CHAPTER
46
Drugs for
Diabetes Mellitus
Laura D. Rosenthal DNP,
ACNP, FAANP
Diabetes Mellitus: Basic Considerations
The
term diabetes mellitus is derived from the Greek word
for fountain and the Latin word for honey. The
term describes one of the prominent symptoms of untreated diabetes: production
of large volumes of glucose-rich urine. Indeed, long ago, the disease we now
call diabetes was “diagnosed” by the sweet smell of urine—and, yes, by its
sweet taste, too. In this chapter we use the terms diabetes mellitus and diabetes interchangeably.
Diabetes is primarily a disorder of carbohydrate metabolism.
Symptoms mainly result from a deficiency of insulin or from cellular resistance
to insulin's actions. The principal sign of diabetes is sustained
hyperglycemia, which results from impaired glucose uptake by cells and
from increased glucose production. When hyperglycemia develops, it can quickly
lead to polyuria, polydipsia, ketonuria, and weight loss. Over time, hyperglycemia
can lead to heart disease, renal failure, blindness, neuropathy, amputations,
impotence, and stroke. There is an often-overlooked point about diabetes: in
addition to affecting carbohydrate metabolism, insulin deficiency disrupts
metabolism of proteins and lipids. We refer to regulation of blood glucose
levels as glycemic control.
In the United States diabetes is the most common endocrine
disorder and the seventh leading cause of death by disease. According to the
2011 National Diabetes Fact Sheet, compiled by the Centers for Disease Control
and Prevention, about 26 million Americans have diabetes, and nearly one fourth
of them have not been diagnosed. Another 79 million or so Americans are
estimated to have prediabetes and are at increased risk for developing diabetes
in the future.
We need to do a better job of diagnosing diabetes and
treating it—and we need to do what we can to reduce the risk for developing the
disease in the first place. Unfortunately, the risk for developing diabetes is
largely genetic, a factor that can't be modified. Nonetheless, we can still
reduce risk significantly by adopting a healthy lifestyle, centered on engaging
in physical activity and establishing a healthy diet.
Types of Diabetes Mellitus
There are
two main forms of diabetes mellitus: type 1 diabetes mellitus (often
abbreviated as T1DM) and type 2 diabetes mellitus (often abbreviated as T2DM).
Both forms have similar signs and symptoms. Major differences concern etiology,
prevalence, treatments, and outcomes (illness severity and deaths). The
distinguishing characteristics of type 1 and type 2 diabetes are shown in Table 46.1 and discussed later. Another important
form—gestational diabetes—is discussed later under “Diabetes and Pregnancy.”
Although there are additional forms of diabetes, they are relatively rare and
will not be discussed specifically here.
TABLE 46.1
Characteristics
of Type 1 and Type 2 Diabetes Mellitus |
||
Type of
Diabetes Mellitus |
||
Characteristics |
Type 1 |
Type 2 |
Age of onset |
Usually childhood or adolescence |
Usually older than 40 years |
Speed of onset |
Abrupt |
Gradual |
Family history |
Frequently negative |
Frequently positive |
Prevalence |
Approximately 5% of people with
diabetes have type 1 diabetes |
90%–95% of people with diabetes
have type 2 diabetes |
Etiology |
Autoimmune process |
Unknown—but there is a strong
familial association, suggesting that heredity is a risk factor |
Primary defect |
Loss of pancreatic beta cells |
Insulin resistance and
inappropriate insulin secretion |
Insulin levels |
Reduced early in the disease and
completely absent later |
Levels may be low (indicating
deficiency), normal, or high (indicating resistance) |
Treatment |
Insulin replacement is mandatory,
along with strict dietary control |
Treat with an oral antidiabetic or
noninsulin injectable agent and/or insulin, but always in combination with a
reduced-calorie diet and appropriate exercise |
Blood glucose |
Levels fluctuate widely in
response to infection, exercise, and changes in caloric intake and insulin
dose |
Levels are generally more stable
than in type 1 diabetes |
Symptoms |
Polyuria, polydipsia, polyphagia,
weight loss |
May be asymptomatic initially |
Body composition |
Usually thin and undernourished at
diagnosis |
Frequently obese |
Ketosis |
Common, especially if insulin
dosage is insufficient |
Uncommon |
Type 1 Diabetes
Type 1
diabetes accounts for about 5% of all diabetes cases. Between 1.2 million and
2.4 million Americans have this disorder. In the past, type 1 diabetes was
called juvenile-onset diabetes mellitus or insulin-dependent
diabetes mellitus (IDDM). These terms have fallen out of favor,
however, because type 2 diabetes is becoming more common in children, and many
people with type 2 diabetes use insulin to manage their diabetes. Accordingly,
the terms juvenile-onset diabetes mellitus and IDDM are
no longer clinically useful. Generally, type 1 diabetes develops during
childhood or adolescence, and symptom onset is relatively abrupt. That being
said, type 1 diabetes can develop during adulthood.
The primary defect in type 1 diabetes is destruction of
pancreatic beta cells—the cells responsible for insulin synthesis and release
into the bloodstream. Insulin levels are reduced early in the disease and
usually fall to zero later. Beta cell destruction is the result of an
autoimmune process (i.e., the patient's immune system inappropriately wages war
against its own beta cells). The trigger for this immune response is not
entirely known, but genetic, environmental, and infectious factors likely play
a role.
Type 2 Diabetes
Type 2
diabetes is the most prevalent form of diabetes, accounting for 90% to 95% of
all diagnosed cases. Approximately 22 million Americans have this disease. In
the past, type 2 diabetes was called non–insulin-dependent diabetes
mellitus (NIDDM) or adult-onset diabetes mellitus. As
discussed previously for type 1 diabetes, these terms are no longer clinically
useful because insulin is commonly used by people with type 2 diabetes and type
2 diabetes can occur in all age groups. The disease most commonly begins in
middle age and progresses gradually. In contrast to type 1 diabetes, type
2 diabetes carries little risk for ketoacidosis. However, type 2 diabetes does
carry the same long-term risks as type 1 diabetes (see later).
Symptoms of type 2 diabetes usually result from a
combination of insulin resistance and impaired insulin
secretion. In contrast to patients with type 1 diabetes, those with
type 2 diabetes are capable of insulin synthesis. In fact, early in the
disease, insulin levels tend to be normal or slightly elevated, a state known
as hyperinsulinemia. However, although insulin is still
produced, its secretion is no longer tightly coupled to plasma glucose content:
release of insulin is delayed, and peak output is subnormal. More important,
the target tissues of insulin (liver, muscle, adipose tissue) exhibit insulin
resistance: for a given blood insulin level, cells in these tissues are less
able to take up and metabolize the glucose available to them. Insulin
resistance appears to result from three causes: reduced binding of insulin to
its receptors, reduced receptor numbers, and reduced receptor responsiveness.
Over time, hyperglycemia leads to diminished pancreatic beta cell function, and
hence insulin production and secretion eventually decline as the beta cells
work harder to overcome insulin resistance within the tissues.
Although the underlying causes of type 2 diabetes are not
entirely known, there is a strong familial association, suggesting that
genetics play a role. This possibility was reinforced by a study that
implicated the gene for insulin receptor substrate-2 (IRS-2),
a compound that helps mediate intracellular responses to insulin.
Diabetes and Pregnancy
Before the
discovery of insulin, virtually all babies born to mothers with severe diabetes
died during infancy. Although insulin therapy has greatly improved outcomes,
successful management of the diabetic pregnancy remains a challenge. Three
factors contribute to the problem. First, the placenta produces hormones that
antagonize insulin's actions. Second, production of cortisol, a hormone that
promotes hyperglycemia, increases threefold during pregnancy. Both factors
increase the body's need for insulin. And third, because glucose can pass
freely from the maternal circulation to the fetal circulation, hyperglycemia in
the mother will stimulate excessive secretion of insulin in the fetus. The
resultant hyperinsulinism can have multiple adverse effects on the fetus.
Successful management of diabetes during pregnancy demands
that proper glucose levels be maintained in both the mother and fetus; failure
to do so may be teratogenic or may otherwise harm the fetus. Achieving glucose
control requires diligence on the part of the mother and her prescriber. Some
experts on diabetes in pregnancy advise that blood glucose levels must be monitored
6 to 7 times a day. Insulin dosage and food intake must be adjusted
accordingly.
Gestational diabetes is defined as diabetes that appears in the pregnant
patient during pregnancy and then subsides rapidly after delivery. Gestational
diabetes is managed in much the same manner as any other diabetic pregnancy:
blood glucose should be monitored and then controlled with diet and insulin. In
most cases, the diabetic state disappears almost immediately after delivery,
permitting discontinuation of insulin. However, if the diabetic state persists
beyond parturition, it is no longer considered gestational and should be
rediagnosed and treated accordingly.
In women taking an oral drug for type 2 diabetes, current
practice is to discontinue the oral drug and switch to insulin. The only
exception is the oral agent metformin, which is often satisfactory for managing
type 2 diabetes in pregnancy. Women who discontinue oral medications can resume
oral therapy after delivery.
Diagnosis
Diagnosis
of diabetes was once made solely by measuring blood levels of glucose. However,
in 2010, the American Diabetes Association (ADA) recommended an alternative
test, based on measuring hemoglobin A1c—a
test that provides an estimate of glycemic control over the previous 2 to
3 months. For all of these tests, diagnostic values of diabetes are shown
in Table 46.2.
TABLE 46.2
Criteria for the Diagnosis of
Diabetes Mellitus |
Fasting plasma glucose ≥126 mg/dL* |
or |
Casual plasma glucose ≥
200 mg/dL plus symptoms of diabetes† |
or |
Oral glucose tolerance test
(OGTT): 2-hr plasma glucose ≥200 mg/dL‡ |
or |
Hemoglobin A1c 6.5% or higher |
*Fasting is defined as no caloric intake for at
least 8 hours.
†Casual is defined as any time of day without
regard to meals. Classical symptoms of diabetes include polyuria, polydipsia,
and unexplained weight loss.
‡In this OGTT, plasma glucose content is measured
2 hours after ingesting the equivalent of 75 g of anhydrous glucose dissolved
in water. The OGTT is not recommended or needed for routine clinical use.
Data from Standards of Medical Care in Diabetes—2014. Diabetes
Care 2014;37(Suppl 1):S14-S80.
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