Owing to concerns about the effects of hypoglycemia and new trials
indicating a lack of benefit of very tight glucose control in acutely ill
patients, the current-recommended goal BG in hospitalized patients is
Although acute hyperglycemic crises can occur in patients with diabetes,
most morbidity and mortality occurs over the course of years and can
be classified as either microvascular (nephropathy, neuropathy, and
retinopathy) or macrovascular (coronary heart disease (CHD), stroke,
and peripheral vascular disease).
Patients with established vascular disease should remain on lifelong
aspirin therapy, whereas patients without established vascular disease
need to be carefully considered to determine the appropriateness of
The incidence and severity of microvascular complications has a strong
correlation with long-term glycemic control as measured by A1C.
Macrovascular complications are influenced by glycemic control, but
are more dependent on multiple etiologic factors including dyslipidemia,
An estimated 29.1 million people, or 9.3% of the US population, currently have
1 Of these, 8.1 million or about one-third are undiagnosed. In 2012 alone,
more than 1.7 million new cases in adults were diagnosed. Globally, the prevalence
of diabetes for all ages is estimated to be 2.8% in 2000 and projected to increase to
2 The incidence of Type 2 diabetes is now epidemic, with alarming
increases in prevalence in both adults and children. Estimates by the Centers for
Disease Control and Prevention indicate that new cases of diabetes annually will
increase from 8/1,000 people to about 15/1,000 in 2050, with as many as 1 in 3
Americans having diabetes in 2050.
3 The dramatic increase in Type 2 diabetes in the
population is related to obesity and decreased physical activity levels, and also the
fact that people with diabetes are living longer. Additional individual factors include
a genetic predisposition for increased insulin resistance and progressive β-cell
failure. Clinical studies have affirmed that Type 2 diabetes can be delayed or
prevented in high-risk populations and that good glycemic control and other
interventions can slow its devastating complications.
DEFINITION, CLASSIFICATION, AND
Diabetes is a chronic condition caused by an absolute lack of insulin or relative lack
of insulin as a result of impaired insulin secretion and action. Its hallmark clinical
characteristics are symptomatic glucose intolerance resulting in hyperglycemia and
alterations in lipid and protein metabolism. In the long term, these metabolic
abnormalities contribute to the development of complications such as cardiovascular
disease (CVD), retinopathy, nephropathy, and neuropathy and a higher risk of
Genetically, etiologically, and clinically, diabetes is a heterogeneous group of
disorders. Nevertheless, most cases of diabetes mellitus can be assigned to Type 1 or
Type 2 diabetes (Table 53-1). The term gestational diabetes mellitus (GDM) is used
to describe glucose intolerance that has its onset during pregnancy. Glucose
intolerance that cannot be ascribed to causes consistent with these three
classifications includes specific genetic defects in β-cell function or insulin action
(usually genetically defective insulin receptors); diseases of the exocrine pancreas;
endocrinopathies; drug- or chemical-induced; infections; and other genetic
syndromes. Early glucose intolerance or “prediabetes” is identified as impaired
fasting glucose (IFG) or impaired glucose tolerance (IGT), and they are considered
risk factors for the future development of diabetes and are associated with obesity,
hypertriglyceridemia, and/or low high-density lipoprotein (HDL) cholesterol and
Approximately 5% to 10% of the diagnosed diabetic population has Type 1
have a tendency to develop ketoacidosis, and require exogenous insulin to sustain
life. The incidence of autoimmune-mediated Type 1 diabetes peaks during childhood
and adolescence, but it can occur at any age. A minority of patients diagnosed with
Type 1 diabetes, mostly of African or Asian ancestry, can have no evidence of
autoimmunity; the etiology is, therefore, unknown. In these individuals, the rate of
pancreatic destruction seems to occur more slowly, leading to a later onset and less
Most people with diabetes have Type 2 diabetes, a heterogeneous disorder that is
characterized by obesity, β-cell dysfunction, resistance to insulin action, and
increased hepatic glucose production. Both the incidence and prevalence of diabetes
increase dramatically with age, obesity, and lack of physical activity.
States, the percentage of patients with diagnosed or undiagnosed diabetes in those 20
to 44 years of age is 4.1%. This increases to 25.9% in those 65 and older.
prevalence of Type 2 diabetes also differs among ethnic populations. Relative to
non-Hispanic whites (7.6%), the prevalence of diagnosed diabetes is higher in
Asian-Americans (9%), Hispanics (12.8%), African-Americans (13.2%), and
American Indians and Alaskan Natives (15.9%).
1 Diabetes is a serious condition that
places people at risk for greater morbidity and mortality relative to the nondiabetic
population. Diabetes is the seventh leading cause of death in the United States,
although deaths attributed to diabetes and its complications are likely to be
underreported. Compared with the general population, the mortality rate for people
with diabetes is about twice that for people without diabetes.
Medical management of people with diabetes is costly. In 2012, the total cost of
diabetes in the United States was estimated to be $245 billion, with 1 of 5 healthcare
dollars being spent on people with diabetes.
8 The average healthcare expenditures
for people with diabetes were approximately 2.3 times higher than those for
individuals without diabetes. The majority (56%) of all healthcare expenditures
attributed to diabetes are used by people aged 65 years and older. Hospital inpatient
costs, nursing facility resources, home care, physician visits, and medications (not
just diabetes agents) made up the majority of these expenditures. Because many
expenditures are related to treatment of long-term complications, considerable effort
has been directed toward early diagnosis and metabolic control of patients with
Other names Previously, type I; insulin-dependent
diabetes mellitus (IDDM); juvenileonset diabetes mellitus
Previously, type II; non-insulindependent diabetes mellitus
Age at onset Usually <30 years; peaks at 12–14
years; rare before 6 months; some
adults develop type 1 during the fifth
Usually >40 years, but increasing
prevalence among obese children
Pancreatic function Usually none, although some residual
C-peptide can sometimes be detected
at diagnosis, especially in adults
Insulin present in low, “normal,” or
Pathogenesis Associated with certain HLA types;
presence of islet cell antibodies
Defect in insulin secretion; tissue
resistance to insulin; ↑ hepatic glucose
Family history Generally not strong Strong
Obesity Uncommon unless “overinsulinized”
History of ketoacidosis Often present Rare, except in circumstances of
unusualstress (e.g., infection)
Clinical presentation Moderate-to-severe symptoms that
generally progress relatively rapidly
(days to weeks): polyuria, polydipsia,
fatigue, weight loss, ketoacidosis
Mild polyuria, fatigue; often diagnosed
Physical activity Physical activity
Antidiabetic agents (biguanides,
thiazolidinediones, α-glucosidase
inhibitors, incretin mimetics/analogs,
DPP-4 inhibitors, SGLT-2 inhibitors)
DPP-4, dipeptidyl peptidase-4; HLA, human leukocyte antigen; MNT, medical nutrition therapy.
An understanding of the signs and symptoms associated with diabetes is based on a
knowledge of glucose metabolism and the metabolic effects of insulin in nondiabetic
and diabetic subjects during the fed (postprandial) and fasting (postabsorptive)
9 Homeostatic mechanisms maintain plasma glucose concentrations between 55
and 140 mg/dL. A minimum concentration of 40 to 60 mg/dL is required to provide
adequate fuel for the central nervous system, which uses glucose as its primary
energy source and is independent of insulin for glucose utilization. When BG
concentrations exceed the reabsorptive capacity of the proximal tubule in the kidneys
(~180 mg/dL), glucose spills into the urine (glucosuria), resulting in a loss of
calories and water. Muscle and fat, which use glucose as a major source of energy,
require insulin for glucose uptake. If glucose is unavailable, these tissues are able to
use other substrates such as amino acids and fatty acids for fuel.
Postprandial Glucose and Lipid Metabolism in the
After food is ingested, BG concentrations rise and stimulate insulin release. Insulin is
the key to efficient glucose utilization. It promotes the uptake of glucose, fatty acids,
and amino acids, and their conversion to storage forms in most tissues. Insulin also
inhibits hepatic glucose production by suppressing glucagon and its effects. In
muscle, insulin promotes the uptake of glucose and its storage as glycogen. It also
stimulates the uptake of amino acids and their conversion to protein. In adipose
tissue, glucose is converted to free fatty acids and stored as triglycerides. Insulin also
prevents a breakdown of these triglycerides to free fatty acids, a form that may be
transported to other tissues for utilization. The liver does not require insulin for
glucose transport, but insulin facilitates the conversion of glucose to glycogen and
suppresses VLDL secretion by reducing the production of fatty acids in the liver.
Once secreted by the liver, VLDL is acted on primarily by hepatic lipase in the liver
and by lipoprotein lipase on endothelial cells.
10 Acting through apolipoprotein (apo)
CII on the surface of the VLDL particle, these lipases remove free fatty acids from
the lipoprotein and convert VLDL to intermediate-density lipoprotein (IDL) and then
IDL to low-density lipoprotein (LDL). Insulin plays a role in stimulating apoCII
expression, which partly explains the hypertriglyceridemia that occurs in Type 2
Fasting Glucose Metabolism in the Nondiabetic
As BG concentrations drop toward normal during the fasting state, insulin release is
inhibited. Simultaneously, a number of counter-regulatory hormones that oppose the
effect of insulin and promote an increase in blood sugar are released (e.g., glucagon,
epinephrine, growth hormone, cortisol). As a result, several processes maintain a
minimum BG concentration for the central nervous system. Glycogen in the liver is
broken down into glucose (glycogenolysis). Amino acids are transported from
muscle to liver, where they are converted to glucose through gluconeogenesis. Uptake
of glucose by insulin-dependent tissues is diminished to conserve glucose for the
brain. Finally, triglycerides are broken down into free fatty acids, which are used as
The loss of insulin secretion in Type 1 diabetes mellitus results from autoimmune
destruction of the insulin-producing β-cells in the pancreas, which is thought to be
triggered by environmental factors, such as viruses or toxins, in genetically
7,11 This form of diabetes is associated closely with
histocompatibility antigens (human leukocyte antigen [HLA]-DR3 or HLA-DR4) and
the presence of circulating antibodies, including insulin autoantibodies, glutamic acid
decarboxylase autoantibodies (GAD65), islet cell autoantibodies (ICA), and
autoantibodies to tyrosine phosphatases (e.g., islet cell antibody 512). The capacity
of normal pancreatic β-cells to secrete insulin far exceeds the normal amounts
needed to control carbohydrate, fat, and protein metabolism. As a result, the clinical
onset of Type 1 diabetes is preceded by an extensive asymptomatic period during
which β-cells are destroyed (Fig. 53-1). β-cell destruction may occur rapidly, but is
more likely to take place over a period of weeks, months, or even years. The earliest
detectable abnormality in insulin secretion is a progressive reduction of immediate
or first-phase plasma insulin response. However, this initial impairment has few
detrimental effects on overall glucose homeostasis, and plasma glucose
concentrations remain normal. Most affected individuals have circulating antibodies
to islet cells or to their own insulin at this stage of the disease. These represent
markers of an ongoing autoimmune process that culminates in Type 1 diabetes.
Fasting hyperglycemia occurs when the β-cell mass is reduced by 80% to 90%. One
or more of the above autoantibodies is usually present in 85% to 90% of individuals
at this point. Initially, only postprandial hyperglycemia occurs, but as insulin
secretion becomes further compromised, progressive fasting hyperglycemia is seen.
Within 8 to 10 years of clinical presentation, β-cell loss is complete and insulin
Although the onset of Type 1 diabetes seems to be abrupt, evidence now exists for an
extended preclinical period that can precede obvious symptoms by several years.
Because insulin secretion becomes compromised, progressive fasting hyperglycemia
occurs. Glucosuria, which occurs when BG levels exceed the renal threshold, results
in an osmotic diuresis, producing the classic symptoms of polyuria with
compensatory polydipsia. If symptoms are untreated, weight loss occurs because
glucose calories are lost in the urine and body fat and protein stores are broken down
owing to increased rates of lipolysis and proteolysis. Muscle begins to metabolize its
own glycogen stores and fatty acids for fuel, and the liver begins to metabolize free
fatty acids that are released in response to epinephrine and low insulin
concentrations. An absolute lack of insulin may cause excessive mobilization of free
fatty acids to the liver, where they are metabolized to ketones. This can result in
ketonemia, ketonuria, and, ultimately, ketoacidosis. Patients present with complaints
of fatigue, significant weight loss, polyuria, and polydipsia. A significant elevation in
A1C confirms weeks or months of preceding hyperglycemia.
Because glucose provides an excellent medium for microorganisms, patients may
present also with recurrent respiratory, vaginal, and other infections. Patients also
may experience blurred vision secondary to osmotically induced changes in the lens
of the eye. Treatment with insulin is essential to prevent severe dehydration,
Within days or weeks after the initial diagnosis and implementing treatment, many
patients with Type 1 diabetes experience an apparent remission, which is reflected
by decreased BG concentrations and markedly decreased insulin requirements. This
is called the honeymoon period because it may last for only a few weeks to months.
Once hyperglycemia, metabolic acidosis, and ketosis resolve, endogenous insulin
secretion recovers temporarily (Fig. 53-1). Although the honeymoon period may last
for up to a year, increasing exogenous insulin requirements are inevitable and should
be anticipated. During this time, patients should be maintained on insulin even if the
dose is very low, because interrupted treatment is associated with a greater
incidence of resistance and allergy to insulin.
Type 2 diabetes is characterized by impaired insulin secretion and resistance to
insulin action. In the presence of insulin resistance,
glucose utilization by tissues is impaired, hepatic glucose and free fatty acid
production is increased, and excess glucose accumulates in the circulation. This
hyperglycemia stimulates the pancreas to produce more insulin in an attempt to
overcome insulin resistance. The simultaneous elevation of both glucose and insulin
levels is strongly suggestive of insulin resistance. Genetic predisposition may play a
role in the development of Type 2 diabetes. People with Type 2 diabetes have a
stronger family history of diabetes than those with Type 1. There is no association
with HLA types, however, and circulating ICAs are absent.
diabetes also exhibit varying degrees of tissue resistance to insulin, impaired insulin
secretion, and increased basal hepatic glucose production. Finally, environmental
factors such as obesity and a sedentary lifestyle also contribute to the development of
Despite being the most common form of diabetes, the exact pathogenesis of Type 2
is less well understood. Basal insulin levels are typically normal or elevated at
diagnosis. First- or early-phase insulin release in response to glucose often is
reduced, and pulsatile insulin secretion is absent, resulting in postprandial
hyperglycemia. The effects of other insulinotropic substances such as incretin
hormones, which contribute to meal-stimulated insulin release, are also altered.
With time, β-cells lose their ability to respond to elevated glucose concentrations,
leading to increasing loss of glucose control. In patients with severe hyperglycemia,
the amount of insulin secreted in response to glucose is diminished and insulin
resistance is worsened (glucose toxicity).
Most individuals with Type 2 exhibit decreased tissue responsiveness to insulin.
Excess weight or hyperglycemia may contribute to hyperinsulinemia, which in time
may lead to a decrease in or downregulation of the number of insulin receptors on the
surface of target tissues and organs. Evidence suggests that decreased peripheral
glucose uptake and utilization in muscle is the primary site of insulin resistance and
results in prolonged postprandial hyperglycemia. Resistance may be secondary to
decreased numbers of insulin receptors on the cell surface, decreased affinity of
receptors for insulin, or defects in insulin signaling and action that follows receptor
binding. Defects in insulin signaling and action are referred to as postreceptor or
postbinding defects and are likely to be the primary sites of insulin resistance.
Patients with Type 2 diabetes also exhibit increased hepatic glucose production
(glycogenolysis and gluconeogenesis) reflected by an elevated fasting plasma or BG
12 As noted, hepatic glucose production is the primary source of
glucose in the fasting state. In patients with Type 2 diabetes, altered hepatic glucose
production may also contribute to or cause postprandial hyperglycemia. Glucagon,
produced by the α-cells in the pancreatic islets and secreted in response to low BG,
stimulates hepatic glucose production.
Its production is inhibited by insulin.
Glucagon response to carbohydrate ingestion is altered in patients with Type 2
diabetes who have a defective or absent early insulin response secondary to β-cell
dysfunction or failure. For patients with Type 2 diabetes, untreated fasting and
postprandial hyperglycemia caused by decreased glucose uptake and increased
hepatic glucose production, hyperinsulinemia, and insulin resistance lead to a vicious
cycle that inflicts ongoing damage to tissues and organs.
Patients with Type 2 diabetes are often subclassified based on weight. Obese
individuals account for more than 80% of patients with Type 2 diabetes.
with Type 2 diabetes who are not obese often have increased body fat distributed in
the abdominal area. Nonobese individuals account for about 10% of the Type 2
population. Typically, they develop a mild form of diabetes during childhood,
adolescence, or as young adults (usually before age 25), and their insulin levels are
low in response to a glucose challenge. Included in this group are patients who have
maturity-onset diabetes of the young (MODY).
7,12 MODY is associated with a strong
family history that suggests an autosomal-dominant transmission. The underlying
defect is heterogeneous, and multiple abnormalities at loci on different chromosomes
have been discovered. More common defects include those for hepatic transcription
factors and glucokinase (the “glucose sensor” in β-cells). Patients with MODY may
present with moderate-to-severe symptoms with or without ketosis. Unlike Type 1
diabetes, however, the disease generally is mild and controlled with diet, oral
agents, or low doses of insulin. With the increasing prevalence of obesity and Type 2
diabetes in children and adolescents, it is important to distinguish between a youth
with Type 2 diabetes and one who really has autoimmune Type 1 diabetes and is also
Type 2 diabetes is associated with a variety of disorders, including dyslipidemia,
hypertension, and premature atherosclerosis (Fig. 53-2). Currently termed the
metabolic syndrome, this triad of clinical findings (hypertension, elevated fasting
glucose, and dyslipidemia) is proposed to derive from insulin resistance itself and
the resulting compensatory hyperinsulinemia.
16 The labeling of this triad as a separate
“syndrome” remains the subject of considerable debate, partly because it appears to
have little diagnostic utility beyond its component parts.
common in the United States, with an estimated prevalence of more than 34% in
adults aged 20 and older, peaking among those 60 to 69 years of age.
highly correlated with cardiovascular events, the National Cholesterol Education
Program has suggested criteria for the diagnosis of metabolic syndrome.
individuals with the metabolic syndrome progress to IGT or diabetes, but those who
do may be genetically predisposed to β-cell dysfunction. Figure 53-3 depicts the
typical dyslipidemia pattern seen in diabetes and how insulin resistance affects
normal lipoprotein metabolism.
to develop IGT, IFG, and type 2 diabetes. Many people with type 2 diabetes already have evidence of
discussion. DM, diabetes mellitus; HTN, hypertension.
before the onset of overt diabetes.
Type 2 diabetes is typically diagnosed incidentally during a routine physical
examination or when the patient seeks attention for another complaint. Because
symptoms are mild in their onset, patients will rarely complain of fatigue, polyuria,
and polydipsia but may admit to them during clinical examination. Because these
patients have sufficient insulin concentrations to prevent lipolysis, there is usually no
history of ketosis except in situations of unusual stress (e.g., infections, trauma).
Weight loss is therefore uncommon because relatively high endogenous insulin levels
promote lipogenesis. Macrovascular disease is also often evident at diagnosis.
Microvascular complications at diagnosis suggest the presence of undiagnosed or
subclinical diabetes for 7 to 10 years. Because Type 2 diabetes patients retain some
pancreatic reserve at the time of diagnosis, they generally can be treated with MNT,
physical activity, and noninsulin antidiabetic medications for several years.
Nevertheless, many eventually require insulin for control of their symptoms.
The ADA advises that adults without risk factors should be screened starting at age
7 Repeat testing should take place every 3 years if results are normal or yearly if
they have prediabetes. Adults may be tested at a younger age and more frequently if
they are overweight (body mass index [BMI] ≥25 or 35 kg/m2
and have one or more of the risk factors listed in Table 53-2. A FPG or A1C is
preferred over the OGTT to test for diabetes, because they are much less
cumbersome. Asymptomatic children who are age 10 or who experience the onset of
puberty before age 10 should be screened every 2 years for Type 2 diabetes if they
are overweight (BMI >85th percentile for age and sex; weight for height >85th
percentile; or weight >120% of ideal for height) and have two or more of the risk
GDM affects about 7% of all pregnancies and is defined as “any carbohydrate
intolerance with onset or first recognition during pregnancy.”
diabetes during pregnancy and its duration affect the prognosis for a good obstetric
and perinatal outcome (see Chapter 49, Obstetric Drug Therapy).
The categories for normal, increased risk for diabetes, and diabetes for FPG, A1C,
and the OGTT are listed in Table 53-3.
7 The Expert Committee of the ADA has
established the diagnostic criteria for diabetes for nonpregnant individuals of any
age. For these individuals, a diagnosis of diabetes can be made when one of the
An A1C of 6.5% or more. The test must be performed in a laboratory (not with a
point-of-care test). It should be performed using a method certified by the National
Glycohemoglobin Standardization Program.
An FPG of 126 mg/dL or more. Fasting means no caloric intake for at least 8 hours.
Classic signs and symptoms of diabetes (polyuria, polydipsia, ketonuria, and
unexplained weight loss) combined with a random plasma glucose of 200 mg/dL
After a standard OGTT (75 g of glucose for an adult or 1.75 g/kg for a child), the
venous plasma glucose concentration is 200 mg/dL or more at 2 hours.
The diagnosis must be confirmed by repeating the test, preferably the same test. If
two different tests are performed (e.g., FPG and A1C), and both are above the
diagnostic threshold, then diabetes is confirmed. If only one test’s value is above the
diagnostic cut point, the test that is above the diagnostic cut point should be repeated.
The diagnosis is made based on the results of the confirmed test.
At times, it may be difficult to classify patients as having Type 1 or Type 2
diabetes mellitus. Type 1 is more likely when a patient is younger than 30 years of
age and lean, and has an elevated FPG and signs and symptoms of diabetes. The
presence of moderate ketonuria with hyperglycemia in an otherwise unstressed
patient also strongly supports a diagnosis of Type 1 diabetes. Absence of ketonuria,
however, is not of diagnostic value. The presence of autoantibodies to insulin or islet
cell components may also indicate the need for eventual insulin therapy.
lean older adults believed to have Type 2 diabetes because they are initially
responsive to oral agents or low doses of insulin may be subsequently diagnosed
with Type 1 diabetes. In addition, clinicians are beginning to observe more cases of
Type 2 diabetes in obese children and adolescents.
Risk Factors for Type 2 Diabetes Mellitus
Overweight (BMI >85th percentile for age and sex; or
weight >120% of ideal for height)
Previous IFG, IGT, or A1C ≥5.7%
History of PCOS, GDM, or macrosomia Maternal history of diabetes (including GDM)
Clinical conditions associated with insulin resistance
(e.g., severe obesity and acanthosis nigricans)
Signs of insulin resistance (e.g., acanthosis nigricans)
Hypertension (≥140/90 mm Hg or on antihypertensive
Conditions associated with insulin resistance (e.g.,
hypertension, dyslipidemia, or PCOS)
Triglyceride >250 mg/dL (2.82 mmol/L)
aChildren are younger than 18 years of age.
Normal and Diabetic Plasma Glucose Levels in mg/dL (mmol/L) and
Glycosylated Hemoglobin (A1C) and Normal and Diabetic Plasma Glucose
Levels for the Oral Glucose Tolerance Test (OGTT)
Normal <100 (5.6) ≤5.6% <140 (7.8)
Prediabetes (i.e., impaired fasting glucose
(IFG), impaired glucose tolerance (IGT))
100–125 (5.6–6.9) ≥5.7–6.4% 140–199 (7.8–11.0)
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