DEFINITION AND DESCRIPTION OF DIABETES MELLITUS
Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting
from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia
of diabetes is associated with long-term damage, dysfunction, and failure of differentorgans,
especially the eyes, kidneys, nerves, heart, and blood vessels.
Several pathogenic processes are involved in the development of diabetes. These range
from autoimmune destruction of the β-cells of the pancreas with consequent insulin
deficiency to abnormalities that result in resistance to insulin action. The basis
of the abnormalities in carbohydrate, fat, and protein metabolism in diabetes is deficient
action of insulin on target tissues. Deficient insulin action results from inadequate
insulin secretion and/or diminished tissue responses to insulin at one or more points
in the complex pathways of hormone action. Impairment of insulin secretion and defects
in insulin action frequently coexist in the same patient, and it is often unclear
which abnormality, if either alone, is the primary cause of the hyperglycemia.
Symptoms of marked hyperglycemia include polyuria, polydipsia, weight loss, sometimes
with polyphagia, and blurred vision. Impairment of growth and susceptibility to certain
infections may also accompany chronic hyperglycemia. Acute, life-threatening consequences
of uncontrolled diabetes are hyperglycemia with ketoacidosis or the nonketotic hyperosmolar
Long-term complications of diabetes include retinopathy with potential loss of vision;
nephropathy leading to renal failure; peripheral neuropathy with risk of foot ulcers,
amputations, and Charcot joints; and autonomic neuropathy causing gastrointestinal,
genitourinary, and cardiovascular symptoms and sexual dysfunction. Patients with diabetes
have an increased incidence of atherosclerotic cardiovascular, peripheral arterial,
and cerebrovascular disease. Hypertension and abnormalities of lipoprotein metabolism
are often found in people with diabetes.
The vast majority of cases of diabetes fall into two broad etiopathogenetic categories
(discussed in greater detail below). In one category, type 1 diabetes, the cause is
an absolute deficiency of insulin secretion. Individuals at increased risk of developing
this type of diabetes can often be identified by serological evidence of an autoimmune
pathologic process occurring in the pancreatic islets and by genetic markers. In the
other, much more prevalent category, type 2 diabetes, the cause is a combination of
resistance to insulin action and an inadequate compensatory insulin secretory response.
In the latter category, a degree of hyperglycemia sufficient to cause pathologic and
functional changes in various target tissues, but without clinical symptoms, may be
present for a long period of time before diabetes is detected. During this asymptomatic
period, it is possible to demonstrate an abnormality in carbohydrate metabolism by
measurement of plasma glucose in the fasting state or after a challenge with an oral
The degree of hyperglycemia (if any) may change over time, depending on the extent
of the underlying disease process (Fig. 1). A disease process may be present but may
not have progressed far enough to cause hyperglycemia. The same disease process can
cause impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) without
fulfilling the criteria for the diagnosis of diabetes. In some individuals with diabetes,
adequate glycemic control can be achieved with weight reduction, exercise, and/or
oral glucose-lowering agents. These individuals therefore do not require insulin.
Other individuals who have some residual insulin secretion but require exogenous insulin
for adequate glycemic control can survive without it. Individuals with extensive β-cell
destruction and therefore no residual insulin secretion require insulin for survival.
The severity of the metabolic abnormality can progress, regress, or stay the same.
Thus, the degree of hyperglycemia reflects the severity of the underlying metabolic
process and its treatment more than the nature of the process itself.
Disorders of glycemia: etiologic types and stages. *Even after presenting in ketoacidosis,
these patients can briefly return to normoglycemia without requiring continuous therapy
(i.e., “honeymoon” remission); **in rare instances, patients in these categories (e.g.,
Vacor toxicity, type 1 diabetes presenting in pregnancy) may require insulin for survival.
CLASSIFICATION OF DIABETES MELLITUS AND OTHER CATEGORIES OF GLUCOSE REGULATION
Assigning a type of diabetes to an individual often depends on the circumstances present
at the time of diagnosis, and many diabetic individuals do not easily fit into a single
class. For example, a person with gestational diabetes mellitus (GDM) may continue
to be hyperglycemic after delivery and may be determined to have, in fact, type 2
diabetes. Alternatively, a person who acquires diabetes because of large doses of
exogenous steroids may become normoglycemic once the glucocorticoids are discontinued,
but then may develop diabetes many years later after recurrent episodes of pancreatitis.
Another example would be a person treated with thiazides who develops diabetes years
later. Because thiazides in themselves seldom cause severe hyperglycemia, such individuals
probably have type 2 diabetes that is exacerbated by the drug. Thus, for the clinician
and patient, it is less important to label the particular type of diabetes than it
is to understand the pathogenesis of the hyperglycemia and to treat it effectively.
Type 1 diabetes (β-cell destruction, usually leading to absolute insulin deficiency)
This form of diabetes, which accounts for only 5–10% of those with diabetes, previously
encompassed by the terms insulin-dependent diabetes, type 1 diabetes, or juvenile-onset
diabetes, results from a cellular-mediated autoimmune destruction of the β-cells of
the pancreas. Markers of the immune destruction of the β-cell include islet cell autoantibodies,
autoantibodies to insulin, autoantibodies to GAD (GAD65), and autoantibodies to the
tyrosine phosphatases IA-2 and IA-2β. One and usually more of these autoantibodies
are present in 85–90% of individuals when fasting hyperglycemia is initially detected.
Also, the disease has strong HLA associations, with linkage to the DQA and DQB genes,
and it is influenced by the DRB genes. These HLA-DR/DQ alleles can be either predisposing
In this form of diabetes, the rate of β-cell destruction is quite variable, being
rapid in some individuals (mainly infants and children) and slow in others (mainly
adults). Some patients, particularly children and adolescents, may present with ketoacidosis
as the first manifestation of the disease. Others have modest fasting hyperglycemia
that can rapidly change to severe hyperglycemia and/or ketoacidosis in the presence
of infection or other stress. Still others, particularly adults, may retain residual
β-cell function sufficient to prevent ketoacidosis for many years; such individuals
eventually become dependent on insulin for survival and are at risk for ketoacidosis.
At this latter stage of the disease, there is little or no insulin secretion, as manifested
by low or undetectable levels of plasma C-peptide. Immune-mediated diabetes commonly
occurs in childhood and adolescence, but it can occur at any age, even in the 8th
and 9th decades of life.
Autoimmune destruction of β-cells has multiple genetic predispositions and is also
related to environmental factors that are still poorly defined. Although patients
are rarely obese when they present with this type of diabetes, the presence of obesity
is not incompatible with the diagnosis. These patients are also prone to other autoimmune
disorders such as Graves' disease, Hashimoto's thyroiditis, Addison's disease, vitiligo,
celiac sprue, autoimmune hepatitis, myasthenia gravis, and pernicious anemia.
Some forms of type 1 diabetes have no known etiologies. Some of these patients have
permanent insulinopenia and are prone to ketoacidosis, but have no evidence of autoimmunity.
Although only a minority of patients with type 1 diabetes fall into this category,
of those who do, most are of African or Asian ancestry. Individuals with this form
of diabetes suffer from episodic ketoacidosis and exhibit varying degrees of insulin
deficiency between episodes. This form of diabetes is strongly inherited, lacks immunological
evidence for β-cell autoimmunity, and is not HLA associated. An absolute requirement
for insulin replacement therapy in affected patients may come and go.
Type 2 diabetes (ranging from predominantly insulin resistance with relative insulin
deficiency to predominantly an insulin secretory defect with insulin resistance)
This form of diabetes, which accounts for ∼90–95% of those with diabetes, previously
referred to as non–insulin-dependent diabetes, type 2 diabetes, or adult-onset diabetes,
encompasses individuals who have insulin resistance and usually have relative (rather
than absolute) insulin deficiency At least initially, and often throughout their lifetime,
these individuals do not need insulin treatment to survive. There are probably many
different causes of this form of diabetes. Although the specific etiologies are not
known, autoimmune destruction of β-cells does not occur, and patients do not have
any of the other causes of diabetes listed above or below.
Most patients with this form of diabetes are obese, and obesity itself causes some
degree of insulin resistance. Patients who are not obese by traditional weight criteria
may have an increased percentage of body fat distributed predominantly in the abdominal
region. Ketoacidosis seldom occurs spontaneously in this type of diabetes; when seen,
it usually arises in association with the stress of another illness such as infection.
This form of diabetes frequently goes undiagnosed for many years because the hyperglycemia
develops gradually and at earlier stages is often not severe enough for the patient
to notice any of the classic symptoms of diabetes. Nevertheless, such patients are
at increased risk of developing macrovascular and microvascular complications. Whereas
patients with this form of diabetes may have insulin levels that appear normal or
elevated, the higher blood glucose levels in these diabetic patients would be expected
to result in even higher insulin values had their β-cell function been normal. Thus,
insulin secretion is defective in these patients and insufficient to compensate for
insulin resistance. Insulin resistance may improve with weight reduction and/or pharmacological
treatment of hyperglycemia but is seldom restored to normal. The risk of developing
this form of diabetes increases with age, obesity, and lack of physical activity.
It occurs more frequently in women with prior GDM and in individuals with hypertension
or dyslipidemia, and its frequency varies in different racial/ethnic subgroups. It
is often associated with a strong genetic predisposition, more so than is the autoimmune
form of type 1 diabetes. However, the genetics of this form of diabetes are complex
and not clearly defined.
Other specific types of diabetes
Genetic defects of the β-cell.
Several forms of diabetes are associated with monogenetic defects in β-cell function.
These forms of diabetes are frequently characterized by onset of hyperglycemia at
an early age (generally before age 25 years). They are referred to as maturity-onset
diabetes of the young (MODY) and are characterized by impaired insulin secretion with
minimal or no defects in insulin action. They are inherited in an autosomal dominant
pattern. Abnormalities at six genetic loci on different chromosomes have been identified
to date. The most common form is associated with mutations on chromosome 12 in a hepatic
transcription factor referred to as hepatocyte nuclear factor (HNF)-1α. A second form
is associated with mutations in the glucokinase gene on chromosome 7p and results
in a defective glucokinase molecule. Glucokinase converts glucose to glucose-6-phosphate,
the metabolism of which, in turn, stimulates insulin secretion by the β-cell. Thus,
glucokinase serves as the “glucose sensor” for the β-cell. Because of defects in the
glucokinase gene, increased plasma levels of glucose are necessary to elicit normal
levels of insulin secretion. The less common forms result from mutations in other
transcription factors, including HNF-4α, HNF-1β, insulin promoter factor (IPF)-1,
Point mutations in mitochondrial DNA have been found to be associated with diabetes
and deafness The most common mutation occurs at position 3,243 in the tRNA leucine
gene, leading to an A-to-G transition. An identical lesion occurs in the MELAS syndrome
(mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like syndrome);
however, diabetes is not part of this syndrome, suggesting different phenotypic expressions
of this genetic lesion.
Genetic abnormalities that result in the inability to convert proinsulin to insulin
have been identified in a few families, and such traits are inherited in an autosomal
dominant pattern. The resultant glucose intolerance is mild. Similarly, the production
of mutant insulin molecules with resultant impaired receptor binding has also been
identified in a few families and is associated with an autosomal inheritance and only
mildly impaired or even normal glucose metabolism.
Genetic defects in insulin action.
There are unusual causes of diabetes that result from genetically determined abnormalities
of insulin action. The metabolic abnormalities associated with mutations of the insulin
receptor may range from hyperinsulinemia and modest hyperglycemia to severe diabetes.
Some individuals with these mutations may have acanthosis nigricans. Women may be
virilized and have enlarged, cystic ovaries. In the past, this syndrome was termed
type A insulin resistance. Leprechaunism and the Rabson-Mendenhall syndrome are two
pediatric syndromes that have mutations in the insulin receptor gene with subsequent
alterations in insulin receptor function and extreme insulin resistance. The former
has characteristic facial features and is usually fatal in infancy, while the latter
is associated with abnormalities of teeth and nails and pineal gland hyperplasia.
Alterations in the structure and function of the insulin receptor cannot be demonstrated
in patients with insulin-resistant lipoatrophic diabetes. Therefore, it is assumed
that the lesion(s) must reside in the postreceptor signal transduction pathways.
Diseases of the exocrine pancreas.
Any process that diffusely injures the pancreas can cause diabetes. Acquired processes
include pancreatitis, trauma, infection, pancreatectomy, and pancreatic carcinoma.
With the exception of that caused by cancer, damage to the pancreas must be extensive
for diabetes to occur; adrenocarcinomas that involve only a small portion of the pancreas
have been associated with diabetes. This implies a mechanism other than simple reduction
in β-cell mass. If extensive enough, cystic fibrosis and hemochromatosis will also
damage β-cells and impair insulin secretion. Fibrocalculous pancreatopathy may be
accompanied by abdominal pain radiating to the back and pancreatic calcifications
identified on X-ray examination. Pancreatic fibrosis and calcium stones in the exocrine
ducts have been found at autopsy.
Several hormones (e.g., growth hormone, cortisol, glucagon, epinephrine) antagonize
insulin action. Excess amounts of these hormones (e.g., acromegaly, Cushing's syndrome,
glucagonoma, pheochromocytoma, respectively) can cause diabetes. This generally occurs
in individuals with preexisting defects in insulin secretion, and hyperglycemia typically
resolves when the hormone excess is resolved.
Somatostatinoma- and aldosteronoma-induced hypokalemia can cause diabetes, at least
in part, by inhibiting insulin secretion. Hyperglycemia generally resolves after successful
removal of the tumor.
Drug- or chemical-induced diabetes.
Many drugs can impair insulin secretion. These drugs may not cause diabetes by themselves,
but they may precipitate diabetes in individuals with insulin resistance. In such
cases, the classification is unclear because the sequence or relative importance of
β-cell dysfunction and insulin resistance is unknown. Certain toxins such as Vacor
(a rat poison) and intravenous pentamidine can permanently destroy pancreatic β-cells.
Such drug reactions fortunately are rare. There are also many drugs and hormones that
can impair insulin action. Examples include nicotinic acid and glucocorticoids. Patients
receiving α-interferon have been reported to develop diabetes associated with islet
cell antibodies and, in certain instances, severe insulin deficiency. The list shown
in Table 1 is not all-inclusive, but reflects the more commonly recognized drug-,
hormone-, or toxin-induced forms of diabetes.
Etiologic classification of diabetes mellitus
Type 1 diabetes (β-cell destruction, usually leading to absolute insulin deficiency)
Type 2 diabetes (may range from predominantly insulin resistance with relative insulin
deficiency to a predominantly secretory defect with insulin resistance)
Other specific types
Genetic defects of β-cell function
Chromosome 12, HNF-1α (MODY3)
Chromosome 7, glucokinase (MODY2)
Chromosome 20, HNF-4α (MODY1)
Chromosome 13, insulin promoter factor-1 (IPF-1; MODY4)
Chromosome 17, HNF-1β (MODY5)
Chromosome 2, NeuroD1 (MODY6)
Genetic defects in insulin action
Type A insulin resistance
Diseases of the exocrine pancreas
Drug or chemical induced
Uncommon forms of immune-mediated diabetes
Anti-insulin receptor antibodies
Other genetic syndromes sometimes associated with diabetes
Gestational diabetes mellitus
Patients with any form of diabetes may require insulin treatment at some stage of
their disease. Such use of insulin does not, of itself, classify the patient.
Certain viruses have been associated with β-cell destruction. Diabetes occurs in patients
with congenital rubella, although most of these patients have HLA and immune markers
characteristic of type 1 diabetes. In addition, coxsackievirus B, cytomegalovirus,
adenovirus, and mumps have been implicated in inducing certain cases of the disease.
Uncommon forms of immune-mediated diabetes.
In this category, there are two known conditions, and others are likely to occur.
The stiff-man syndrome is an autoimmune disorder of the central nervous system characterized
by stiffness of the axial muscles with painful spasms. Patients usually have high
titers of the GAD autoantibodies, and approximately one-third will develop diabetes.
Anti-insulin receptor antibodies can cause diabetes by binding to the insulin receptor,
thereby blocking the binding of insulin to its receptor in target tissues. However,
in some cases, these antibodies can act as an insulin agonist after binding to the
receptor and can thereby cause hypoglycemia. Anti-insulin receptor antibodies are
occasionally found in patients with systemic lupus erythematosus and other autoimmune
diseases. As in other states of extreme insulin resistance, patients with anti-insulin
receptor antibodies often have acanthosis nigricans. In the past, this syndrome was
termed type B insulin resistance.
Other genetic syndromes sometimes associated with diabetes.
Many genetic syndromes are accompanied by an increased incidence of diabetes. These
include the chromosomal abnormalities of Down syndrome, Klinefelter syndrome, and
Turner syndrome. Wolfram's syndrome is an autosomal recessive disorder characterized
by insulin-deficient diabetes and the absence of β-cells at autopsy. Additional manifestations
include diabetes insipidus, hypogonadism, optic atrophy, and neural deafness. Other
syndromes are listed in Table 1.
Gestational diabetes mellitus
For many years, GDM has been defined as any degree of glucose intolerance with onset
or first recognition during pregnancy. Although most cases resolve with delivery,
the definition applied whether or not the condition persisted after pregnancy and
did not exclude the possibility that unrecognized glucose intolerance may have antedated
or begun concomitantly with the pregnancy. This definition facilitated a uniform strategy
for detection and classification of GDM, but its limitations were recognized for many
years. As the ongoing epidemic of obesity and diabetes has led to more type 2 diabetes
in women of childbearing age, the number of pregnant women with undiagnosed type 2
diabetes has increased.
After deliberations in 2008–2009, the International Association of Diabetes and Pregnancy
Study Groups (IADPSG), an international consensus group with representatives from
multiple obstetrical and diabetes organizations, including the American Diabetes Association
(ADA), recommended that high-risk women found to have diabetes at their initial prenatal
visit, using standard criteria (Table 3), receive a diagnosis of overt, not gestational,
diabetes. Approximately 7% of all pregnancies (ranging from 1 to 14%, depending on
the population studied and the diagnostic tests employed) are complicated by GDM,
resulting in more than 200,000 cases annually.
CATEGORIES OF INCREASED RISK FOR DIABETES
In 1997 and 2003, The Expert Committee on Diagnosis and Classification of Diabetes
Mellitus (1,2) recognized an intermediate group of individuals whose glucose levels
do not meet criteria for diabetes, yet are higher than those considered normal. These
people were defined as having impaired fasting glucose (IFG) [fasting plasma glucose
(FPG) levels 100 mg/dl (5.6 mmol/l) to 125 mg/dl (6.9 mmol/l)], or impaired glucose
tolerance (IGT) [2-h values in the oral glucose tolerance test (OGTT) of 140 mg/dl
(7.8 mmol/l) to 199 mg/dl (11.0 mmol/l)].
Individuals with IFG and/or IGT have been referred to as having pre-diabetes, indicating
the relatively high risk for the future development of diabetes. IFG and IGT should
not be viewed as clinical entities in their own right but rather risk factors for
diabetes as well as cardiovascular disease. They can be observed as intermediate stages
in any of the disease processes listed in Table 1. IFG and IGT are associated with
obesity (especially abdominal or visceral obesity), dyslipidemia with high triglycerides
and/or low HDL cholesterol, and hypertension. Structured lifestyle intervention, aimed
at increasing physical activity and producing 5–10% loss of body weight, and certain
pharmacological agents have been demonstrated to prevent or delay the development
of diabetes in people with IGT; the potential impact of such interventions to reduce
mortality or the incidence of cardiovascular disease has not been demonstrated to
date. It should be noted that the 2003 ADA Expert Committee report reduced the lower
FPG cut point to define IFG from 110 mg/dl (6.1 mmol/l) to 100 mg/dl (5.6 mmol/l),
in part to ensure that prevalence of IFG was similar to that of IGT. However, the
World Health Organization (WHO) and many other diabetes organizations did not adopt
this change in the definition of IFG.
As A1C is used more commonly to diagnose diabetes in individuals with risk factors,
it will also identify those at higher risk for developing diabetes in the future.
When recommending the use of the A1C to diagnose diabetes in its 2009 report, the
International Expert Committee (3) stressed the continuum of risk for diabetes with
all glycemic measures and did not formally identify an equivalent intermediate category
for A1C. The group did note that those with A1C levels above the laboratory “normal”
range but below the diagnostic cut point for diabetes (6.0 to <6.5%) are at very high
risk of developing diabetes. Indeed, incidence of diabetes in people with A1C levels
in this range is more than 10 times that of people with lower levels (4
–7). However, the 6.0 to <6.5% range fails to identify a substantial number of patients
who have IFG and/or IGT. Prospective studies indicate that people within the A1C range
of 5.5–6.0% have a 5-year cumulative incidence of diabetes that ranges from 12 to
–7), which is appreciably (three- to eightfold) higher than incidence in the U.S.
population as a whole (8). Analyses of nationally representative data from the National
Health and Nutrition Examination Survey (NHANES) indicate that the A1C value that
most accurately identifies people with IFG or IGT falls between 5.5 and 6.0%. In addition,
linear regression analyses of these data indicate that among the nondiabetic adult
population, an FPG of 110 mg/dl (6.1 mmol/l) corresponds to an A1C of 5.6%, while
an FPG of 100 mg/dl (5.6 mmol/l) corresponds to an A1C of 5.4% (R.T. Ackerman, personal
communication). Finally, evidence from the Diabetes Prevention Program (DPP), wherein
the mean A1C was 5.9% (SD 0.5%), indicates that preventive interventions are effective
in groups of people with A1C levels both below and above 5.9% (9). For these reasons,
the most appropriate A1C level above which to initiate preventive interventions is
likely to be somewhere in the range of 5.5–6%.
As was the case with FPG and 2-h PG, defining a lower limit of an intermediate category
of A1C is somewhat arbitrary, as the risk of diabetes with any measure or surrogate
of glycemia is a continuum, extending well into the normal ranges. To maximize equity
and efficiency of preventive interventions, such an A1C cut point should balance the
costs of “false negatives” (failing to identify those who are going to develop diabetes)
against the costs of “false positives” (falsely identifying and then spending intervention
resources on those who were not going to develop diabetes anyway).
Compared to the fasting glucose cutpoint of 100 mg/dl (5.6 mmol/l), an A1C cutpoint
of 5.7% is less sensitive but more specific and has a higher positive predictive value
to identify people at risk for later development of diabetes. A large prospective
study found that a 5.7% cutpoint has a sensitivity of 66% and specificity of 88% for
the identification of subsequent 6-year diabetes incidence (10). Receiver operating
curve analyses of nationally representative U.S. data (NHANES 1999-2006) indicate
that an A1C value of 5.7% has modest sensitivity (39-45%) but high specificity (81-91%)
to identify cases of IFP (FPG >100 mg/dl) (5.6 mmol/l) or IGT (2-h glucose > 140 mg/dl)
(R.T. Ackerman, personal communication). Other analyses suggest that an A1C of 5.7%
is associated with diabetes risk similar to the high-risk participants in the DPP
(R.T. Ackerman, personal communication). Hence, it is reasonable to consider an A1C
range of 5.7 to 6.4% as identifying individuals with high risk for future diabetes
and to whom the term pre-diabetes may be applied if desired.
Individuals with an A1C of 5.7–6.4% should be informed of their increased risk for
diabetes as well as cardiovascular disease and counseled about effective strategies,
such as weight loss and physical activity, to lower their risks. As with glucose measurements,
the continuum of risk is curvilinear, so that as A1C rises, the risk of diabetes rises
disproportionately. Accordingly, interventions should be most intensive and follow-up
should be particularly vigilant for those with A1C levels above 6.0%, who should be
considered to be at very high risk. However, just as an individual with a fasting
glucose of 98 mg/dl (5.4 mmol/l) may not be at negligible risk for diabetes, individuals
with A1C levels below 5.7% may still be at risk, depending on level of A1C and presence
of other risk factors, such as obesity and family history.
Table 2 summarizes the categories of increased risk for diabetes. Evaluation of patients
at risk should incorporate a global risk factor assessment for both diabetes and cardiovascular
disease. Screening for and counseling about risk of diabetes should always be in the
pragmatic context of the patient's comorbidities, life expectancy, personal capacity
to engage in lifestyle change, and overall health goals.
Categories of increased risk for diabetes*
FPG 100 mg/dl (5.6 mmol/l) to 125 mg/dl (6.9 mmol/l) [IFG]
2-h PG in the 75-g OGTT 140 mg/dl (7.8 mmol/l) to 199 mg/dl (11.0 mmol/l) [IGT]
*For all three tests, risk is continuous, extending below the lower limit of the range
and becoming disproportionately greater at higher ends of the range.
DIAGNOSTIC CRITERIA FOR DIABETES MELLITUS
For decades, the diagnosis of diabetes has been based on glucose criteria, either
the FPG or the 75-g OGTT. In 1997, the first Expert Committee on the Diagnosis and
Classification of Diabetes Mellitus revised the diagnostic criteria, using the observed
association between FPG levels and presence of retinopathy as the key factor with
which to identify threshold glucose level. The Committee examined data from three
cross-sectional epidemiologic studies that assessed retinopathy with fundus photography
or direct ophthalmoscopy and measured glycemia as FPG, 2-h PG, and A1C. These studies
demonstrated glycemic levels below which there was little prevalent retinopathy and
above which the prevalence of retinopathy increased in an apparently linear fashion.
The deciles of the three measures at which retinopathy began to increase were the
same for each measure within each population. Moreover, the glycemic values above
which retinopathy increased were similar among the populations. These analyses helped
to inform a new diagnostic cut point of ≥126 mg/dl (7.0 mmol/l) for FPG and confirmed
the long-standing diagnostic 2-h PG value of ≥200 mg/dl (11.1 mmol/l).
A1C is a widely used marker of chronic glycemia, reflecting average blood glucose
levels over a 2- to 3-month period of time. The test plays a critical role in the
management of the patient with diabetes, since it correlates well with both microvascular
and, to a lesser extent, macrovascular complications and is widely used as the standard
biomarker for the adequacy of glycemic management. Prior Expert Committees have not
recommended use of the A1C for diagnosis of diabetes, in part due to lack of standardization
of the assay. However, A1C assays are now highly standardized so that their results
can be uniformly applied both temporally and across populations. In their recent report
(3), an International Expert Committee, after an extensive review of both established
and emerging epidemiological evidence, recommended the use of the A1C test to diagnose
diabetes, with a threshold of ≥6.5%, and ADA affirms this decision. The diagnostic
A1C cut point of 6.5% is associated with an inflection point for retinopathy prevalence,
as are the diagnostic thresholds for FPG and 2-h PG (3). The diagnostic test should
be performed using a method that is certified by the National Glycohemoglobin Standardization
Program (NGSP) and standardized or traceable to the Diabetes Control and Complications
Trial reference assay. Point-of-care A1C assays are not sufficiently accurate at this
time to use for diagnostic purposes.
There is an inherent logic to using a more chronic versus an acute marker of dysglycemia,
particularly since the A1C is already widely familiar to clinicians as a marker of
glycemic control. Moreover, the A1C has several advantages to the FPG, including greater
convenience, since fasting is not required, evidence to suggest greater preanalytical
stability, and less day-to-day perturbations during periods of stress and illness.
These advantages, however, must be balanced by greater cost, the limited availability
of A1C testing in certain regions of the developing world, and the incomplete correlation
between A1C and average glucose in certain individuals. In addition, the A1C can be
misleading in patients with certain forms of anemia and hemoglobinopathies, which
may also have unique ethnic or geographic distributions. For patients with a hemoglobinopathy
but normal red cell turnover, such as sickle cell trait, an A1C assay without interference
from abnormal hemoglobins should be used (an updated list is available at www.ngsp.org/prog/index3.html).
For conditions with abnormal red cell turnover, such as anemias from hemolysis and
iron deficiency, the diagnosis of diabetes must employ glucose criteria exclusively.
The established glucose criteria for the diagnosis of diabetes remain valid. These
include the FPG and 2-h PG. Additionally, patients with severe hyperglycemia such
as those who present with severe classic hyperglycemic symptoms or hyperglycemic crisis
can continue to be diagnosed when a random (or casual) plasma glucose of ≥200 mg/dl
(11.1 mmol/l) is found. It is likely that in such cases the health care professional
would also measure an A1C test as part of the initial assessment of the severity of
the diabetes and that it would (in most cases) be above the diagnostic cut point for
diabetes. However, in rapidly evolving diabetes, such as the development of type 1
diabetes in some children, A1C may not be significantly elevated despite frank diabetes.
Just as there is less than 100% concordance between the FPG and 2-h PG tests, there
is not full concordance between A1C and either glucose-based test. Analyses of NHANES
data indicate that, assuming universal screening of the undiagnosed, the A1C cut point
of ≥6.5% identifies one-third fewer cases of undiagnosed diabetes than a fasting glucose
cut point of ≥126 mg/dl (7.0 mmol/l) (cdc website tbd). However, in practice, a large
portion of the population with type 2 diabetes remains unaware of their condition.
Thus, it is conceivable that the lower sensitivity of A1C at the designated cut point
will be offset by the test's greater practicality, and that wider application of a
more convenient test (A1C) may actually increase the number of diagnoses made.
Further research is needed to better characterize those patients whose glycemic status
might be categorized differently by two different tests (e.g., FPG and A1C), obtained
in close temporal approximation. Such discordance may arise from measurement variability,
change over time, or because A1C, FPG, and postchallenge glucose each measure different
physiological processes. In the setting of an elevated A1C but “nondiabetic” FPG,
the likelihood of greater postprandial glucose levels or increased glycation rates
for a given degree of hyperglycemia may be present. In the opposite scenario (high
FPG yet A1C below the diabetes cut point), augmented hepatic glucose production or
reduced glycation rates may be present.
As with most diagnostic tests, a test result diagnostic of diabetes should be repeated
to rule out laboratory error, unless the diagnosis is clear on clinical grounds, such
as a patient with classic symptoms of hyperglycemia or hyperglycemic crisis. It is
preferable that the same test be repeated for confirmation, since there will be a
greater likelihood of concurrence in this case. For example, if the A1C is 7.0% and
a repeat result is 6.8%, the diagnosis of diabetes is confirmed. However, there are
scenarios in which results of two different tests (e.g., FPG and A1C) are available
for the same patient. In this situation, if the two different tests are both above
the diagnostic thresholds, the diagnosis of diabetes is confirmed.
On the other hand, when two different tests are available in an individual and the
results are discordant, the test whose result is above the diagnostic cut point should
be repeated, and the diagnosis is made on the basis of the confirmed test. That is,
if a patient meets the diabetes criterion of the A1C (two results ≥6.5%) but not the
FPG (<126 mg/dl or 7.0 mmol/l), or vice versa, that person should be considered to
have diabetes. Admittedly, in most circumstance the “nondiabetic” test is likely to
be in a range very close to the threshold that defines diabetes.
Since there is preanalytic and analytic variability of all the tests, it is also possible
that when a test whose result was above the diagnostic threshold is repeated, the
second value will be below the diagnostic cut point. This is least likely for A1C,
somewhat more likely for FPG, and most likely for the 2-h PG. Barring a laboratory
error, such patients are likely to have test results near the margins of the threshold
for a diagnosis. The healthcare professional might opt to follow the patient closely
and repeat the testing in 3–6 months.
The decision about which test to use to assess a specific patient for diabetes should
be at the discretion of the health care professional, taking into account the availability
and practicality of testing an individual patient or groups of patients. Perhaps more
important than which diagnostic test is used, is that the testing for diabetes be
performed when indicated. There is discouraging evidence indicating that many at-risk
patients still do not receive adequate testing and counseling for this increasingly
common disease, or for its frequently accompanying cardiovascular risk factors. The
current diagnostic criteria for diabetes are summarized in Table 3.
Criteria for the diagnosis of diabetes
1. A1C ≥6.5%. The test should be performed in a laboratory using a method that is
NGSP certified and standardized to the DCCT assay.*
2. FPG ≥126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least
3. 2-h plasma glucose ≥200 mg/dl (11.1 mmol/l) during an OGTT. The test should be
performed as described by the World Health Organization, using a glucose load containing
the equivalent of 75 g anhydrous glucose dissolved in water.*
4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a
random plasma glucose ≥200 mg/dl (11.1 mmol/l).
*In the absence of unequivocal hyperglycemia, criteria 1–3 should be confirmed by
Diagnosis of GDM
At the time of publication of this statement, the criteria for abnormal glucose tolerance
in pregnancy are those of Carpenter and Coustan (11). Recommendations from ADA's Fourth
International Workshop-Conference on Gestational Diabetes Mellitus held in March 1997
support the use of the Carpenter/Coustan diagnostic criteria as well as the alternative
use of a diagnostic 75-g 2-h OGTT. These criteria are summarized below.
Testing for gestational diabetes.
Previous recommendations included screening for GDM performed in all pregnancies.
However, there are certain factors that place women at lower risk for the development
of glucose intolerance during pregnancy, and it is likely not cost-effective to screen
such patients. Pregnant women who fulfill all of these criteria need not be screened
This low-risk group comprises women who:
are <25 years of age
are a normal body weight
have no family history (i.e., first-degree relative) of diabetes
have no history of abnormal glucose metabolism
have no history of poor obstetric outcome
are not members of an ethnic/racial group with a high prevalence of diabetes (e.g.,
Hispanic American, Native American, Asian American, African American, Pacific Islander)
Risk assessment for GDM should be undertaken at the first prenatal visit. Women with
clinical characteristics consistent with a high risk of GDM (marked obesity, personal
history of GDM, glycosuria, or a strong family history of diabetes) should undergo
glucose testing (see below) as soon as feasible. If they are found not to have GDM
at that initial screening, they should be retested between 24 and 28 weeks of gestation.
Women of average risk should have testing undertaken at 24–28 weeks of gestation.
An FPG level >126 mg/dl (7.0 mmol/l) or a casual plasma glucose >200 mg/dl (11.1 mmol/l)
meets the threshold for the diagnosis of diabetes. In the absence of unequivocal hyperglycemia,
the diagnosis must be confirmed on a subsequent day. Confirmation of the diagnosis
precludes the need for any glucose challenge. In the absence of this degree of hyperglycemia,
evaluation for GDM in women with average or high-risk characteristics should follow
one of two approaches.
Perform a diagnostic OGTT without prior plasma or serum glucose screening. The one-step
approach may be cost-effective in high-risk patients or populations (e.g., some Native-American
Perform an initial screening by measuring the plasma or serum glucose concentration
1 h after a 50-g oral glucose load (glucose challenge test [GCT]) and perform a diagnostic
OGTT on that subset of women exceeding the glucose threshold value on the GCT. When
the two-step approach is used, a glucose threshold value >140 mg/dl (7.8 mmol/l) identifies
∼80% of women with GDM, and the yield is further increased to 90% by using a cutoff
of >130 mg/dl (7.2 mmol/l).
With either approach, the diagnosis of GDM is based on an OGTT. Diagnostic criteria
for the 100-g OGTT are derived from the original work of O'Sullivan and Mahan (12)
modified by Carpenter and Coustan (11) and are shown at the top of Table 4. Alternatively,
the diagnosis can be made using a 75-g glucose load and the glucose threshold values
listed for fasting, 1 h, and 2 h (Table 4, bottom); however, this test is not as well
validated as the 100-g OGTT.
Diagnosis of GDM with a 100-g or 75-g glucose load
100-g glucose load
75-g glucose load
Two or more of the venous plasma concentrations must be met or exceeded for a positive
diagnosis. The test should be done in the morning after an overnight fast of between
8 and 14 h and after at least 3 days of unrestricted diet (≥150 g carbohydrate per
day) and unlimited physical activity. The subject should remain seated and should
not smoke throughout the test.
Results of the Hyperglycemia and Adverse Pregnancy Outcomes study (13), a large-scale
(∼25,000 pregnant women) multinational epidemiologic study, demonstrated that risk
of adverse maternal, fetal, and neonatal outcomes continuously increased as a function
of maternal glycemia at 24–28 weeks, even within ranges previously considered normal
for pregnancy. For most complications, there was no threshold for risk. These results
have led to careful reconsideration of the diagnostic criteria for GDM. The IADPSG
recommended that all women not known to have prior diabetes undergo a 75-g OGTT at
24–28 weeks of gestation. The group developed diagnostic cut points for the fasting,
1-h, and 2-h plasma glucose measurements that conveyed an odds ratio for adverse outcomes
of at least 1.75 compared with women with the mean glucose levels in the HAPO study.
At the time of publication of this update, ADA is planning to work with U.S. obstetrical
organizations to consider adoption of the IADPSG diagnostic criteria and to discuss
the implications of this change. While this change will significantly increase the
prevalence of GDM, there is mounting evidence that treating even mild GDM reduces
morbidity for both mother and baby (14).