eMedicine - Diabetes Mellitus, Type 2 - A Review : Article by Scott R Votey
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Diabetes Mellitus, Type 2 - A Review
Article Last Updated: Jun 6, 2007
AUTHOR AND EDITOR INFORMATION
Authors and Editors Introduction
Miscellaneous References
Clinical
Differentials
Section 1 of 10
Workup
Treatment
Medication
Follow-up
Author: Scott R Votey, MD, Assistant Dean for Graduate Medical Education, Professor of
Medicine/Emergency Medicine, David Geffen School of Medicine at UCLA, UCLA Medical
Center
Scott R Votey is a member of the following medical societies: Society for Academic Emergency
Medicine
Coauthor(s): Anne L Peters, MD, Director of Clinical Diabetes Program, Professor, Department
of Medicine, Los Angeles County/University of Southern California Medical Center
Editors: Erik D Schraga, MD, Consulting Staff, Permanente Medical Group, Kaiser
Permanente, Santa Clara Medical Center; Francisco Talavera, PharmD, PhD, Senior
Pharmacy Editor, eMedicine; Howard A Bessen, MD, Professor of Medicine, Department of
Emergency Medicine, UCLA School of Medicine; Program Director, Harbor-UCLA Medical
Center; John Halamka, MD, Chief Information Officer, CareGroup Healthcare System,
Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess
Medical Center; Assistant Professor of Medicine, Harvard Medical School; Barry E Brenner,
MD, PhD, FACEP, Program Director, Department of Emergency Medicine, University Hospitals,
Case Medical Center
Author and Editor Disclosure
Synonyms and related keywords: DM, type 2 DM, type 2 diabetes, type II diabetes, noninsulin-dependent diabetes, non–insulin-dependent diabetes mellitus, adult-onset diabetes,
adult-onset diabetes mellitus, maturity-onset diabetes, maturity-onset diabetes mellitus,
maturity-onset diabetes of the young, MODY, amputation, nontraumatic lower-extremity
amputation, end-stage renal disease, ESRD, macrovascular disease, diabetic foot, obesity,
hypoglycemia, diabetic ketoacidosis, hyperosmolar nonketotic syndrome, HNKS, insulin
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resistance, gestational diabetes mellitus, GDM, hyperglycemia, retinopathy, nephropathy,
neuropathy, HbA1c, hypertension, coronary artery disease, CAD, peripheral vascular disease,
cerebrovascular disease, hyperlipidemia, latent autoimmune diabetes of the adult, LADA,
prediabetes, metabolic syndrome, syndrome X, insulin-resistance syndrome
Section 2 of 10
INTRODUCTION
Authors and Editors Introduction
Miscellaneous References
Clinical
Differentials
Workup
Treatment
Medication
Follow-up
Background
Diabetes mellitus is a chronic disease that requires long-term medical attention both to limit the
development of its devastating complications and to manage them when they do occur. It is a
disproportionately expensive disease; patients diagnosed with diabetes accounted for 6.2% of
the US population in 2002, or 18.2 million people. In that year, the per capita cost of healthcare
for people with diabetes was $13,243 for people with diabetes and $2560 for people without
diabetes.
This article focuses on the ED evaluation and treatment of the acute and chronic complications
of diabetes other than those directly associated with hypoglycemia and severe metabolic
disturbances such as diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic syndrome
(HHS). (Please see Hypoglycemia, Diabetic Ketoacidosis, and Hyperosmolar Hyperglycemic
Nonketotic Coma for more information on these disorders.)
Pathophysiology
The 2 basic types of diabetes mellitus are type 1 and type 2. Type 1 diabetes is reviewed more
fully in a separate eMedicine article (see Diabetes Mellitus, Type 1 - A Review).
Type 2 diabetes mellitus was once called adult-onset diabetes. Now, because the epidemic of
obesity and inactivity in children, type 2 diabetes is occurring at younger and younger ages.
Although type 2 diabetes typically affects individuals older than 40 years, it has been diagnosed
in children as young as 2 years of age who have a family history of diabetes.
Type 2 diabetes is characterized by peripheral insulin resistance with an insulin-secretory defect
that varies in severity. For type 2 diabetes to develop, both defects must exist: All overweight
individuals have insulin resistance, but only those with an inability to increase beta-cell
production of insulin develop diabetes. In the progression from normal glucose tolerance to
abnormal glucose tolerance, postprandial glucose levels first increase. Eventually, in hepatic
gluconeogenesis increases, resulting in fasting hyperglycemia.
About 90% of patients who develop type 2 diabetes are obese. Because patients with type 2
diabetes retain the ability to secrete some endogenous insulin, those who are taking insulin do
not develop DKA if they stop taking it for some reason. Therefore, they are considered to require
insulin but not to depend on insulin. Moreover, patients with type 2 diabetes often do not need
treatment with oral antidiabetic medication or insulin if they lose weight.
Maturity-onset diabetes of the young (MODY) is a form of type 2 diabetes that affects many
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generations in the same family with an onset in individuals younger than 25 years. Several types
exist. Some of the genes responsible can be detected by using commercially available assays.
Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset
or first recognition during pregnancy. GDM is a complication in approximately 4% of all
pregnancies in the United States, though the rates may be 1-14% depending on the population
studied. Untreated GDM can lead to fetal macrosomia, hypoglycemia, hypocalcemia, and
hyperbilirubinemia. In addition, mothers with GDM have increased rates of cesarean delivery
and chronic hypertension. To screen for GDM, a 50-g glucose screening test should be done at
24-28 weeks of gestation. This is followed by a 100-g, 3-hour oral glucose tolerance test if the
patient's plasma glucose concentration at 1 hour after screening is greater than >140 mg/dL.
Frequency
United States
Approximately 13 million people in the United States have a diagnosis of diabetes, and diabetes is undia
another 5 million. Approximately 10% have type 1 diabetes, and the rest have type 2.
Mortality/Morbidity
The morbidity and mortality associated with diabetes are related to the short- and long-term complication
Complications include hypoglycemia and hyperglycemia, increased risk of infections, microvascula
complications (eg, retinopathy, nephropathy), neuropathic complications, and macrovascular disea
Diabetes is the major cause of blindness in adults aged 20-74 years, as well as the leading cause o
nontraumatic lower-extremity amputation and end-stage renal disease (ESRD).
Race
Type 2 diabetes mellitus is more prevalent among Hispanics, Native Americans, African Americans, and
Asians/Pacific Islanders than in non-Hispanic whites.
Sex
The incidence is essentially equal in women and men in all populations.
Age
Type 2 diabetes is becoming increasingly common because people are living longer, and the preva
diabetes increases with age.
It is also seen more frequently now than before in young people, in association with the rising preva
childhood obesity.
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Although type 2 diabetes still occurs most commonly in adults aged 40 years or older, though the in
disease is increasing more rapidly in adolescents and young adults than in other age groups.
Section 3 of 10
CLINICAL
Authors and Editors Introduction
Miscellaneous References
Clinical
Differentials
Workup
Treatment
Medication
Follow-up
History
Correctly determining whether a patient has type 1 or type 2 diabetes is extremely important because pa
type 1 diabetes are dependent on a continuous source of exogenous insulin and carbohydrates for surviv
with type 2 diabetes may not need treatment for hyperglycemia during periods of fasting or decreased or
patient whose diabetes is controlled with diet or an oral antidiabetic agent clearly has type 2 diabetes. A
who has had diabetes since childhood, who has always been dependent on insulin, or who has a history
almost certainly has type 1 diabetes.
Distinguishing the type of diabetes can be difficult in (1) patients who are treated with insulin and are you
clinically appear to have type 2 diabetes and (2) older patients with late onset of diabetes who nonethele
insulin and seem to share characteristics of patients with type 1 diabetes. (This latter group is now said t
autoimmune diabetes of the adult [LADA]). When in doubt, treat the patient with insulin and closely moni
glucose levels. Some adolescents or young adults, mostly Hispanic or African American patients, who pr
with classic DKA are subsequently found to have type 2 diabetes.
Many patients with type 2 diabetes are asymptomatic, and their disease is undiagnosed for many years.
suggest that the typical patient with new-onset type 2 diabetes has had diabetes for at least 4diagnosed. Among patients with type 2 diabetes, 25% are believed to have retinopathy; 9%, neuropathy;
nephropathy at the time of diagnosis.
Prediabetes often precedes overt type 2 diabetes. Prediabetes is defined by a fasting blood glucose leve
mg/dL. Patients who have prediabetes have an increased risk for macrovascular disease, as well as diab
Often confused with prediabetes is the metabolic syndrome (also called syndrome X or the insulin
syndrome). Metabolic syndrome, thought to be due to insulin resistance, can occur in patients with overtl
glucose tolerance, prediabetes, or diabetes. It is characterized by central obesity, then by dyslipidemia. H
is a common feature. Eventually, clinically apparent insulin resistance develops. Unfortunately, insulin re
not measured clinically, except in research settings. An elevated fasting blood glucose level is the first in
insulin resistance, but fasting insulin levels are generally increased long before this occurs. Measuremen
insulin levels are not yet recommended for the diagnosis of insulin resistance. An effort to standardize in
is underway and may allow for the use of fasting insulin levels to diagnose insulin resistance in the future
See Workup for more information on diagnosis of diabetes. See Diabetes Mellitus, Type 1 - A Review
information on the symptomatic patient with diabetes.
During history taking, inquire about the type and duration of the patient's diabetes and about the care the
receiving for diabetes.
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Type and estimated of diabetes: This information helps to determine if the patient is insulin depend
diagnosis is based on history, therapy, and clinical judgment, as described above.
Diabetes care: Inquire about the patient's current treatment for diabetes and about his or her usual
blood glucose levels based on self-monitoring and/or recent measurements of hemoglobin A
indicator of long-term glucose control).
A focused diabetes history should include the following questions:
Is the patient's diabetes generally well controlled (with near-normal blood sugar levels)? Patients w
controlled blood glucose levels heal more slowly, and at increased risk for infection and other comp
Does the patient have severe hypoglycemic reactions? If the patient has episodes of severe hypog
therefore is at risk for losing consciousness, this possibility must be addressed, especially if the pat
Does the patient have peripheral neuropathy?
Are there any unrecognized foot ulcers or lesions that need treatment?
Does the patient have diabetic nephropathy that might alter use of medications or intravenous (IV)
contrast material?
Does the patient have macrovascular disease, such as coronary artery disease (CAD) that should
considered in the ED?
As circumstances dictate, additional questions may be warranted.
Diabetes care
What is the patient's diet? Does he or she use oral antidiabetic agents and/or insulin? If so, w
doses and frequencies of the medications?
Does the patient self-monitor his or her glucose levels? If yes, what is the frequency and the u
of values at each time of day?
When was the patient's HbA1C level last measured? What was it?
Does the patient adhere to a specific diet or exercise regularly?
Hyperglycemia: Ask about polyuria, polydipsia, nocturia, weight loss, and fatigue.
Hypoglycemia
Does patient have episodes of hypoglycemia? Are these episodes explicable? Are these epis
severe?
Does the patient require the assistance of another person for treatment?
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Does the patient have hypoglycemia unawareness (ie, does he or she lack adrenergic warnin
hypoglycemia)?
Retinopathy: When was the patient's last dilated eye examination? What were the results?
Nephropathy: Does the patient have known kidney disease? What were the results and dates
measurements of urine protein and serum creatinine levels?
Macrovascular complications
Hypertension: Does the patient have hypertension? What medications are taken?
CAD: Does the patient have CAD? Does the patient have a family history of CAD?
When and how often do these episodes occur? How does the patient treat them?
Microvascular complications
Page 6 of 30
Peripheral vascular disease: Does the patient have symptoms of claudication or a history of v
bypass?
Cerebrovascular disease: Has the patient had a cerebrovascular accident or transient ischem
Hyperlipidemia: What are the patient's most recent lipid levels? Is the patient taking lipid
medication?
Neuropathy: Does the patient have any history of neuropathy or symptoms of peripheral neur
autonomic neuropathy (including impotence if the patient is male)?
Diabetic foot: Does the patient have a history of foot ulcers or amputations? Are any foot ulce
Infections: Are frequent infections a problem?
Physical
A diabetes-focused examination includes vital signs, funduscopic examination, limited vascular and neur
examinations, and a foot assessment. Other organ systems should be examined as indicated by the pati
situation.
Assessment of vital signs
Is the patient hypertensive or hypotensive? Orthostatic vital signs may be useful in assessing
status and in suggesting the presence of an autonomic neuropathy.
If the respiratory rate and pattern suggest Kussmaul respiration, DKA must be considered imm
and appropriate tests ordered.
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Funduscopic examination
Page 7 of 30
The funduscopic examination should include a careful view of the retina, including both the op
the macula.
If hemorrhages or exudates are seen, the patient should be referred to an ophthalmologist as
possible. Examiners who are not ophthalmologists tend to underestimate the severity of retino
especially if the patients' pupils are not dilated.
Foot examination
The dorsalis pedis and posterior tibialis pulses should be palpated and their presence or abse
This is particularly important in patients who have foot infections because poor lower
can delay healing and increase the risk of amputation.
Documenting lower-extremity sensory neuropathy is useful in patients who present with foot u
because decreased sensation limits the patient's ability to protect the feet and ankles.
If peripheral neuropathy is found, the patient should be made aware that foot care (including d
examination) is very important for the prevention of foot ulcers and lower-extremity amputatio
Causes
The major risk factors for type 2 diabetes mellitus are the following:
Age - Older than 45 years (though, as noted above, type 2 diabetes is occurring with increasing fre
young individuals)
Obesity - Weight >120% of desirable body weight (true for approximately 90% of patients with type
Family history of type 2 diabetes in a first-degree relative (eg, parent or sibling)
Hispanic, Native American, African American, Asian American, or Pacific Islander descent
History of previous impaired glucose tolerance (IGT) or impaired fasting glucose (IFG)
Hypertension (>140/90 mm Hg) or dyslipidemia (high-density lipoprotein [HDL] cholesterol level <4
triglyceride level >150 mg/dL)
History of GDM or of delivering a baby with a birth weight of > 9 lbs
Polycystic ovarian syndrome (which results in insulin resistance)
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Section 4 of 10
DIFFERENTIALS
Authors and Editors Introduction
Miscellaneous References
Page 8 of 30
Clinical
Differentials
Workup
Treatment
Medication
Follow-up
Diabetes Mellitus, Type 1 - A Review
Diabetic Ketoacidosis
Hyperosmolar Hyperglycemic Nonketotic Coma
Hypoglycemia
Section 5 of 10
WORKUP
Authors and Editors Introduction
Miscellaneous References
Clinical
Differentials
Workup
Treatment
Medication
Follow-up
Lab Studies
A fingerstick glucose test is appropriate in the ED for virtually all patients with diabetes. All other lab
studies should be individualized to the clinical situation.
In patients who present with symptoms of uncontrolled diabetes (eg, polyuria, polydipsia, nocturia,
weight loss) with a confirmatory random plasma glucose level of >200 mg/dL, diabetes can be diag
In asymptomatic patients whose random serum glucose level suggests diabetes, a fasting plasma
(FPG) concentration should be measured. The oral glucose tolerance test no longer is recommend
routine diagnosis of diabetes.
An FPG level of >126 mg/dL on 2 separate occasions is diagnostic for diabetes.
An FPG level of 110-125 mg/dL is considered impaired IFG.
An FPG level of <110 mg/dL is considered normal glucose tolerance, though blood glucose le
>90 mg/dL may be associated with an increased risk for the metabolic syndrome if other featu
present.
A fasting C-peptide level > 1 ng/dL in a patient who has had diabetes for more than 1-2 years is su
type 2 diabetes (ie, residual beta-cell function).
Islet-cell autoantibodies are present in early type 1 but not type 2 diabetes.
Measurements of these autoantibodies within 6 months of diagnosis can help differentiate typ
2 diabetes.
Titers of islet-cell autoantibodies decrease after 6 months.
Anti–glutamate decarboxylase (GAD) antibodies can be present at diagnosis and are persiste
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over time.
Other Tests
A glucose tolerance test usually is not necessary, except when GDM or IGT is being diagnosed.
Section 6 of 10
TREATMENT
Authors and Editors Introduction
Miscellaneous References
Clinical
Differentials
Workup
Treatment
Medication
Follow-up
Emergency Department Care
The ED care of patients with type 2 diabetes requires attention to both the patient's glycemic control and
numerous complications of diabetes the patient may have.
New-onset diabetes
Most diabetic patients have type 2 diabetes, and most of those are asymptomatic at diagnosi
treatment for these patients is a trial of medical nutrition therapy (MNT, diet therapy). Therefo
asymptomatic patient is incidentally found to have an elevated blood glucose level in the ED,
primary physician can perform follow-up. Patients with mild symptoms of poorly controlled an
undiagnosed diabetes can usually be treated as an outpatient, often with the initiation of a low
sulfonylurea agent or metformin.
The treatment of markedly symptomatic patients with newly discovered type 2 diabetes and g
levels >400 mg/dL is controversial. If close follow-up can be arranged, maximal doses of a su
agent can be started, and they can be treated as outpatients. Patients generally feel better in
and in a week, their blood glucose levels are markedly lower. Their sulfonylurea dose can be
they comply with MNT; in some, diabetes can be controlled with diet alone. Patients who can
adequate amounts of fluid, those with serious coexisting medical conditions (eg, myocardial in
[MI], systemic infection), and those without reliable follow-up should generally be hospitalized
therapy.
Abnormalities caused by hyperglycemia
Acute hyperglycemia, even when not associated with DKA or hyperglycemic hyperosmolar no
syndrome (HNKS), is harmful for a number of reasons. If the blood glucose level exceeds the
threshold for glucose, an osmotic diuresis ensues, with loss of glucose, electrolytes, and wate
Hyperglycemia impairs leukocyte function through a variety of mechanisms. Patients with dia
an increased rate of wound infection, and hyperglycemia may impair wound healing.
In patients with known type 2 diabetes that is poorly controlled, no absolute level of blood glu
elevation requires admission to the hospital or administration of insulin in the ED. If the patien
symptomatic or if the precipitating cause of hyperglycemia cannot be treated adequately in th
patient may need to be admitted. In general, lowering the patient's blood glucose level in the
correct the underlying cause and has no long-term effects on the patient's blood glucose leve
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Therefore, a plan for lowering and monitoring the patients' glucose levels is needed. Adequac
up is extremely important. Whether insulin is given in the ED is of less consequence and can
on an individual basis.
Hyperglycemia during medical illness and surgery
Serious medical illness and surgery produce a state of increased insulin resistance. Hypergly
occur, even in nondiabetic patients, because of stress-induced insulin resistance plus the use
containing IV fluids. Increases in glucagon, catecholamines, cortisol, and growth hormone lev
antagonize the effects of insulin, and the alpha-adrenergic effect of increased catecholamine
insulin secretion. Counterregulatory hormones also directly increase hepatic gluconeogenesis
Increasing evidence shows the benefits of treatment of hyperglycemia in severely ill patients
without preexisting diabetes. In ICU patients, patients before and after coronary artery bypass
(CABG), and those with an acute MI morbidity and mortality are reduced when they receive g
insulin-potassium infusion (GIK infusion) designed to maintain glucose levels in the normal ra
hospitals are implementing GIK-infusion protocols for patients in ICU, surgical SICU, and CCU
Treatment regimens must be modified for patients not requiring an ICU setting to compensate
decreased caloric intake and increased physiologic stress. Blood glucose levels of 100
be maintained in medical and surgical patients with diabetes for the following reasons:
To prevent electrolyte abnormalities and volume depletion secondary to osmotic diuresi
To prevent the impairment of leukocyte function that occurs when blood glucose levels
To prevent the impairment of wound healing that occurs when blood glucose levels are
(>250 mg/dL)
Cardiovascular disease (CVD) or renal dysfunction increases surgical morbidity and mortality
with or without diabetes, and diabetic autonomic neuropathy increases the risk of cardiovascu
instability. The emergency physician caring for the diabetic patient who requires emergency s
notify the surgeon and the anesthesiologist of the patient's condition, consult medical speciali
appropriate, and promptly initiate a thorough medical evaluation to avoid delaying surgery.
Infections in general
Infections cause considerable morbidity and mortality in patients with diabetes. Infections ma
metabolic derangements and, conversely, the metabolic derangements of diabetes may facili
infection.
A few infections, such as malignant otitis externa, rhinocerebral mucormycosis, and emphyse
pyelonephritis, occur almost exclusively in patients with diabetes. Infections, such as staphylo
sepsis, occur more frequently and result in greater mortality in patients with diabetes than in o
Infections such as pneumococcal pneumonia affect diabetic patients and others the same.
Although diabetes can compromise all aspects of the host's defenses against infection, diabe
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are not equally susceptible to infection. Hyperglycemia and acidemia exacerbate impairments
immunity and polymorphonuclear leukocyte and lymphocyte functions but are substantially, if
reversed when pH and blood glucose levels return to normal. Although the exact level above
leukocyte function is impaired is not defined, in vitro evidence suggests that glucose levels >2
impair leukocytic function.
Ear, nose, and throat infections
Patients with long-standing diabetes tend to have microvascular and macrovascular disease
poor tissue perfusion and increased risk of infection. The ability of the skin to act as a barrier
may be compromised when the diminished sensation of diabetic neuropathy results in unnotic
Two head and neck infections that are associated with high rates of morbidity and mortality a
otitis externa and rhinocerebral mucormycosis; these are seen almost exclusively in diabetic
Malignant or necrotizing otitis externa principally occurs in patients with diabetes >35 years a
always caused by Pseudomonas aeruginosa. Infection starts in the external auditory canal an
the adjacent soft tissue, cartilage, and bone. Patients typically present with severe ear pain a
Although they often have preexisting otitis externa, the progression to invasive disease is usu
Examination of the auditory canal may reveal granulation tissue, but spread of infection to the
preauricular tissue, and mastoid often makes the diagnosis apparent. Involvement of the cran
particularly the facial nerve, is common; infection extending to the meninges is often lethal.
CT helps define the extent of disease. Prompt surgical consultation is mandatory for malignan
externa because surgical debridement is often an essential part of therapy. IV antipseudomon
antibiotics should be started at once in patients with invasive disease. Diabetic patients with s
externa but no evidence of invasive disease can be treated with an otic antibiotic drop and or
ciprofloxacin; they require close follow-up.
Mucormycosis collectively refers to infections caused by various ubiquitous molds. Invasive d
occurs in patients with poorly controlled diabetes, especially with DKA. Organisms colonize th
paranasal sinuses, spreading to adjacent tissues by invading blood vessels and causing soft
necrosis and bony erosion.
Patients with mucormycosis usually present with periorbital or perinasal pain, swelling, and in
Bloody nasal discharge may be present. Involvement of the orbits, with lid swelling, proptosis
diplopia, is common. The nasal turbinates may appear dusky red or frankly necrotic. Black ne
is an important visual clue.
The infection may invade the cranial vault through the cribriform plate, resulting in cerebral ab
cavernous sinus thrombosis, or internal carotid artery thrombosis.
Wet smears of necrotic tissue often reveal broad hyphae and distinguish mucormycosis from
facial cellulitis. CT helps delineate the extent of disease. Treatment consists of controlling the
predisposing hyperglycemia and acidemia, giving IV amphotericin B, and immediate surgical
debridement. Until the diagnosis is confirmed, antistaphylococcal antibiotic therapy is appropr
Urinary tract infections
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Patients with diabetes have increased risk of cystitis and, more important, of serious upper ur
infection. Intrarenal bacterial infection should be considered in the differential diagnosis of an
diabetes who presents with flank or abdominal pain.
The treatment of cystitis is essentially the same as that in nondiabetic patients, though individ
neurogenic bladder due to diabetic neuropathy may not empty their bladder well and may req
referral. Sulfonamide antibiotics can cause hypoglycemia in patients taking sulfonylurea agen
displacing the sulfonylurea agents from their binding sites and increasing their hypoglycemic
Treatment of pyelonephritis does not differ for diabetic patients, but a lower threshold for hosp
admission is appropriate. First, pyelonephritis makes control of diabetes more difficult by caus
resistance; in addition, nausea may limit the patient's ability to maintain normal hydration. The
hyperglycemia further compromises their immune response. Second, diabetic patients are mo
susceptible than others to the complications of pyelonephritis (eg, renal abscess, emphysema
pyelonephritis, renal papillary necrosis, gram-negative sepsis).
In 1 series, 36 of 52 patients with renal abscess had diabetes, and >70% of cases of emphys
pyelonephritis occurred in patients with diabetes. Emphysematous pyelonephritis is an uncom
necrotizing renal infection caused by Escherichia coli, Klebsiella pneumoniae, or other organi
of fermenting glucose to carbon dioxide. The presentation is usually similar to that of uncomp
pyelonephritis, and the diagnosis is established by identifying renal gas on plain radiography
sonography. Surgery is indicated at diagnosis.
Skin and soft tissue infections
Page 12 of 30
Sensory neuropathy, atherosclerotic vascular disease, and hyperglycemia all predispose diab
to skin and soft tissue infections. These can affect any skin surface but most commonly involv
Blood glucose levels >250 mg/dL significantly increase a patient's risk of soft tissue infection.
Cellulitis; lymphangitis; and, most ominously, staphylococcal sepsis can complicate even the
wound. Minor wound infections and cellulitis are typically caused by Staphylococcus aureus
streptococci and can be treated with a penicillinase-resistant synthetic penicillin or a first
cephalosporin.
Outpatient treatment of minor infections is appropriate for patients who are reliable, who mon
blood glucose and urine ketone levels, and who have access to close follow-up.
Necrotizing infections of the skin, subcutaneous tissues, fascia, or muscle can also complicat
and particularly cutaneous ulcers. These infections are typically polymicrobial, involving group
streptococci, enterococci, S aureus, Enterobacteriaceae, and various anaerobes. Radiograph
spreading soft tissue infection in a diabetic patient should be obtained to look for the soft tissu
characterizes necrosis. Surgical debridement is necessary for necrotizing infections. Gram st
surface cultures are not helpful; antibiotic coverage should reflect the range of potential patho
Osteomyelitis
Contiguous spread of a polymicrobial infection from a skin ulcer to adjacent bone is common
patients.
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In 1 study, osteomyelitis was the underlying cause of 68% of diabetic foot ulcers, and findings
examination and plain radiographs did not help in diagnosing one half of the cases. Unfortuna
diagnostic modalities are often the only ones available in the ED, and the diagnosis might be
but not established.
If osteomyelitis is apparent on radiography or physical examination (eg, if the wounds are dee
expose tendons or bone), the patient should be admitted for IV antibiotics. If osteomyelitis is s
but the soft tissue infection or metabolic disturbances do not warrant admission, the patient c
discharged for outpatient workup.
Other infections
Page 13 of 30
Although cholecystitis is probably no more common in patients with diabetes than in the gene
population, severe fulminating infection, especially with gas-forming organisms, is more comm
early clinical manifestations of emphysematous cholecystitis are indistinguishable from those
cholecystitis. The diagnosis can be made by finding gas in the gallbladder lumen, wall, or sur
tissues. Even with immediate surgery, the rate of mortality is high. Clostridial species are foun
50% of cases.
The incidence of staphylococcal and K pneumoniae infections is greater in people with diabet
people without diabetes.
Diabetes is a risk factor for reactivation of tuberculosis.
Cryptococcal infections and coccidioidomycoses are more virulent in diabetic patients than in
Ophthalmologic complications
Diabetes can affect the lens, vitreous, and retina, causing visual symptoms that may prompt t
come to the ED. Visual blurring may develop acutely as the lens changes shape with marked
blood glucose concentrations. This effect, which is caused by osmotic fluxes of water into and
lens, usually occurs as hyperglycemia increases, but it also may be seen when high glucose
lowered rapidly. In either case, recovery to baseline visual acuity can take up to a month, and
patients are almost completely unable to read small print or do close work during this period.
Patients with diabetes also tend to develop senile cataracts sooner than persons without diab
this is not related to the degree of glycemic control.
Whether patients develop diabetic retinopathy depends on the duration of their diabetes and
of glycemic control maintained. Because the diagnosis of type 2 diabetes often is delayed, 20
patients have some degree of retinopathy at diagnosis. The following are the 5 stages in the p
of diabetic retinopathy:
1. Dilation of the retinal venules and formation of retinal capillary microaneurysms
2. Increased vascular permeability
3. Vascular occlusion and retinal ischemia
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4. Proliferation of new blood vessels on the surface of the retina
5. Hemorrhage and contraction of the fibrovascular proliferation and the vitreous
The first 2 stages of diabetic retinopathy are known as background or nonproliferative retinop
Initially, the retinal venules dilate, then microaneurysms, (tiny red dots on the retina that
visual impairment) appear.
As the microaneurysms or retinal capillaries become more permeable, and hard exudat
reflecting the leakage of plasma. Rupture of intraretinal capillaries results in hemorrhage
superficial capillary ruptures, a flame-shaped hemorrhage appears.
Hard exudates are often found in partial or complete rings (circinate pattern), which usu
multiple microaneurysms. These rings usually mark an area of edematous retina.
The patient may not notice a change in visual acuity unless the center of the macula is i
Macular edema can cause visual loss; therefore, all patients with suspected macular ed
be referred to an ophthalmologist for evaluation and possible laser therapy. Laser thera
effective in decreasing macular edema and preserving vision but less effective in restor
Preproliferative and proliferative diabetic retinopathy are the next stages in the progression of
Cotton-wool spots can be seen in preproliferative retinopathy. These represent retinal microin
caused by capillary occlusion and appear as patches that range from off-white to gray and ha
defined margins.
Proliferative retinopathy is characterized by neovascularization, or the development of networ
new vessels that often are seen on the optic disc or along the main vascular arcades. The ve
undergo cycles of proliferation and regression. During proliferation, fibrous adhesions develop
the vessels and the vitreous. Subsequent contraction of the adhesions can result in traction o
and retinal detachment. Contraction also tears the new vessels, which hemorrhage into the v
Patients may notice a small hemorrhage, which appears as a floater, though a large hemorrh
result in marked visual loss.
Patients with preproliferative or proliferative retinopathy must immediately be referred for oph
evaluation because laser therapy is effective in this condition, especially before actual hemor
occurs. Patients with retinal hemorrhage should be advised to limit their activity and to keep t
upright (even while sleeping) so that the blood settles to the inferior portion of the retina, mini
obscuration of their central vision.
Patients with active proliferative diabetic retinopathy are at increased risk of retinal hemorrhag
receive thrombolytic therapy; therefore, this condition is a relative contraindication to the use
thrombolytic agents.
Nephropathy
Patients with type 2 diabetes account for most diabetic patients with ESRD. All patients with d
should be considered to have the potential for renal impairment unless proven otherwise. The
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extreme care should be exercised when using any nephrotoxic agent in a patient with diabete
The use of contrast media can precipitate acute renal failure in patients with underlying diabe
nephropathy. Caution should be used when contrast-enhanced studies are being considered
patients with a creatinine level > 2 mg/dL; such studies should absolutely be avoided in patien
creatinine level > 3 mg/dL. Although most recover within 10 days, some develop irreversible r
Patients with diabetes who must undergo such studies should be well hydrated before, during
the study, and their renal function should be carefully monitored. A better solution is to seek e
clinical information by using an alternative study that does not require the use of contrast mat
sonography).
Potentially nephrotoxic drugs should be avoided whenever possible. Renally excreted or pote
nephrotoxic drugs should be given at reduced dosage as appropriate to the patient's serum c
level. Because chronically elevated blood pressure contributes to the decline in renal function
hypertensive patients with diabetes must be referred for long-term management of their blood
antihypertensive therapy is started in the ED, an angiotensin-converting enzyme (ACE) inhibi
choice because these agents decrease proteinuria and slow decline in renal function indepen
effect on blood pressure. ACE inhibitors tend to increase the serum potassium level and there
be used with caution in patients with renal insufficiency or elevated serum potassium levels.
Neuropathy
Of the many types of peripheral and autonomic diabetic neuropathy, distal symmetric sensori
polyneuropathy (in a glove-and-stocking distribution) is the most frequent. Besides causing pa
early stages, this type of neuropathy eventually results in the loss of peripheral sensation. Th
combination of decreased sensation and peripheral arterial insufficiency often leads to foot ul
eventual amputation.
Acute-onset mononeuropathies in diabetes include acute cranial mononeuropathies, monone
multiplex, focal lesions of the brachial or lumbosacral plexus, and radiculopathies. Of the cran
neuropathies, the third cranial nerve (oculomotor) is most commonly affected, followed by the
(abducens) and the fourth nerve (trochlear). Patients can present with diplopia and eye pain.
In diabetic third-nerve palsy, the pupil is usually spared, whereas in third-nerve palsy due to in
aneurysm or tumor, the pupil is affected in 80-90% of cases.
Consideration of nondiabetic causes of cranial nerve palsies is important, because 42% are d
causes other than diabetes. Therefore, evaluation should include nonenhanced and contrast
CT or, preferably, MRI. Neurologic consultation is recommended. Acute cranial-nerve monon
usually resolve in 2-9 months. Acute thrombosis or ischemia of the blood vessels supplying th
involved is thought to cause these neuropathies.
Autonomic dysfunction can involve any part of the sympathetic or parasympathetic chains an
myriad manifestations. Patients likely to seek care in the ED are those with diabetic gastropar
vomiting, severe diarrhea, or bladder dysfunction and urinary retention. Treatment is symptom
symptoms tend to wax and wane. Patients with gastroparesis may benefit from metocloprami
erythromycin. Before these therapies are started, the degree of dehydration and metabolic im
must be assessed, and other serious causes of vomiting must be excluded.
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In severe cases, gastric pacing has been used. Patients with disabling orthostatic hypotensio
treated with salt tablets, support stockings, or fludrocortisone. Alleviating the functional abnor
associated with the autonomic neuropathy is often difficult and frustrating for both doctor and
patient's physician should be involved in devising a long-term treatment plan.
Diabetic foot
Page 16 of 30
About 50-70% of all nontraumatic lower-extremity amputations occur in diabetic patients. The
poorly perfused foot is at risk for ulcers from pressure necrosis or inflammation from repeated
and unnoticed minor trauma. These can evolve into cellulitis, osteomyelitis, or nonclostridial g
end in amputation.
Diabetic patients presenting with wounds, infections, or ulcers of the foot should be treated in
addition to appropriate use of antibiotics, avoidance of further trauma to the healing foot by us
crutches, wheelchairs, or bed rest is mandatory. Patients should be treated by a podiatrist or
orthopedist with experience in the care of the diabetic foot. If bone or tendon is visible, osteom
present, and hospitalization for IV antibiotics is often necessary. Many patients need a vascul
in conjunction with local treatment of the foot ulcer because a revascularization procedure ma
required to provide adequate blood flow for wound healing.
Because curing ulcers and foot infections is difficult, their prevention is extremely important. A
the rate of amputation was halved after patients were required to remove their shoes and soc
visit. The emergency physician can facilitate this practice by briefly inspecting the feet of each
diabetes and by educating them about the need for proper foot care. Patients with distal sens
neuropathy to pinprick or light touch, decreased peripheral pulses, moderate-to-severe onych
impending skin breakdown should be referred to a podiatrist.
Macrovascular disease
This is the leading cause of death in patients with diabetes, causing 75% of deaths in this gro
approximately 35% of deaths in people without diabetes. Diabetes increases the risk of myoc
infarction (MI) 2-fold in men and 4-fold in women, and many patients have other risk factors fo
The risk of stroke in diabetic patients is double that of nondiabetic people, and the risk of peri
vascular disease is 4 times that of people without diabetes. Subtle differences in the pathoph
atherosclerosis in patients with diabetes result in both earlier development and a more malign
Therefore, lipid abnormalities must be treated aggressively to lower the risk of serious athero
Findings suggest that statin therapy should be started in all patients with type 2 diabetes, reg
their lipid levels, to lower their risk of CVD.
Hypertension, which also increases the risk of atherosclerosis, is twice as common in patients
diabetes as in persons without diabetes. In patients with diabetes, hypertension must be treat
aggressively to lower their risk of serious atherosclerosis. ACE inhibitors and angiotensin II
blockers (ARBs) may also reduce CVD risk independent of its effects on blood pressure. Man
their use, in addition to statins, in most patients with type 2 diabetes.
Patients with diabetes may have an increased incidence of silent ischemia. However, silent is
common in many patients with CAD, and the apparently increased incidence may be because
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with diabetes are more likely than others to have CAD to begin with. Nevertheless, ECG is pr
patients with diabetes and a serious illness or who present with generalized weakness, malai
nonspecific symptoms that are not expected to be due to myocardial ischemia.
Diastolic dysfunction is common in patients with diabetes and should be considered in the patient w
symptoms of congestive heart failure and a normal ejection fraction.
Section 7 of 10
MEDICATION
Authors and Editors Introduction
Miscellaneous References
Clinical
Differentials
Workup
Treatment
Medication
Follow-up
Chronic hyperglycemia is associated with an increased risk of microvascular complications, as shown in
Control and Complications Trial (DCCT) of type 1 diabetes and the United Kingdom Prospective Diabete
(UKPDS) of type 2 diabetes. In the DCCT, intensive therapy to maintain normal blood glucose levels gre
the development and progression of retinopathy, microalbuminuria, proteinuria, and neuropathy over 7 y
Intensive therapy was not associated with increased mortality or incidence of major macrovascular event
not decrease the quality of life, though it did increase the likelihood of severe hypoglycemic episodes.
In the UKPDS, more than 5000 patients with type 2 diabetes were followed up for up to 15 years. Those
intensely treated group had a significantly lower rate of progression of microvascular complications than
receiving standard care. Rates of macrovascular disease were not altered except in the metformin
in which the risk of MI was significantly decreased. Moreover, severe hypoglycemia occurred less often t
patients with type 1 diabetes in the DCCT.
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The goal of oral antidiabetic therapy is to lower blood glucose levels to near-normal (preprandial levels o
mg/dL or 80-140 mg/dL and HbA1C levels <7%) and to maintain them in this range for the patient's lifetim
with no or mild symptoms should initially be treated with MNT (diet therapy), and MNT should be encoura
throughout treatment. In the ED, drugs are started when a patient presents with moderate-to-marked sym
diabetes.
Some patients should not aim for near-normal blood glucose levels. In elderly patients who have a life ex
<5 years or in any patient with a terminal disease, tight control is unnecessary. Patients with known CAD
cerebrovascular disease should have higher preprandial glucose targets (eg, 100-160 mg/dL) to prevent
hypoglycemia. Patients with advanced microvascular and neuropathic diabetic complications and may no
benefit from maintenance of near-euglycemia. Last, patients with hypoglycemia unawareness (ie, lack of
warning signs of hypoglycemia) or those with recurrent episodes of severe hypoglycemia (ie, hypoglycem
treatment by another means) should also have high target levels.
Throughout treatment for type 2 diabetes, adherence to MNT and exercise should be stressed because b
modification can have a large effect on the degree of diabetic control they achieve.
Treatment of type 2 diabetes is aimed at lowering insulin resistance and increasing function of beta cells
patients, beta-cell dysfunction worsens over time, necessitating exogenous insulin. Because patients wit
diabetes have both insulin resistance and beta-cell dysfunction, oral medication to increase insulin sensi
metformin, a thiazolidinedione [TZD]) is often given with an intermediate-acting insulin (eg, neutral protam
Hagedorn [NPH]) at bedtime or a long-acting insulin (eg, glargine [Lantus] insulin, insulin detemir [Levem
the morning or evening. An insulin secretagogue, such as a sulfonylurea agent, can also be given to incr
preprandial insulin secretion.
The goal of these combined daytime oral agent plus once-a-day insulin is to lower the fasting glucose lev
mg/dL by using the insulin. When this target is achieved, the oral agents are effective in maintaining prep
postprandial blood glucose levels throughout the day. If a regimen combining oral agents and insulin fails
glucose levels into the normal range, patients should be switched to a daily multiple-injection schedule w
premeal rapid-acting insulin and a longer-acting basal insulin.
Although ED physicians rarely start new therapy for diabetes, being acquainted with the drugs used and
adverse effects and contraindications is useful. For descriptions of insulins, see Diabetes Mellitus, Type
Review.
Drug Category: Incretin mimetics -- Mimics glucose-dependent insulin secretion, suppresses elevated
secretion, and delays gastric emptying.
Drug Name
Adult Dose
Pediatric Dose
Exenatide (Byetta) -- Incretin mimetic agent that mimics glucose-dependent insulin s
and several other antihyperglycemic actions of incretins. Improves glycemic control
with type 2 diabetes mellitus by enhancing glucose-dependent insulin secretion by p
beta cells, suppresses inappropriately elevated glucagon secretion, and slows gastr
The drug's 39–amino acid sequence partially overlaps that of the human incretin, gl
peptide-1. Indicated as adjunctive therapy to improve glycemic control in patients w
diabetes who are taking metformin or a sulfonylurea but have not achieved glycemic
5 mcg SC bid within 1 h ac in morning and evening; based on response, may increa
mcg SC bid after 1 mo
Not established
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Contraindications Documented hypersensitivity
Data limited; coadministration decreases digoxin Cmax and delays Tmax, decreases
AUC and Cmax, delays lisinopril Tmax, and decreases acetaminophen AUC and C
Interactions
pharmacokinetic alterations do not appear to be clinically significant; may decrease
of orally administered drugs (take drugs requiring rapid absorption, eg, oral contrace
antibiotics, at least 1 h before exenatide)
C - Safety for use during pregnancy has not been established.
Pregnancy
Administer in thigh, abdomen, or upper arm; may cause hypoglycemia, nausea, vom
diarrhea, jittery feeling, dizziness, headache, or dyspepsia; may develop antibodies
Precautions
contents
Drug Category: Dipeptidyl peptidase IV (DPP-4) inhibitors-- Blocks the action of DPP-4, which is kno
degrade incretin.
Drug Name
Adult Dose
Pediatric Dose
Contraindications
Interactions
Pregnancy
Precautions
Sitagliptin (Januvia) -- First of new class of antidiabetic agents known as dipeptidyl p
(DPP-4) inhibitors. Blocks the enzyme DPP-4, which is known to degrade incretin ho
Increases concentrations of active intact incretin hormones (GLP-1 and GIP). The h
stimulate insulin release in response to increased blood glucose levels following me
action enhances glycemic control. Indicated for monotherapy or combined with metf
peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist (eg,
thiazolidinediones).
100 mg PO qd
CrCl >30 to <50 mL/min: 50 mg PO qd
CrCl <30 mL/min: 25 mg PO qd
Not established
Documented hypersensitivity
Data limited; caution with other drugs that decrease glucose levels
B - Usually safe but benefits must outweigh the risks.
Common adverse effects include upper respiratory tract infection, nasopharyngitis,
headache; assess renal function before initiating therapy and periodically thereafter
dose with moderate or severe renal insufficiency
Drug Category: Sulfonylurea agents
These agents reduce glucose by increasing insulin secretion from pancreatic beta cells in patients with re
cell function. All are well absorbed; half-life and duration of action vary. First-generation (chlorpropamide
tolbutamide, tolazamide, acetohexamide), second generation (glyburide, glipizide), and third generation (
All may cause mild hypoglycemia; severe hypoglycemia is uncommon.
Drug Name
Description
Adult Dose
Chlorpropamide (Diabinese)
May increase insulin secretion from pancreatic beta cells.
100-250 mg PO qd; not to exceed 750 mg/d
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Pediatric Dose
Contraindications
Interactions
Pregnancy
Precautions
Drug Name
Description
Adult Dose
Pediatric Dose
Contraindications
Interactions
Pregnancy
Precautions
Page 20 of 30
Not established
Documented hypersensitivity; DKA; type 1 diabetes
Numerous possible, few clinically significant; sulfonamides
may enhance hypoglycemic effect
C - Safety for use during pregnancy has not been
established.
Caution in hepatic or renal impairment; cardiovascular
disorders may occur; other risk factors are older age,
malnutrition, and irregular eating (if prolonged or recurrent,
consider admission); may cause rash, nausea, vomiting,
leukopenia, agranulocytosis, aplastic anemia (rare),
intrahepatic cholestasis (rare), disulfiramlike reaction,
flushing, headache, and SIADH causing hyponatremia
Tolbutamide (Orinase)
Increases insulin secretion from pancreatic beta cells.
500-1000 mg PO qd or divided bid/tid; not to exceed 2 g/d
Not established
Documented hypersensitivity; DKA; type 1 diabetes
Numerous possible, few clinically significant; sulfonamides
may enhance hypoglycemic effect
C - Safety for use during pregnancy has not been
established.
Caution in hepatic or renal impairment; cardiovascular
disorders may occur; other risk factors are older age,
malnutrition, and irregular eating (if prolonged or recurrent,
consider admission); may cause rash, nausea, vomiting,
leukopenia, agranulocytosis, aplastic anemia (rare),
intrahepatic cholestasis (rare), disulfiramlike reaction,
flushing, headache, and SIADH causing hyponatremia
Drug Name
Tolazamide (Tolinase)
Description
Increases insulin secretion from pancreatic beta cells.
100 mg PO qd or divided bid; increase q2-4wk; not to
exceed 1000 mg/d
Not established
Documented hypersensitivity; DKA; type 1 diabetes
Numerous possible, few clinically significant; sulfonamides
may enhance hypoglycemic effect
C - Safety for use during pregnancy has not been
established.
Adult Dose
Pediatric Dose
Contraindications
Interactions
Pregnancy
Caution in hepatic or renal impairment; cardiovascular
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Precautions
Drug Name
Description
Adult Dose
Pediatric Dose
Contraindications
Interactions
Pregnancy
Precautions
Drug Name
Description
Adult Dose
Pediatric Dose
Contraindications
Interactions
Pregnancy
Page 21 of 30
disorders may occur; other risk factors are older age,
malnutrition, and irregular eating (if prolonged or recurrent,
consider admission); may cause rash, nausea, vomiting,
leukopenia, agranulocytosis, aplastic anemia (rare),
intrahepatic cholestasis (rare), disulfiramlike reaction,
flushing, headache, and SIADH causing hyponatremia
Acetohexamide (Dymelor)
Increases insulin secretion from pancreatic beta cells.
250 mg-1.5 g/d PO or divided bid
Not established
Documented hypersensitivity; DKA; type 1 diabetes
Numerous possible, few clinically significant; sulfonamides
may enhance hypoglycemic effects
D - Unsafe in pregnancy
Caution in hepatic or renal impairment; cardiovascular
disorders may occur; other risk factors are older age,
malnutrition, and irregular eating (if prolonged or recurrent,
consider admission); may cause rash, nausea, vomiting,
leukopenia, agranulocytosis, aplastic anemia (rare),
intrahepatic cholestasis (rare), disulfiramlike reaction,
flushing, headache, and SIADH causing hyponatremia
Glyburide (DiaBeta, Micronase, PresTab, Glynase)
Increases insulin secretion from pancreatic beta cells.
Listed as pregnancy category C, but some data support its
safety. Dosing for Glynase (micronized formulation) differs.
5 mg/d PO initially in untreated, symptomatic patients; not to
exceed 20 mg/d PO
Start 2.5 mg/d PO for elderly patients and patients with
hepatic or renal disease; may start at <20 mg/d in patients
with severe hyperglycemia or symptoms, if home glucose
monitoring and close follow-up can be arranged
Glynase: 3 mg/d PO initially; not to exceed 12 mg/d
Not established
Documented hypersensitivity; DKA; type 1 diabetes
Numerous possible, few clinically significant; sulfonamides
may enhance hypoglycemic effect
C - Safety for use during pregnancy has not been
established.
Caution in hepatic or renal impairment; cardiovascular
disorders may occur; other risk factors are older age,
malnutrition, and irregular eating (if prolonged or recurrent,
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Precautions
Drug Name
Description
Adult Dose
Pediatric Dose
Contraindications
Interactions
Pregnancy
Precautions
Page 22 of 30
consider admission); may cause rash, nausea, vomiting,
leukopenia, agranulocytosis, aplastic anemia (rare),
intrahepatic cholestasis (rare), disulfiramlike reaction,
flushing, headache, and SIADH causing hyponatremia
Glipizide (Glucotrol, Glucotrol XL)
Second-generation sulfonylurea; stimulates insulin release
from pancreatic beta cells.
5 mg/d PO initially in untreated patients with symptomatic
hyperglycemia; not to exceed 40 mg/d PO; daily doses >20
mg given in divided doses bid; Glucotrol XL not to exceed
20 mg/d PO
Start at 2.5 mg/d PO for elderly patients and patients with
hepatic or renal disease; may start at higher doses in
patients with severe hyperglycemia or symptoms, if home
glucose monitoring and close follow-up can be arranged
Not established
Documented hypersensitivity; DKA; type 1 diabetes
Numerous possible, few clinically significant; sulfonamides
may enhance hypoglycemic effect
C - Safety for use during pregnancy has not been
established.
Caution in hepatic or renal impairment; cardiovascular
disorders may occur; other risk factors are older age,
malnutrition, and irregular eating (if prolonged or recurrent,
consider admission); may cause rash, nausea, vomiting,
leukopenia, agranulocytosis, aplastic anemia (rare),
intrahepatic cholestasis (rare), disulfiramlike reaction,
flushing, headache, and SIADH causing hyponatremia
Drug Category: Meglitinides
These agents are short-acting insulin secretagogues. They act on the ATP-dependent potassium channe
pancreatic beta cells, allowing opening of calcium channels and increased insulin release.
Drug Name
Description
Adult Dose
Pediatric Dose
Contraindications
Repaglinide (Prandin)
Stimulates insulin release from pancreatic beta cells.
0.5-4 mg PO ac; may dose bid/qid preprandial, not to
exceed 16 mg/d
Not established
Documented hypersensitivity; DKA; type 1 diabetes
CYP3A4 inhibitors (eg, clarithromycin, ketoconazole,
miconazole, erythromycin) decrease metabolism, increasing
serum levels and effects; thiazides, diuretics,
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Interactions
Pregnancy
Precautions
Page 23 of 30
corticosteroids, estrogens, oral contraceptives, nicotinic
acid, CCBs, phenothiazines, and thyroid products, may
lower glycemic control; toxicity increased with highly
protein-bound drugs (eg, NSAIDs, sulfonamides,
anticoagulants, hydantoins, salicylates, phenylbutazone)
C - Safety for use during pregnancy has not been
established.
Hypoglycemia, especially if carbohydrate not eaten after
drug; caution in hepatic impairment
Drug Category: Biguanides
These increase sensitivity of insulin by decreasing hepatic gluconeogenesis (primary effect) and increasi
peripheral insulin sensitivity (secondary effect). They do not increase insulin levels or weight gain. Alone,
cause hypoglycemia.
Absorbed from intestine (bioavailability 50-60%). Not bound to plasma proteins, not metabolized; rapidly
by kidneys. Levels increase markedly in renal insufficiency. Accumulates in intestine; may decrease loca
absorption (may explain GI effects). At high levels (eg, renal failure), accumulates in mitochondria; inhibi
phosphorylation and causes lactic acidosis (potentiated by alcohol).
Drug Name
Description
Adult Dose
Pediatric Dose
Contraindications
Interactions
Pregnancy
Precautions
Metformin (Glucophage)
Monotherapy or with sulfonylurea, TZD, or insulin. Take with
food to minimize adverse GI effects.
500 or 850 mg/d PO with dinner; increase less than q2wk to
desired effect (1 g PO bid), GI effects prevent increase, or
2550 mg/d
Not established
Serum creatinine level >1.5 (men) or >1.4 (women) mg/dL;
hepatic dysfunction; acute or chronic acidosis; local or
systemic tissue hypoxia; excessive alcohol intake; drug
therapy for CHF
Numerous possible, few (if any) clinically significant
B - Usually safe but benefits must outweigh the risks.
Fatal lactic acidosis if given with contraindication (rare
without contraindication); discontinue before IV contrast
enhancement, do not restart until creatinine level normal;
withhold in acute hypoxia; check renal function regularly
and discontinue if abnormal; adverse effects (including GI,
especially diarrhea [30%]), may cause discontinuation (5%)
Drug Category: Alpha-glucosidase inhibitors (AGIs)
These inhibit action of alpha-glucosidase (carbohydrate digestion), delaying and attenuating postprandia
glucose peaks. Undigested sugars are delivered to the colon, where they are converted into short
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methane, carbon dioxide, and hydrogen.
AGIs do not increase insulin levels or inhibit lactase; their major effect is to lower postprandial glucose le
effect on fasting levels). They do not cause weight gain and may restore ovulation in anovulation due to i
resistance.
Alone, AGIs do not cause hypoglycemia. Less than 2% is absorbed as active drug. Used as monotherap
sulfonylurea, TZD, metformin, or insulin. Take with food to minimize GI effects.
Drug Name
Description
Adult Dose
Pediatric Dose
Contraindications
Interactions
Pregnancy
Precautions
Drug Name
Description
Adult Dose
Pediatric Dose
Contraindications
Acarbose (Precose)
Delays hydrolysis of ingested complex carbohydrates and
disaccharides and absorption of glucose. Inhibits
metabolism of sucrose to glucose and fructose.
25 mg PO tid ac initially with first bite of food; adjust q4-8wk
based on 1-h postprandial glucose levels and tolerance;
may increase dose prn, not to exceed 100 mg PO tid
Not established
Documented hypersensitivity; DKA or cirrhosis; IBD; colonic
ulceration; serum creatinine level > 2 mg/dL; elevated liver
enzyme levels; partial or predisposition to intestinal
obstruction
Hypoglycemia with insulin or sulfonylurea agents (give
glucose as dextrose, as absorption of long-chain
carbohydrates is delayed); may decrease absorption and
bioavailability of digoxin, propranolol, and ranitidine;
digestive enzymes (eg, amylase, pancreatin) may reduce
effects
B - Usually safe but benefits must outweigh the risks.
GI effects (eg, flatulence, diarrhea, abdominal discomfort)
common, especially with metformin (17% discontinue);
systemic accumulation at high doses and in renal
dysfunction, with possible drug-induced hepatitis
Miglitol (Glyset)
Delays glucose absorption in small intestine; lowers
postprandial hyperglycemia.
25 mg PO tid ac initially with first bite of food; increase to 50
mg tid after 4-8 wk; may increase prn; not to exceed 100 mg
PO tid
Not established
Documented hypersensitivity; DKA; colonic ulceration;
partial or predisposition to intestinal obstruction; IBD
Hypoglycemia with insulin or sulfonylurea agents (give
glucose as dextrose, as absorption of long-chain
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Interactions
Pregnancy
Precautions
Page 25 of 30
carbohydrates is delayed); may decrease absorption and
bioavailability of digoxin, propranolol, and ranitidine;
digestive enzymes (eg, amylase, pancreatin) may reduce
effects
B - Usually safe but benefits must outweigh the risks.
May cause GI symptoms; not recommended in significant
renal dysfunction
Drug Category: Thiazolidinediones
These agents increase peripheral insulin sensitivity by increasing transcription of nuclear proteins that he
uptake of glucose, probably with effects on free fatty acid levels. About 12-16 weeks to achieve maximal
restore ovulation in anovulation due to insulin resistance. Monotherapy or with sulfonylurea, metformin, m
or insulin.
The US Food and Drug Administration issued an alert on May 21, 2007, to patients and health care profe
rosiglitazone potentially causing an increased risk of myocardial infarction (MI) and heart-related deaths
online publication of a meta-analysis. Rosiglitazone is an antidiabetic agent (thiazolidinedione derivative)
improves glycemic control by improving insulin sensitivity. The drug is highly selective and a potent agon
peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Activation of PPAR-gamma receptor
insulin-responsive gene transcription involved in glucose production, transport, and utilization, thereby re
glucose concentrations and reducing hyperinsulinemia. Potent PPAR-gamma agonists have been shown
the incidence of edema. A large-scale phase III trial (RECORD) is currently underway that is specifically
study cardiovascular outcomes of rosiglitazone.
For more information, see FDA's Safety Alert on Avandia. The online published meta-analysis entitled "
Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes" can be viewe
New England Journal of Medicine. Additionally, responses to the controversy can be viewed at the Heart
(the heart.org from WebMD) including the following articles: (1) Rosiglitazone increases MI and CV death
analysis, (2) The rosiglitazone aftermath: Legitimate concerns or hype? and (3) RECORD interim analys
rosiglitazone safety: No clear-cut answers.
Drug Name
Description
Adult Dose
Pediatric Dose
Contraindications
Interactions
Pregnancy
Pioglitazone (Actos)
Improves target cell response to insulin without increasing
insulin secretion from pancreas. Decreases hepatic glucose
output and increases insulin-dependent glucose use in
skeletal muscle and possibly liver and adipose tissue.
15 or 30 mg PO qd; may increase prn; not to exceed 45
mg/d
Not established
Documented hypersensitivity; active liver disease; DKA;
type 1 diabetes; class III or IV CHF
With insulin or oral hypoglycemics (eg, sulfonylureas) may
increase risk of hypoglycemia
C - Safety for use during pregnancy has not been
established.
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Precautions
Drug Name
Description
Adult Dose
Pediatric Dose
Contraindications
Interactions
Pregnancy
Precautions
Page 26 of 30
Monitor transaminases q2mo for first year, periodically
thereafter; discontinue if ALT above 3X ULN; caution in
edema and CHF; may decrease hemoglobin, hematocrit,
and WBC counts (dilution); effects on lipids neutral or
beneficial (decreased triglyceride, increased HDL levels)
Rosiglitazone (Avandia)
Insulin sensitizer; major effect in stimulating glucose uptake
in skeletal muscle and adipose tissue. Lowers plasma
insulin levels. Used to treat type 2 diabetes with insulin
resistance.
4-8 mg/d PO or divided bid
Not established
Documented hypersensitivity; active liver disease; DKA;
type 1 diabetes; class III or IV CHF
With insulin or oral hypoglycemics (eg, sulfonylureas) may
increase risk of hypoglycemia
C - Safety for use during pregnancy has not been
established.
Monitor transaminases q2mo for first year, periodically
thereafter; discontinue if ALT level above 3X upper ULN;
caution in edema and CHF; may decrease hemoglobin,
hematocrit, and WBC counts (dilution); may increase LDL
and triglyceride levels
Drug Category: Amylin analogs
These agents have endogenous amylin effects by delaying gastric emptying, decreasing postprandial glu
release, and modulating appetite.
Drug Name
Pramlintide acetate (Symlin)
Description
Synthetic analogue of human amylin, hormone made in
beta cells. Slows gastric emptying, suppresses postprandial
glucagon secretion, and regulates food intake (centrally
mediated appetite modulation). Indicated to treat type 1 or 2
diabetes, with insulin.
Given before meals in patients without desired glucose
control despite optimal insulin therapy. Helps lower glucose
levels after meals, lowers fluctuation during day, and
improves long-term control (HbA1C), as compared with
insulin alone. Lowers insulin use and body weight.
Adult Dose
60 mcg SC ac initially; titrate up (if no significant nausea for
> 3 d) to maintenance dose of 120 mcg; insulin dose is
decreased during initiation; after target dose achieved,
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Pediatric Dose
Contraindications
Interactions
Pregnancy
Precautions
Page 27 of 30
optimize insulin dose to maintain glycemic control
Not established
Documented hypersensitivity to pramlintide, components, or
metacresol; gastroparesis; hypoglycemia unawareness;
drugs that slow gastric emptying (eg, anticholinergics, eg,
atropine) or that slow intestinal nutrient absorption (eg,
alpha-glucosidase)
May delay absorption of concomitant oral drug (administer
other drug 1 h before or 2 h after)
C - Safety for use during pregnancy has not been
established.
Increases risk of insulin-induced severe hypoglycemia,
especially with type 1 diabetes or gastroparesis; reduce
insulin dose in all patients at start of therapy (monitor
glucose level and adjust insulin dose during initiation);
common adverse effects are GI complaints, especially
nausea (decreased when dose increased gradually); always
use separate insulin syringe to measure and administer, do
not mix in same syringe (insulin alters pharmacokinetics);
redness, swelling, or itching at injection site; do not
administer without major meal (>250 cal or 30 g
carbohydrates)
Section 8 of 10
FOLLOW-UP
Authors and Editors Introduction
Miscellaneous References
Clinical
Differentials
Workup
Treatment
Medication
Follow-up
Further Inpatient Care
Inpatient care generally is warranted only for the management of major acute complications such a
recurrent hypoglycemia, major infections, or HNKS.
Further Outpatient Care
Although a few of the complications require hospitalization, type 2 diabetes can usually be manage
outpatient basis.
Deterrence/Prevention
Moderation in diet, weight loss, and exercise are all important deterrents of type 2 diabetes.
Complications
The complications of diabetes include hypoglycemia and hyperglycemia, increased risk of infection
microvascular complications (ie, retinopathy, nephropathy), neuropathic complications, and macrov
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Page 28 of 30
disease.
Diabetes is the major cause of blindness in adults aged 20-74 years.
Diabetes is the leading cause of nontraumatic lower-extremity amputation and ESRD.
For a detailed discussion of complications, see Emergency Department Care.
Prognosis
Patients with diabetes have a lifelong struggle to achieve and maintain blood glucose levels as clos
normal range as possible. With appropriate glycemic control, the risk of microvascular and neuropa
complications is decreased markedly. In addition, if hypertension and hyperlipidemia are treated ag
the risk of macrovascular complications decreases as well.
These benefits are weighed against the risk of hypoglycemia and the short-term costs of providing
preventive care. Studies have shown cost savings due to a reduction in acute diabetes-related com
within 1-3 years after starting effective preventive care.
With each physician encounter, patients with diabetes should be educated about and encouraged t
appropriate treatment plan. The physician must ensure that the care for each patient with diabetes
necessary laboratory tests, examinations (eg, foot and neurologic examinations), and referrals to s
(eg, ophthalmologist, podiatrist).
Patient Education
For excellent patient education resources, see eMedicine's Diabetes Center. Also, visit eMedicine's
education article Diabetes.
Section 9 of 10
MISCELLANEOUS
Authors and Editors Introduction
Miscellaneous References
Clinical
Differentials
Workup
Treatment
Medication
Follow-up
Medical/Legal Pitfalls
Overtreatment or undertreatment of hypoglycemia, eg, premature discharge of a patient who devel
hypoglycemia due to a sulfonylurea agent, is a pitfall.
Failure to record the blood glucose levels of patients with wounds or active infections when they ar
mg/dL is a pitfall and may lead to poor healing.
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Another pitfall is underestimation of the severity of diabetic retinopathy on funduscopic examination
failure to dilate the pupils or the failure to urgently refer a patient with lesions near the macula to an
ophthalmologist.
Failure to provide adequate hydration to patients with mild diabetic nephropathy before contrast ma
given may precipitate acute renal failure.
Failure to examine the patient's feet and failure to detect small ulcers or underestimation of their se
are also pitfalls.
Failure to consider myocardial ischemia in patients with nonspecific symptoms is a pitfall.
Special Concerns
Pregnancy
MNT is the treatment of choice for GDM. If diet fails, the treatment is insulin.
In the past, oral antidiabetic agents were considered contraindicated in pregnancy. Glyburide
effective in the treatment of GDM. Evidence suggests that metformin may be safe and effectiv
pregnancy, as well. Studies are underway to assess their role in pregnant patients with increa
resistance.
Because patient education and ongoing glycemic control are essential to optimize fetal outco
consultation and specific follow-up are imperative.
Childhood diabetes: Although the predominant form of diabetes in children is type 1, type 2 diabete
occur in children.
Section 10 of 10
REFERENCES
Authors and Editors Introduction
Miscellaneous References
Clinical
Differentials
Workup
Treatment
Medication
Follow-up
ADA. American Diabetes Association: clinical practice recommendations. Diabetes Care. 1998;21(
70. [Medline].
CDC. National Diabetes Fact Sheet. United States. 2003;Available at:
http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2003.pdf. [Full Text].
DCCT Group. The Diabetes Control and Complications Trial Research Group: the effect of intensiv
of diabetes on the development and progression of long-term complications in insulin-dependent di
mellitus. N Engl J Med. Sep 30 1993;329(14):977-86. [Medline].
Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.
Care. Jul 1997;20(7):1183-97. [Medline].
Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabeti
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Page 30 of 30
microvascular complications in Japanese patients with non-insulin- dependent diabetes mellitus: a
prospective 6-year study. Diabetes Res Clin Pract. May 1995;28(2):103-17. [Medline].
Peters AL, Davidson MB, Schriger DL, Hasselblad V. A clinical approach for the diagnosis of diabe
an analysis using glycosylated hemoglobin levels. Meta-analysis Research Group on the Diagnosis
Using Glycated Hemoglobin Levels. JAMA. Oct 16 1996;276(15):1246-52. [Medline].
Turner R, Cull C, Holman R. United Kingdom Prospective Diabetes Study 17: a 9-year update of a
controlled trial on the effect of improved metabolic control on complications in non-insulin
mellitus. Ann Intern Med. Jan 1 1996;124(1 Pt 2):136-45. [Medline].
White JR. The pharmacological reduction of blood glucose in patients with type 2 diabetes mellitus
Diabetes. 1998;16:58-67.
Diabetes Mellitus, Type 2 - A Review excerpt
Article Last Updated: Jun 6, 2007
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