disease include

retinopathy, nephropathy, and neuropathy
These long-term complications are responsible for the majority of the morbidity and morbidity (mawr-BID-i-tee):
sickness or disease
mortality associated with diabetes. For example:
mortality (mawr-TAL-i-tee):
The death rate from heart disease is 2 to 4 times higher in adults with diabetes death rate
compared to adults without the disease; while cardiovascular disease occurs in people
without diabetes, the interaction of hyperglycemia with the factors that cause
cardiovascular disease in diabetes has a synergistic effect, causing cardiovascular
disease to progress more rapidly in people with diabetes
Damage to the retina can result in impairment in vision and even blindnessdiabetes
is the leading cause of new cases of blindness in adults aged 20 to 74 years of age retina (RET-n-uh): the back portion
of the eye that contains the nervous
system tissue for receiving and
Damage to kidneys can lead to kidney failure; in fact, diabetes is the leading cause of transmitting visual stimuli
kidney failure and accounted for 44% of all new cases in 2008; that same year, more
than 200,000 individuals with end-stage renal disease due to diabetes were receiving
chronic dialysis or living with a kidney transplant
end-stage renal disease (ESRD):
The majority of patients with diabetes (60% to 70%) have some form of mild to kidney failure
severe nerve damage (e.g., numbness, tingling, burning). Nearly 30% of patients dialysis (dahy-AL-uh-sis):
with diabetes who are 40 years of age or older have impaired sensation in their feet; a process that mimics the action
of the kidney in filtering the blood;
severe forms of diabetic neuropathy are a major contributing cause of lower extremity the patients blood is filtered through
amputations in patients with diabetes the dialysis machine

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Figure 3. Long-term Complications of Diabetes
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 postprandial
(pohst-PRAN-dee-uhl): after a meal
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

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Type 1 Diabetes
autoimmune disorder Type 1 diabetes is an autoimmune disorder in which the beta-cells of the pancreas are
(aw-toh-i-MYOON dis-AWR-der): destroyed. Beta-cell destruction eventually results in a complete inability to produce
a disorder in which the body
mistakenly recognizes its own insulin. When insulin is not available, muscle, fat, and liver cells are unable to absorb the
tissues as foreign and attacks glucose they need, and glucose accumulates in the blood. Left untreated, blood glucose
and destroys them levels increase significantly, leading to chronic hyperglycemia and potentially fatal acute
ketoacidosis (KEE-toh-as-uh-DOH- conditions, such as diabetic ketoacidosis. Individuals with type 1 diabetes must receive
sis): acidosis that is caused by an daily insulin through injections or an insulin pump in order to survive.
excess of ketone bodies; it occurs
in individuals who do not produce
enough insulin to maintain normal Type 1 diabetes is responsible for approximately 5% to10% of all cases of diabetes.
fat metabolism 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.
Table 1. Key Signs and Symptoms of Type 1 Diabetes
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 beta-cell failure: decreased
secretion of insulin by the beta-cells
diabetes is presented in Chapter 2. because they are worn out

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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.
Table 2. Presenting Symptoms of Patients With Type 2 Diabetes
Patients with type 2 diabetes may present with symptoms of the long-term
complications of diabetes
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 Microalbuminuria or macroalbuminuria
(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
Gestational Diabetes
200 mcg/min
Gestational diabetes is a disorder in which glucose levels become elevated during
macroalbuminuria
(MAK-roh-al-byoo-muh-NYOOR-ee-
pregnancy; the glucose levels usually return to normal after delivery. However, the
uh): the leakage of large amounts of risk of developing type 2 diabetes later in life is substantially increased.
albumin into the urine; defined as
>200 mcg/min

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POPULATIONS AT RISK FOR DEVELOPING TYPE 2 DIABETES
Impaired Fasting Glucose and Impaired Glucose Tolerance

Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are conditions impaired fasting glucose (IFG):
fasting glucose levels higher than
in which glucose levels are higher than normal but not high enough to qualify as diabetes. normal but not high enough for a
Patients with IFG and IGT are at an increased risk for later developing type 2 diabetes. diagnosis of diabetes; defined as
glucose 110 mg/dL to 125 mg/dL
(6.1 mmol/L to 6.9 mmol/L)
When fasting levels are higher than normal but not high enough for a diagnosis of
diabetes, the patient is classified as having IFG. When glucose levels after an oral impaired glucose tolerance (IGT):
glucose tolerance test (OGTT) are higher than normal but not high enough for a diagnosis glucose levels measured during an
oral glucose tolerance test that are
of diabetes, the patient is classified as having IGT. higher than normal but not high
enough for a diagnosis of diabetes;
Under ADA and AACE guidelines, an individual with an FPG of 100 mg/dL to 125 mg/dL defined as glucose 140 mg/dL to
199 mg/dL (7.8 mmol/L to 11 mmol/L)
(5.6 mmol/L to 6.9 mmol/L) is considered to have IFG. A patient with a plasma blood
glucose between 140 mg/dL and 199 mg/dL (7.8 mmol/L to 11.0 mmol/L) 2 hours after
oral ingestion of a 75-gram glucose load (OGTT) has IGT.
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.
Table 3. Diagnostic Glucose Values and A1C Levels
Diagnostic Glucose Values and A1C Levels From the ADA

Fasting plasma glucose (at least 8 hours without caloric intake)*
IFG 100 mg/dL to 125 mg/dL (5.6 mmol/L to 6.9 mmol/L)
Diabetes 126 mg/dL (7 mmol/L)
OGTT (2-hour plasma glucose after ingesting 75-g load)*
IGT 140 mg/dL to 199 mg/dL (7.8 mmol/L to 11.0 mmol/L)
Diabetes 200 mg/dL (11.1 mmol/L)
Casual plasma glucose (plasma glucose taken without regard to fasting)
Diabetes levels 200 mg/dL (11.1 mmol/L) are considered diagnostic
of diabetes in a patient with classic symptoms of
hyperglycemia or hyperglycemic crisis
A1C (measurement of blood glucose over a 2- to 3-month period)*
High risk for 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.
Figure 4. Number of Civilian, Noninstitutionalized US Individuals With Diagnosed

Diabetes, 19902010
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 non-
modifiable 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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Figure 5. 2009 Age-Adjusted Estimates of the Percentage of Adults Aged

20 Years or Older With Diagnosed Diabetes
FINANCIAL IMPACT OF DIABETES

Compared with individuals who do not have diabetes, individuals with diabetes visit
their health care professional more frequently, are admitted to the hospital more often
and stay in the hospital longer, and use more prescription medications.
It is estimated that $174 billion dollars were spent on direct and indirect costs associated
with diabetes in 2007. Direct medical costs were estimated to be $116 billion for
individuals with diabetes, approximately 2.3 times higher than the estimated direct
medical costs for individuals without the disease. Indirect costs related to disability, work
loss, and premature mortality, were estimated to be $58 billion for patients with diabetes.
It has been projected that by 2021, approximately 40 million adults living in the United
States could have diabetes and an additional 100 million could be diagnosed with
prediabetes. Based on these projections, it has been estimated that health care spending
for diabetes and prediabetes could be as high as $512 billion annually.

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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.
visceral fat (VIS-er-uhl): also known This excess weight may be carried intra-abdominally, termed visceral fat, or as
as abdominal fat; excess fat
surrounding the abdominal organs;
subcutaneous abdominal fat. This is sometimes referred to as an apple shape. In
people with visceral fat have an contrast, excess weight in the hip region is part of the subcutaneous (sub = under,
apple shape rather than a cutaneous = skin) fat. This is sometimes referred to as a pear shape. Many of the
pear shape
complications associated with obesity, including insulin resistance, diabetes, and
subcutaneous fat cardiovascular disease, are more strongly linked to excess fat in the abdominal area.
(suhb-kyoo-TEY-nee-uhs):
the fat layer under the skin
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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Table 4. Key Risk Factors for Type 2 Diabetes
Risk Factor Description

Obesity Approximately 80% of patients are obese
Visceral fat may be more dangerous in terms of risk
for type 2 diabetes and cardiovascular disease
Obesity increases insulin resistance
Family history of diabetes There is a genetic predisposition for type 2 diabetes
Older age Most individuals are 40 years of age or older when
diagnosed with type 2 diabetes
History of gestational Women who have had gestational diabetes
diabetes (that is, glucose elevations diagnostic of diabetes
during pregnancy that return to normal after delivery)
or who delivered a baby weighing >9 lbs, have an
increased risk of subsequently developing diabetes
Polycystic Ovary Women with polycystic ovary syndrome, or PCOS,
Syndrome (PCOS) are at increased risk of developing type 2 diabetes
Impaired fasting People with IFG, IGT, or A1C of 5.7% to 6.4%
glucose/impaired (glucose levels higher than normal but not high
glucose tolerance/ enough for a diagnosis of diabetes) are at increased
A1C of 5.7% to 6.4% risk of developing type 2 diabetes
Sometimes referred to as prediabetes
Physical inactivity/ Modest physical activity, in combination with a
sedentary lifestyle healthy diet, can help decrease the risk for type 2
diabetes
Race/ethnicity People of certain races/ethnic groups (e.g., African
American, Latino, Native American, Asian American,
Pacific Islander) are more likely to develop type 2
diabetes

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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): Plasma triglycerides 150 mg/dL

lipid molecule containing 3 fatty acids
bound to glycerol; is the primary fat in
the diet and the primary molecule Plasma HDL-cholesterol <40 mg/dL in men, <50 mg/dL in women
used for fuel storage
high-density lipoprotein (HDL) Blood pressure 130/85 mm Hg

cholesterol: good cholesterol;
transports excess cholesterol from
tissues to the liver for elimination Fasting plasma glucose 110 mg/dL
LIVING WITH TYPE 2 DIABETES

The diagnosis of type 2 diabetes can have serious effects on individuals and their
families. When patients are diagnosed with type 2 diabetes, they frequently face the
need for ongoing medical care for the rest of their lives, and the need for significant
lifestyle changes; in addition, they face the potential for long-term complications as
the disease progresses.
For example, because many patients with type 2 diabetes are asymptomatic, the
diagnosis of type 2 diabetes is unexpected, often occurring incidentally during a routine
medical exam. They may face the need for multiple office visits to many different
healthcare professionals.
People may be apprehensive after being diagnosed with type 2 diabetes, and as they
learn more about diabetes from the healthcare professionals, their anxiety can increase.
For example, patients are faced with the prospect that they have an increased risk for
heart attack, stroke, peripheral vascular disease, and other vascular conditions. Similarly,
they face the prospect of possibly becoming blind, having a reduced quality of life, and
possibly developing kidney failure, which would result in treatment with dialysis or a
kidney transplant.

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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
The major types of diabetes are:
Type 1 diabetes: an autoimmune disease in which the body produces no (or very little) insulin
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
Gestational diabetes: glucose levels become abnormal during pregnancy and usually return to normal after
delivery, although they have a substantially increased risk of developing diabetes later in life
Patients at high risk for development of type 2 diabetes (IFG, IGT, A1C of 5.7% to 6.4%): glucose levels are higher
than normal but not high enough for a diagnosis of diabetes; these individuals are at a high risk for later developing
type 2 diabetes
(cont.)

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Defining Diabetes (cont.)

Epidemiology
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
Living With Diabetes
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 ___________ 1. produced in alpha-cells of the pancreas
B. Glucagon _________ 2. produced in beta-cells of the pancreas
3. secreted when blood glucose is low
4. secreted when blood glucose is high
5. facilitates transport of glucose to muscle, fat, and liver cells
6. induces liver to produce more glucose
7. excess production is a key defect in type 2 diabetes
8. deficient production is a key defect in type 2 diabetes
2. Long-term complications of diabetes associated with increased morbidity include:
_____ A. polyuria.
_____ B. cardiovascular disease.
_____ C. damage to the retina.
_____ D. damage to the kidneys.
3. __________ is an autoimmune disorder.
_____ A. Type 1 diabetes
_____ B. Type 2 diabetes
_____ C. Gestational diabetes
_____ D. Impaired fasting glucose

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___________________________________________________________________________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 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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_____________________________________________________________ Chapter 2: Pathogenesis of Type 2 Diabetes
CHAPTER 2: PATHOGENESIS OF TYPE 2 DIABETES

INTRODUCTION
Diabetes is a metabolic disease in which carbohydrate, fat, and protein metabolism are
disrupted, which can lead to serious consequences. This chapter describes the core
defects in type 2 diabetes and how they lead to the development and progression of
the disease. The subsequent chapter describes the consequences of these defects
on carbohydrate, fat, and protein metabolism.
LEARNING OBJECTIVES
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.

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CORE DEFECTS IN TYPE 2 DIABETES

As noted in Chapter 1, the core defects in type 2 diabetes are:
Insulin resistance in peripheral tissues (mostly muscle and fat but also the liver)
Insulin deficiency due to insufficient pancreatic insulin release
Excess hepatic glucose production due to increased glucagon secretion and insulin
insufficiency
These defects work in concert, with the development of diabetes as the result. By the time
type 2 diabetes is diagnosed, both insulin resistance and inadequate insulin production by
the beta-cells often exist. Most studies suggest that insulin resistance develops prior to
insufficient insulin secretion, but that diabetes develops only when insulin secretion is
inadequate to compensate for the insulin resistance. Figure 6 illustrates the progression
to type 2 diabetes, and then subsequent figures describe the progression in more detail.
Figure 6. Hyperbolic Relationship Between Beta-Cell Function and Insulin

Sensitivity
IGT = impaired glucose tolerance; NGT = normal glucose tolerance;

T2DM = type 2 diabetes mellitus

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NORMAL GLUCOSE REGULATION

Normal glucose regulation is dependant on a closed feedback loop relationship between
the pancreatic islet cells, peripheral tissue (mainly muscle and fat), and the liver.
As shown in Figure 7, in people without insulin resistance and without diabetes:
1. Blood glucose levels become elevated following a meal. Elevated blood glucose
levels stimulate the release of insulin from the beta cells of the pancreas.
2. The body responds to insulin, and thus insulin is effective at facilitating the transport
of glucose into muscle, fat, and liver cells; that is, one is considered to have normal
insulin sensitivity (the body is not resistant to insulin).
3. In the liver, insulin inhibits hepatic glucose production.
4. Elevated glucose levels trigger the release of insulin and the beta-cells continue
to secrete insulin until plasma glucose levels return to premeal levels (80 mg/dL to
90 mg/dL. This feedback loop is known as glucose homeostasis and acts to maintain
plasma glucose levels within a narrow range (termed euglycemia; eu = good, glyc =
glucose, emia = blood).

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Figure 7. Schematic Representation of the Normal Effects of Insulin on a

Nondiabetic Person

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INSULIN RESISTANCE BEGINS

Figure 8 shows the pathogenesis of type 2 diabetes:
1. In individuals who will eventually develop type 2 diabetes, one of the early stages in
the development of this disease is that muscle, fat, and liver cells become resistant
to (less sensitive to) the effects of insulin. This means that insulin is less effective at
facilitating the transport of glucose into muscle, fat, and liver cells.
2. Because muscle, fat, and liver cells are resistant to the effects of insulin, the beta-
cells 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 (HAHY-per-IN- hyperinsulinemia (hyper = high, insulin = insulin, emia = in the blood). However,
suh-luh-NEE-mee-uh): increased beta-cells begin to slowly fail.
levels of insulin in the plasma due to
increased secretion of insulin by the
beta-cells of the pancreatic islets 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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Figure 8. Insulin Resistance Begins

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IMPAIRED FASTING GLUCOSE

As the disease progresses, insulin resistance worsens and the beta-cells continue to fail.
As shown in Figure 9:
1. Insulin resistance continues to worsen (increases).
2. The body produces more and more insulinresulting in hyperinsulinemia.
3. Eventually insulin levels fall and the remaining insulin is unable to move enough
glucose into the cells, and blood glucose levels start to rise above normal range,
termed impaired fasting glucose or impaired glucose tolerance. Blood glucose also
rises because the liver produces excess glucose, due to increased glucagon and
insulin insufficiency.
4. Eventually the beta-cells can no longer produce sufficient amounts of insulin. This
decline in insulin production is termed beta-cell failure. As beta-cell failure continues:
The amount of insulin in the blood decreases
The amount of glucose in the blood increases even more
Figure 9. Impaired Fasting Glucose and Impaired Glucose Tolerance

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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
(GLOO-koh-tok-SIS-i-tee):
Glucotoxicity also negatively affects beta-cell function and survival the concept that high levels of
glucose can further exacerbate
A related concept, that high levels of glucose and free fatty acids in the blood act type 2 diabetes metabolism by
promoting insulin resistance
synergistically to negatively impact beta-cell function and survival, has been termed and beta-cell dysfunction
glucolipotoxicity
glucolipotoxicity (GLOO-koh-li-
POH-tok-SIS-i-tee): the concept
Prior to beta-cell failure and development of type 2 diabetes: that high levels of glucose and free
fatty acids can act synergistically
There is a compensatory phase during which insulin resistance develops; to to exacerbate type 2 diabetes
metabolism by promoting insulin
compensate for the insulin resistance, beta-cell mass and insulin secretion resistance and beta-cell dysfunction
are increased :
There is a decompensatory phase
Beta-cell mass and insulin secretion decrease during the decompensation

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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Figure 10. Hypothetical Representation of the Progression From Beta-Cell

Compensation to Failure in the Face of Obesity-Induced Insulin Resistance,
and the Role of Glucolipotoxicity
In summary, the clinical picture in type 2 diabetes is:
Insulin resistance is present
Progressive beta-cell failure occurs over time
Because of continued release of glucagon and insufficient insulin, the liver produces
excess glucose
As a result of beta-cell failure, insulin resistance, and excess hepatic glucose production,
plasma glucose levels rise above the normal range, resulting in hyperglycemia
A patient is diagnosed with type 2 diabetes when:
Hyperglycemia reaches 126 mg/dL (7.0 mmol/L) when the glucose is measured
as a FPG
during an oral glucose tolerance test
A1C is 6.5%
as a random plasma glucose AND the patient has classic symptoms of hyperglycemia
or hyperglycemic crisis

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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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1. The core defects of type 2 diabetes are:
____ A. insulin resistance in the peripheral tissues.
_____ B. insulin deficiency due to insufficient pancreatic insulin release.
_____ C. excess hepatic glucose production.
_____ D. decreased glucagon secretion due to beta-cell failure and increased insulin sensitivity.
2. _______________________ is dependent on a closed loop feedback system between the pancreatic islet cells,
peripheral tissues, and liver in people without type 2 diabetes.
____ A. Euglycemia
_____ B. Fat metabolism
_____ C. Glucose homeostasis
_____ D. Pancreatic exocrine secretions
3. In the early stages of the development of type 2 diabetes, insulin levels in the blood are _______ normal.
_____ A. lower than
_____ B. higher than
_____ C. the same as
4. When beta-cell failure occurs:
_____ A. the amount of insulin in the blood increases.
_____ B. the amount of insulin in the blood decreases.
_____ C. the amount of glucose in the blood increases.
_____ D. the amount of glucose in the blood decreases.

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5. __________ ultimately determines the onset of type 2 diabetes.
_____ A. Insulin resistance
_____ B. Excess glucagon
_____ C. Beta-cell dysfunction
_____ D. Alpha-cell dysfunction

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1. A,
B,
C
2. C
3. B
4. B,
C
5. C

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____________________________________ Chapter 3: Carbohydrate, Lipid, and Protein Metabolism in Type 2 Diabetes
CHAPTER 3: CARBOHYDRATE, LIPID, AND

PROTEIN METABOLISM IN TYPE 2 DIABETES
INTRODUCTION
Chapter 2 described the core defects in type 2 diabetesinsulin resistance, insulin
insufficiency, and excess hepatic glucose productionand what these defects mean
in terms of blood glucose levels. This chapter focuses on carbohydrate (i.e., glucose),
lipid (fat), and protein metabolism, including the role of insulin in the use and storage
of glucose, and how these are disrupted by insulin resistance and insulin insufficiency.
LEARNING OBJECTIVES
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.

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OVERVIEW OF NORMAL CARBOHYDRATE METABOLISM

When you eat carbohydrates, such as those in fruit, table sugar, breads, cereals, and
pasta, they are broken down into compounds that are composed of 1 or 2 sugars.
Glucose makes up about 80% of the simple sugars initially produced, and other simple
sugars can be converted into glucose. Overall, glucose is the major and preferred fuel
used by the body for energy.
Key steps in carbohydrate metabolism include the following, which are discussed in more
detail on the following pages:
The presence of food in the gastrointestinal (GI) tract triggers the release of incretin
hormones, which stimulate insulin synthesis and release by beta-cells and suppress
glucagon release from alpha-cells
Insulin facilitates glucose transport into cells
Once within the cells, glucose is either used immediately for energy production or
converted to storage molecules
THE INCRETIN RESPONSE

The presence of food in the GI tract stimulates a variety of control systems that help
regulate gastric emptying, gut motility, and nutrient metabolism. Specifically, the GI tract
plays an important role in metabolizing carbohydrates by secreting hormones called
incretins that adjust beta-cell insulin production to the amount of nutrients that has been
ingested. Two key incretins are:
Glucagon-like peptide-1 (GLP-1)
Glucose-dependent insulinotropic peptide (GIP)
Both GLP-1 and GIP are produced by cells in the small intestine and are rapidly (within
minutes) released into the circulation after food ingestion.
GLP-1 and GIP are activated by binding their respective receptors. GLP-1 receptors are
expressed in many places throughout the body including the pancreatic beta-cells, where
they mediate insulin release; pancreatic islets; the central nervous system; the kidneys;
and the gastrointestinal tract. GIP, while primarily expressed in pancreatic beta-cells and
pancreatic islets, is also expressed in other areas of the body, including the stomach,
small intestine, adipose tissue, and kidneys.

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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
apoptosis (ap-uhp-TOH-sis): decrease beta-cell apoptosis in some, but not all, animal models. GLP-1 has been shown
programmed cell death
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.
Table 5. GLP-1 and GIP Effects on Glucose Regulation
Effect GLP-1 GIP

Increases insulin production and release by beta-cells Yes* Yes*
Inhibits glucagon secretion by alpha-cells Yes* No
* These events lead to a decrease in blood glucose levels
Other effects of GLP-1 that decrease postprandial glucose levels include:
Promotes satiety*
Slows gastric emptying and inhibits gastric acid secretion*
Both GLP-1 and GIP are rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4).
Figure 11 summarizes the role of incretins in the function of beta-cells and alpha-cells.
* Effect with pharmacologic levels of GLP-1

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Figure 11. The Incretin Response

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Type 2 diabetes is associated with a reduced incretin response.
While concentrations of GIP are maintained or even increased in patients with type 2
diabetes, the effects of GIP are absent. It has not been determined why the effects of
GIP are absent in patients with type 2 diabetes. It has been hypothesized that it may
be a result of impaired beta-cell response to glucose or possibly a postreceptor defect.
The secretion of GLP-1 is often reduced in patients with type 2 diabetes. However, GLP-1
remains active in patients with type 2 diabetes although increased levels of the incretin
are needed to be effective.
INSULIN AND GLUCOSE TRANSPORT

Now lets take a closer look at how insulin exerts its effects on glucose metabolism.
In order to be used for immediate energy needs or stored for later use, glucose must first
enter the cells. Glucose can freely enter brain cells without help; however, most cells in the
body, including resting muscle, fat, and liver cells, require insulin to facilitate the entry of
glucose into the cell.
As illustrated in Figure 12, the following sequence of events occurs:
1. Beta-cells in the pancreas secrete insulin
2. Insulin binds to a receptor on the cell surface of muscle, fat, and liver cells
3. This binding activates the insulin receptor
4. The activated insulin receptor signals glucose transporters, called GLUT4, to move
from the inside of the cell to the cell surface
GLUT4: the transporter molecule 5. GLUT4 transports glucose into the cell
that, when signaled by insulin, moves
from the cell interior to the cell
surface and transports glucose 6. GLUT4 returns to and resides in the interior of the cell until signaled by insulin at
into the cell a later time

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Figure 12. Insulin and Glucose Transport
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

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GLUCOSE USE AND STORAGE

As shown in Figure 13, once it is within the cells, glucose can either be:
1. Used immediately for the production of energy
2. Transformed to storage molecules that will be used for energy later
If energy is needed immediately, glucose is metabolized to produce energy via a process

glycolysis (glahy-KOL-uh-sis): called glycolysis (glyco = glucose, lysis = break down).
the metabolism of glucose
to produce energy
If more glucose is available than what the cells need immediately for energy, the extra
glycogen (GLAYH-kuh-jen): glucose is converted to a storage molecule called glycogen via a process called glycogen
molecule that is the main form
of carbohydrate storage; occurs
synthesis. Glycogen synthesis occurs primarily in liver cells and to a more limited extent in
primarily in the liver and muscle muscle cells. When the storage capacity for glycogen is reached, and when glucose is not
tissue; readily converted to glucose immediately required for energy, additional glucose is converted to fat.
as needed by the body to satisfy
its energy needs
Figure 13. Glucose Use and Storage

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GLUCOSE PRODUCTION WHEN GLUCOSE LEVELS ARE LOW

In contrast, an opposite process occurs when you have not eaten for a while and the
blood glucose concentration is low because the available glucose has been used up.
As illustrated in Figure 14:
1. The alpha-cells of the pancreas secrete glucagon (GLP-1 does not suppress the
release of glucagon when blood glucose concentrations are low)
2. Glucagon causes 2 events:
2a. Glucagon stimulates glycogen breakdown into glucose in the liver; this
process is called glycogenolysis (glycogen = glycogen, lysis = break down) glycogenolysis
(GLAHY-kuh-juh-NOL-uh-sis):
breakdown of glycogen to glucose
2b. Glucagon also causes the liver to increase uptake of amino acids, and then
acts on these precursor molecules to create new glucose, a process called
gluconeogenesis (gluco = glucose, neo = new, genesis = synthesis) gluconeogenesis
(gloo-koh-nee-uh-JEN-uh-sis):
formation of new glucose from
3. The end result is that the glucose is released into the blood, and the blood glucose protein or fat
level quickly increases
Figure 14. Glucose Production in the Liver

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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
CARBOHYDRATE METABOLISM IN TYPE 2 DIABETES

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, reduced use of glucose by the
cells of the body, and the use of fats and proteins by the body for energy. Additionally,
the body makes more glucose available by:
Increasing glycogenolysis (breaking down glycogen to glucose) in the liver
An increase in gluconeogenesis (synthesis of new glucose) in the liver
A decrease in the storage of glucose and glycogen in the liver and muscle

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LIPID METABOLISM IN TYPE 2 DIABETES

Lipids, that is, fats, come from foods and are also made by the body. Lipids play important
roles in the body, one of which is to store energy. Two key types of lipids are triglycerides
and cholesterol, as described in the following table.
Table 6. Key Types of Lipids in the Body
Triglycerides: the most common fat in the diet and in the body
Composed of 3 fatty acids and a glycerol molecule fatty acid: any of the saturated or
unsaturated organic acids that have
Main role is energy storage: excess glucose, proteins, and other fats are a single carboxyl group and usually
converted to triglycerides for storage an even number of carbon atoms;
one component of triglycerides
Cholesterol: found in foods and synthesized in the body glycerol (GLIS-uh-rawl): a simple
Acts as a building block for essential cellular substances carbohydrate that serves as the
backbone for triglycerides; attaches
(for example, cell membranes) to 3 fatty acids to form a triglyceride
Both triglycerides and cholesterol are carried in the blood by proteins; the
combination molecule is called a lipoprotein lipoprotein (lip-oh-PROH-teen):
the combination of lipids and proteins;
Key lipoproteins include: examples are low-density lipoproteins
and high-density lipoproteins
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.

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As shown in Figure 16, in this metabolic pathway:
free fatty acids (FFA): fatty acids Triglycerides are broken down into fatty acids and glycerol, releasing free fatty acids
that are bound to albumin and are
in the blood
(FFA) and glycerol into the bloodstream
Tissues throughout the body use the free fatty acids for energy production
ketone bodies (KEE-tohn): Ketone bodies are produced when free fatty acids are metabolized
keto-acid compounds produced
during the metabolism of fatty acids,
which at high levels can be toxic In type 1 diabetes, in particular, elevated levels of ketone bodies and
accompanying dehydration can precipitate a potentially life-threatening
diabetic ketoacidosis state called diabetic ketoacidosis
(dahy-uh-BET-ik KEE-toh-as-uh-
DOH-sis): buildup of ketone bodies
(keto-acids) in the blood of patients Excess fatty acids also cause the liver to synthesize triglyceride-rich lipoproteins
with type 1 diabetes, which increases and cholesterol-rich LDL
the acidity of the blood
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
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 (li-POH-tok-SIS-i-tee): lipotoxicity. A related concept, that high levels of glucose and free fatty acids in the blood
the concept that high levels of free act synergistically to negatively impact beta-cell function and survival, has been termed
fatty acids can further exacerbate
type 2 diabetes metabolism by glucolipotoxicity.
promoting insulin resistance and
beta-cell dysfunction
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

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Figure 16. Lipid Metabolism in Type 2 Diabetes

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PROTEIN METABOLISM IN TYPE 2 DIABETES

Proteins fulfill a variety of key roles in the body:
Protein can form the structure of organs and muscles
enzyme (EN-zahym): a protein Some proteins are enzymes that facilitate the chemical reactions of metabolism
produced by living cells that
catalyzes chemical reactions
Proteins can also be broken down for energy production when glucose is not available
amino acid (uh-MEE-noh): Proteins are synthesized from molecules called amino acids. Much like beads in a
one of the building blocks of
proteins; 20 amino acids are
necklace, amino acids are linked together in long chains called peptides. A complicated
used in different combinations protein molecule can have thousands of amino acids combined by peptide linkages; the
to produce the different/proteins average is about 400 amino acids. Some proteins are formed when one or more peptide
peptide (PEP-tahyd): a chain chains are coiled and folded in configurations specific to each protein.
of amino acids
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): 4. When insulin is not available, protein storage is virtually stopped. The catabolism of
a metabolic process in which complex
substances are broken down into
proteins increases, protein synthesis is halted, and large quantities of amino acids
simple compounds 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.

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Figure 17. Protein Metabolism in Type 2 Diabetes

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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.)
* Effect with pharmacologic levels of GLP-1

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Carbohydrate, Lipid, and Protein Metabolism in Type 2 Diabetes (cont.)

Carbohydrate Metabolism in Type 2 Diabetes
Because of insulin resistance and insulin insufficiency, glucose is no longer
effectively transported out of the blood and into muscle, fat, and liver cells
In response to the perceived lack in glucose, the body makes more glucose by:
Breaking down glycogen (glycogenolysis)
Synthesizing new glucose (gluconeogenesis)
Preventing the synthesis of glycogen
The body turns to fats and proteins for energy production when glucose
is not available
Lipid Metabolism in Type 2 Diabetes
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)
Protein Metabolism in Type 2 Diabetes
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

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SELF-ASSESMENT QUESTIONS
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.

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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.

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1. C,
D
2. B,
C,
D
3. D
4. B
5. C

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____________________________________________________ Chapter 4: Long-term Complications of Type 2 Diabetes
CHAPTER 4: LONG-TERM COMPLICATIONS

OF TYPE 2 DIABETES
INTRODUCTION
Patients with type 2 diabetes face a range of long-term complications that are responsible
for the majority of the morbidity and mortality associated with type 2 diabetes. This
chapter describes the major long-term complications of type 2 diabetes, which are
microvascular and macrovascular. These include:
Cardiovascular disease
Retinopathy: damage to the retina of the eye
Nephropathy: damage to the kidney
Neuropathy: damage to the nerves
LEARNING OBJECTIVES
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.

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COMPLICATIONS OF TYPE 2 DIABETES

Although diabetes can cause a variety of acute symptoms, its major impact on health is
due to the long-term complications it causes. Cardiovascular and cerebrovascular events
(heart attacks and strokes) are significantly more likely to occur in patients with diabetes
than patients without diabetes. In adults who have heart disease, the heart disease death
rate is 2 to 4 times higher in patients with diabetes compared to patients without diabetes.
In 2007, diabetes was the seventh leading cause of death in the United States. It was
listed as the underlying cause of death on nearly 72,000 death certificates and as a
contributing cause of death on more than 160,000 additional death certificates. The CDC,
which published these statistics in 2011, notes that is it likely that diabetes is
underreported as a cause of death.
The long-term vascular complications of diabetes can be categorized as:
Macrovascular (macro = large, vascular = blood vessel) disease has many of the
same characteristics of atherosclerosis; a combination of abnormalities caused atherosclerosis
by insulin insufficiency may lead to this type of vascular disease (ath-uh-roh-skluh-ROH-sis):
progressive process in which smooth
muscle cells proliferate in the walls of
Microvascular (micro = small, vascular = blood vessel) disease includes damage to blood vessels and fatty plaques are
the retina, the kidney, and nerves deposited on the inside of blood
vessels, obstructing blood flow
While it is known that chronic hyperglycemia is an important cause in the development

of the long-term complications of diabetes, exactly how it causes such diverse cellular
and organ dysfunction is not yet known.
The mechanisms for development of macrovascular complications are not completely

understood. However, they likely include multiple effects of hyperglycemia and other
metabolic abnormalities that damage the proteins of endothelial and vascular smooth
muscle cells, in addition to other tissues. Abnormal lipid development often leads to
atherosclerosis in patients with diabetes, and magnifies the damage caused by
hyperglycemia. Atherosclerosis is a progressive condition in which the smooth muscle
cells of the blood vessels proliferate and fatty plaques are deposited on the walls of blood
vessels. While atherosclerosis occurs in people without diabetes, it is more common,
appears at a younger age, and progresses more rapidly in people with diabetes.

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basement membrane: a layer In microvascular complications, hyperglycemia causes a thickening of the basement
that secures the thin layer of tissue
that surrounds organs to the
membrane of the cells lining small blood, which then limits the passage of nutrients and
underlying tissue oxygen to the tissues these blood vessels supply
There are varying hypotheses as to what causes nerve damage (neuropathy) in diabetes.
heterogeneous Neuropathy is a heterogeneous disease with varying pathology. The underlying cause
(het-er-uh-JEE-nee-uhs): likely involves multiple mechanisms.
arising from dissimilar causes
The following pages describe the different types of long-term complications in greater detail.
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 High blood pressure, termed hypertension (hyper = high, tension = to stretch), is also
(hahy-per-TEN-shuhn): common in patients with type 2 diabetes and can accelerate other complications of
elevated blood pressure
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

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Table 7. Types of Macrovascular Disease
Type Description
Coronary artery Narrowing or blockage of the arteries that supply the
disease heart with blood
Reduced blood flow and resulting lack of oxygen can lead
to myocardial infarction (MI) myocardial infarction (MI)
(mahy-uh-KAHR-dee-uhl in-
Cerebrovascular Narrowing or blockage of the major arteries that supply the FAHRK-shuhn): death of a portion
of the heart muscle as a result
disease brain with blood of deprivation of its blood supply
(heart attack)
Reduced flow of oxygen and nutrients to the brain leads to a
stroke when the artery becomes completely blocked by the stroke: any acute clinical event
plaque or by a clot related to impairment of cerebral
circulation that lasts longer than
Peripheral Narrowing or blockage of the arteries that supply the 24 hours
vascular disease extremities with blood
Leads to slow healing of trauma or even tissue death, which
can lead to amputation, particularly in the feet; nerve damage
is also often involved
Diabetes is the most common cause of nontraumatic lower
limb amputation
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 retinopathy (ret-n-OP-uh-thee):
the leading cause of blindness in adults between 20 and 74 years of age. Individuals with damage to the retina of the eye;
can lead to blindness
diabetes are 25 times more likely to become legally blind than those without.
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
nephropathy (nuh-FROP-uh-thee):
damage to the kidneysis termed nephropathy (nephro = kidney, pathy = damage). kidney damage that can arise
as a complication of chronic
hyperglycemia

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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.
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
albumin (al-BYOO-muhn): a modest amount of protein in the urine (30 mg and <300 mg of albumin per day) and
the main protein in the blood 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
glomerular filtration rate (GFR): changes in the glomerular filtration rate (GFR), albumin excretion, and blood pressure.
amount of fluid filtered from
the kidney per unit time; used While this staging is not a diagnostic classification, it helps to illustrate the natural
to measure kidney function progression of diabetic nephropathy (see Table 8).
Table 8. Stages of Progression of Diabetic Nephropathy
Glomerular Urinary Albumin Years After Diagnosis

Stage Blood Pressure
Filtration Rate Excretion of Diabetes
1 Hyperfiltration Higher than normal <30 mg/day Normal 0
2 Microalbuminuria High normalnormal 30299 mg/day Rising 515 years
3 Overt proteinuria Normaldecreasing 300 mg/day Elevated 1020 years
4 Progressive
Decreasing Increasing Elevated 1525 years
nephropathy
5 End-stage
<15 mL/min Massive Elevated 2030 years
renal disease

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If ESRD, end-stage renal disease, occurs, patients have 2 options:
Renal dialysis, a process in which a machine filters the patients blood; this process
takes several hours and must be done several times a week
Kidney transplantation
NEUROPATHY
Neuropathy (neuro = nerve, pathy = disease) is among the most common long-term neuropathy (nyoo-ROP-uh-thee):
nerve damage, primarily peripheral
complications of diabetes, occurring in 60% to 70% of all patients. Nerve damage is neuropathy (in which the nerves in
probably the result of several factors, including how long the patient has had diabetes, the extremities are affected); loss
the degree of blood glucose control, dyslipidemia, obesity, and smoking. Another potential of sensation may occur, which may
result in serious infection, gangrene,
cause is damage to the blood vessels that carry oxygen and nutrients to the nerves. and the need for amputation
Diabetic neuropathy is categorized based on its clinical presentation. Classifications

include peripheral, autonomic, proximal, and focal neuropathies. It is likely that peripheral neuropathy (puh-RIF-er-
uhl nyoo-ROP-uh-thee): the most
different types of diabetic neuropathies have different factors. common type of diabetic neuropathy;
results in pain or loss of feeling in the
Peripheral Neuropathy extremities
autonomic neuropathy (aw-tuh-

Peripheral neuropathy is the most common type of diabetic neuropathy. The damage to NOM-ik nyoo-ROP-uh-thee): any
neuropathy of the autonomic nervous
the nerves of the extremities produces a variety of symptoms, including pain, system, including digestion, bowels,
strange/unpleasant sensations, decreased sensation, and muscle weakness that starts in bladder, and the nerves that serve
the ends of the extremities. The legs are usually affected more often than the arms. the heart and control blood pressure
proximal neuropathy (PROK-suh-

The decreased sensation in the feet means that patients often do not notice a cut or a muhl nyoo-ROP-uh-thee):
sore, and serious infections can then develop. The impairment in blood flow that can neuropathy that affects the thighs,
hips, or buttocks and that can lead to
occur with peripheral vascular diseasea vascular complication of diabetesmakes the weakness in the legs
problem worse. Hyperglycemia also provides more nutrients for pathogens, increasing
focal neuropathy (FOH-kuhl nyoo-
risk of infection. In many cases, the end result is the development of gangrene or a bone ROP-uh-thee): neuropathy that
infection and the need to amputate the affected body part. As noted previously, diabetes results in a sudden weakness of one
is the most common cause of nontraumatic lower limb amputation. nerve or a group of nerves that can
cause muscle weakness or pain
gangrene (GANG-green):
tissue death due to lack of
blood supply to the tissue

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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.
Figure 18. Long-term Complications in Type 2 Diabetes

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Long-term Complications in Type 2 Diabetes

Overview
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
Macrovascular disease is associated with:
Atherosclerosis: progressive condition of blood vessels resulting from a variety
of processes
Occurs more commonly, appears at a younger age, and progresses more
rapidly in patients with type 2 diabetes
Cardiovascular disease: a major cause of death for people with
type 2 diabetes
People with diabetes are at particularly high risk of developing
cardiovascular disease due to:
o Abnormally high levels of cholesterol in the blood
(hypercholesterolemia)
o High blood pressure (hypertension)
o Obesity Types of macrovascular disease:
Coronary artery disease: affects the arteries of the heart; can lead to
heart attack
Cerebrovascular disease: affects the arteries supplying the brain; can lead
to stroke
Peripheral vascular disease: affects the arteries that supply the extremities;
can lead to amputation
(cont.)

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Long-term Complications in Type 2 Diabetes (cont.)

Microvascular Disease
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

DIAB-1061087-0000 12/5/2012
___________________________________________________________________________Self Assessment Questions
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.

DIAB-1061087-0000 12/5/2012
4. Modifiable risk factors for the development of diabetic nephropathy include:
_____ A. hyperglycemia.
_____ B. hypertension.
_____ C. hypotension.
_____ D. macroalbuminuria.
5. _________ is one of the most common long-term complications of diabetes, occurring in 60% to 70% of all patients.
_____ A. Retinopathy
_____ B. Neuropathy
_____ C. Cardiovascular disease
_____ D. Nephropathy

DIAB-1061087-0000 12/5/2012
___________________________________________________________________________Self Assessment Questions

DIAB-1061087-0000 12/5/2012
1. A,
C,
D
2. A,
B,
D
3. A,
C
4. A,
B
5. B

DIAB-1061087-0000 12/5/2012
___________________________________________________________________________________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:

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
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 1 diabetes: an autoimmune disease in which the body produces no
(or very little) insulin
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
Gestational diabetes: glucose levels become abnormal during pregnancy
and usually return to normal after delivery, although the risk of developing
type 2 diabetes later in life is substantially
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.

DIAB-1061087-0000 12/5/2012
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
Insulin insufficiency: inadequate production of insulin by the beta-cells of the
pancreas
Excess hepatic glucose production: excess production of glucose by the liver
because of release of glucagon and insufficient insulin, as well as insulin
resistance
People without insulin resistance and without diabetes:

Respond to insulin; that is, insulin is effective at facilitating the transport of
glucose to muscle, fat, and liver cells
Are able to secrete adequate amounts of insulin to keep blood glucose levels in
the normal range
Have normal glucose levels (euglycemia)
In the early stage of progression to type 2 diabetes:

Insulin resistance begins to increase
The beta-cells begin to slowly fail
Circulating insulin levels rise
Glucose levels remain within normal range

DIAB-1061087-0000 12/5/2012
___________________________________________________________________________________Module Summary
At the stage of 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
In type 2 diabetes:
Insulin resistance is present
Beta-cell dysfunction continues to progress and beta-cell failure occurs
Because of continued release of glucagon and insufficient insulin, the liver
produces excess glucose
Glucose levels rise above normal range (hyperglycemia)
3) In 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 GLP-1 suppresses release of glucagon by
alpha-cells.
The insulin secreted by the beta-cells of the pancreas facilitates the transfer
of glucose into muscle, fat, and liver cells and prevents the liver from making
more glucose.
Once within the cells, glucose can either be:

Used immediately to produce energy
Transformed to storage molecules
Converted to fat if the limit of glycogen storage capacity is reached
When glucose levels are low, the body makes more glucose by breaking down
glycogen (glycogenolysis) or by synthesizing new glucose (gluconeogenesis)
in the liver.

DIAB-1061087-0000 12/5/2012
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:
Breaking down glycogen (glycogenolysis)
Synthesizing new glucose (gluconeogenesis)
Suppressing the synthesis of glycogen
Turning to fats and proteins for energy production
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:
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.

DIAB-1061087-0000 12/5/2012
___________________________________________________________________________________Module Summary
Macrovascular disease is associated with atherosclerosis and cardiovascular

disease. Atherosclerosis is a progressive condition of blood vessels resulting from a
variety of processes that occurs more commonly, appears at a younger age, and
progresses more rapidly in patients with type 2 diabetes.
Cardiovascular disease is the major cause of death for people with type 2 diabetes.
People with diabetes are at particularly high risk of developing cardiovascular disease
due to:
Abnormally high levels of cholesterol in the blood (hypercholesterolemia)
High blood pressure (hypertension)
Obesity
There are 3 major types of macrovascular disease:

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).

DIAB-1061087-0000 12/5/2012
Treatment options for ESRD include dialysis or kidney transplantation.
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,
which can progress to serious infection, gangrene, and the need for amputation.
Neuropathy in nerves leading to body organs can include 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.

DIAB-1061087-0000 12/5/2012
__________________________________________________________________________________________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

DIAB-1061087-0000 12/5/2012
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

DIAB-1061087-0000 12/5/2012
__________________________________________________________________________________________Glossary
glycogenolysis (GLAHY-kuh-juh-NOL-uh-sis): breakdown of glycogen to glucose
glycolysis (glahy-KOL-uh-sis): the metabolism of glucose to produce energy
heterogeneous (het-er-uh-JEE-nee-uhs): arising from dissimilar causes
high-density lipoprotein (HDL) cholesterol: good cholesterol; transports excess cholesterol to the liver for elimination
homeostasis (hoh-mee-uh-STEY-sis): a tendency to stability in the normal body states of an organism that is achieved
by a system of controls activated by a negative feedback mechanism
hypoglycemia (hahy-poh-glahy-SEE-mee-uh): abnormally low concentrations of glucose in the circulating blood
hyperglycemia (hahy-per-glahy-SEE-mee-uh): abnormally high blood glucose levels
hyperinsulinemia (HAHY-per-IN-suh-luh-NEE-mee-uh): increased levels of insulin in the plasma due to increased

secretion of insulin by the beta-cells of the pancreatic islets
hypertension (hahy-per-TEN-shuhn): elevated blood pressure
impaired fasting glucose (IFG): fasting glucose levels higher than normal but not high enough for a diagnosis of diabetes;
defined as glucose 100 mg/dL to 125 mg/dL (5.6 mmol/L to 6.9 mmol/L)
impaired glucose tolerance (IGT): glucose levels measured during an oral glucose tolerance test that are higher than
normal but not high enough for a diagnosis of diabetes; defined as glucose 140 mg/dL to 199 mg/dL (7.8 mmol/L to
11 mmol/L)
incretin (in-KREE-tin): class of insulinotropic substances that are released in the gastrointestinal tract in response
to food ingestion
insulin (IN-suh-lin): hormone secreted by the beta-cells of the pancreas that is the key regulator of the metabolism of
glucose and processes necessary for metabolism of fats, carbohydrates, and proteins; opposes the action of glucagon
insulin resistance: a condition in which the body cells are less responsive to (resistant to) the actions of insulin
islets of Langerhans (IHY-let Lan-JER-hanz): microscopic structures scattered throughout the pancreas that comprise
its endocrine functions
ketoacidosis (KEE-toh-as-uh-DOH-sis): 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
ketone bodies (KEE-tohn): keto-acid compounds produced during the metabolism of fatty acids, which at high levels can
be toxic

DIAB-1061087-0000 12/5/2012
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 high-
density 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)

DIAB-1061087-0000 12/5/2012
__________________________________________________________________________________________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

DIAB-1061087-0000 12/5/2012

DIAB-1061087-0000 12/5/2012
________________________________________________________________________________________References
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Module 1 Understanding Type 2 Diabetes

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Module 1 Understanding Type 2 Diabetes

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DIABETES LEARNING SYSTEM

MODULE 1: EXPLORING DIABETES

CONFIDENTIAL: For Training Purposes OnlyNot for Promotional Use

CONFIDENTIAL: For Training Purposes OnlyNot for Promotional Use

CHAPTER 1: DEFINING DIABETES ..................................................................................................................................... 3

SELF-ASSESSMENT QUESTIONS .................................................................................................................................... 26

CONFIDENTIAL: For Training Purposes OnlyNot for Promotional Use m

CHAPTER 2: PATHOGENESIS OF TYPE 2 DIABETES .....................................................................................................31

CHAPTER 3: CARBOHYDRATE, LIPID, AND PROTEIN METABOLISM IN TYPE 2 DIABETES .......................................47

SELF-ASSESMENT QUESTIONS .......................................................................................................................................64

m CONFIDENTIAL: For Training Purposes OnlyNot for Promotional Use

CHAPTER 4: LONG-TERM COMPLICATIONS OF TYPE 2 DIABETES............................................................................. 67

SELF-ASSESSMENT QUESTIONS .................................................................................................................................... 77

MODULE SUMMARY .......................................................................................................................................................... 81

CONFIDENTIAL: For Training Purposes OnlyNot for Promotional Use m

m CONFIDENTIAL: For Training Purposes OnlyNot for Promotional Use

Chapter 4 discusses the long-term complications of type 2 diabetes

CONFIDENTIAL: For Training Purposes OnlyNot for Promotional Use 1

2 CONFIDENTIAL: For Training Purposes OnlyNot for Promotional Use

CHAPTER 1: DEFINING DIABETES

CONFIDENTIAL: For Training Purposes OnlyNot for Promotional Use 3

4 CONFIDENTIAL: For Training Purposes OnlyNot for Promotional Use

DEFINITION OF DIABETES MELLITUS

islets of Langerhans (IHY-let LANJ-

the islets of Langerhans include (see Figure 1): glucagon (GLOO-kuh-gon):

insulin (IN-suh-lin): hormone

CONFIDENTIAL: For Training Purposes OnlyNot for Promotional Use 5

Figure 1. The Pancreas

6 CONFIDENTIAL: For Training Purposes OnlyNot for Promotional Use

Figure 2. Insulin and Glucagon Regulate Blood Glucose Levels

CONFIDENTIAL: For Training Purposes OnlyNot for Promotional Use 7

Type 2 Diabetes Is a Metabolic Disease

Get rid of some excess blood glucose by eliminating it in the urine

Weight loss, weakness, and fatigue

8 CONFIDENTIAL: For Training Purposes OnlyNot for Promotional Use

Long-term Complications of Type 2 Diabetes

Damage to large blood vessels; forms of macrovascular disease include

Damage to small blood vessels; forms of microvascular disease include

CONFIDENTIAL: For Training Purposes OnlyNot for Promotional Use 9

Figure 3. Long-term Complications of Diabetes

American Diabetes Association (ADA), which publishes a variety of clinical materials,

American Association of Clinical Endocrinologists (AACE), which publishes a variety

US government organizations that have developed diabetes awareness and prevention

10 CONFIDENTIAL: For Training Purposes OnlyNot for Promotional Use

Diabetes is differentiated from associated conditions on the basis of plasma glucose

CONFIDENTIAL: For Training Purposes OnlyNot for Promotional Use 11

Table 1. Key Signs and Symptoms of Type 1 Diabetes

12 CONFIDENTIAL: For Training Purposes OnlyNot for Promotional Use

Impaired insulin secretion resulting from declining beta-cell function

Excess hepatic glucose production due to increased glucagon secretion and

In the face of insulin resistance, the beta-cells compensate by producing a greater

CONFIDENTIAL: For Training Purposes OnlyNot for Promotional Use 13

Table 2. Presenting Symptoms of Patients With Type 2 Diabetes

14 CONFIDENTIAL: For Training Purposes OnlyNot for Promotional Use

POPULATIONS AT RISK FOR DEVELOPING TYPE 2 DIABETES

Impaired Fasting Glucose and Impaired Glucose Tolerance

CONFIDENTIAL: For Training Purposes OnlyNot for Promotional Use 15

Table 3. Diagnostic Glucose Values and A1C Levels

Diagnostic Glucose Values and A1C Levels From the ADA

16 CONFIDENTIAL: For Training Purposes OnlyNot for Promotional Use

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