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Diabetes Care Volume 37, Supplement 1, January 2014 S81

Diagnosis and Classication of American Diabetes Association

Diabetes Mellitus
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
different organs, 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 pancreatic b-cells with consequent
insulin deciency to abnormalities that result in resistance to insulin action. The
basis of the abnormalities in carbohydrate, fat, and protein metabolism in diabetes
is decient action of insulin on target tissues. Decient insulin action results from

POSITION STATEMENT
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 syndrome.
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 deciency of insulin secretion. Individuals at increased risk of
developing this type of diabetes can often be identied 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 sufcient 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 glucose load or by A1C.
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 fullling the criteria for the diagnosis of diabetes. In some individuals
Updated Fall 2013.
with diabetes, adequate glycemic control can be achieved with weight reduction, DOI: 10.2337/dc14-S081
exercise, and/or oral glucose-lowering agents. These individuals therefore do not 2014 by the American Diabetes Association.
require insulin. Other individuals who have some residual insulin secretion but See http://creativecommons.org/licenses/by-
require exogenous insulin for adequate glycemic control can survive without it. nc-nd/3.0/ for details.
S82 Position Statement Diabetes Care Volume 37, Supplement 1, January 2014

Figure 1Disorders of glycemia: etiologic types and stages. *Even after presenting in ketoacidosis, these patients can briey 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.

Individuals with extensive b-cell develops diabetes years later. Because HLA-DR/DQ alleles can be either
destruction and therefore no residual thiazides in themselves seldom cause predisposing or protective.
insulin secretion require insulin for severe hyperglycemia, such individuals In this form of diabetes, the rate of
survival. The severity of the metabolic probably have type 2 diabetes that is b-cell destruction is quite variable,
abnormality can progress, regress, or exacerbated by the drug. Thus, for the being rapid in some individuals (mainly
stay the same. Thus, the degree of clinician and patient, it is less important infants and children) and slow in others
hyperglycemia reects the severity of to label the particular type of diabetes (mainly adults). Some patients,
the underlying metabolic process and its than it is to understand the particularly children and adolescents,
treatment more than the nature of the pathogenesis of the hyperglycemia and may present with ketoacidosis as the
process itself. to treat it effectively. rst manifestation of the disease.
CLASSIFICATION OF DIABETES Type 1 Diabetes (b-Cell Destruction, Others have modest fasting
MELLITUS AND OTHER Usually Leading to Absolute Insulin hyperglycemia that can rapidly change
CATEGORIES OF GLUCOSE Deciency) to severe hyperglycemia and/or
REGULATION Immune-Mediated Diabetes
ketoacidosis in the presence of infection
Assigning a type of diabetes to an This form of diabetes, which accounts or other stress. Still others, particularly
individual often depends on the for only 510% of those with diabetes, adults, may retain residual b-cell
circumstances present at the time of previously encompassed by the terms function sufcient to prevent
diagnosis, and many diabetic individuals insulin-dependent diabetes or juvenile- ketoacidosis for many years; such
do not easily t into a single class. For onset diabetes, results from a cellular- individuals eventually become
example, a person diagnosed with mediated autoimmune destruction of dependent on insulin for survival and
gestational diabetes mellitus (GDM) the b-cells of the pancreas. Markers of are at risk for ketoacidosis. At this latter
may continue to be hyperglycemic after the immune destruction of the b-cell stage of the disease, there is little or no
delivery and may be determined to include islet cell autoantibodies, insulin secretion, as manifested by low
have, in fact, type 2 diabetes. autoantibodies to insulin, autoantibodies or undetectable levels of plasma
Alternatively, a person who acquires to GAD (GAD65), and autoantibodies to C-peptide. Immune-mediated diabetes
diabetes because of large doses of the tyrosine phosphatases IA-2 and commonly occurs in childhood and
exogenous steroids may become IA-2b. One and usually more of these adolescence, but it can occur at any age,
normoglycemic once the autoantibodies are present in 8590% even in the 8th and 9th decades of life.
glucocorticoids are discontinued, but of individuals when fasting hyperglycemia Autoimmune destruction of b-cells
then may develop diabetes many years is initially detected. Also, the disease has has multiple genetic predispositions and
later after recurrent episodes of strong HLA associations, with linkage to is also related to environmental factors
pancreatitis. Another example would the DQA and DQB genes, and it is that are still poorly dened. Although
be a person treated with thiazides who inuenced by the DRB genes. These patients are rarely obese when they
care.diabetesjournals.org Position Statement S83

present with this type of diabetes, the abdominal region. Ketoacidosis seldom chromosome 12 in a hepatic
presence of obesity is not incompatible occurs spontaneously in this type of transcription factor referred to as
with the diagnosis. These patients are diabetes; when seen, it usually arises in hepatocyte nuclear factor (HNF)-1a.
also prone to other autoimmune association with the stress of another A second form is associated with
disorders such as Graves disease, illness such as infection. This form of mutations in the glucokinase gene on
Hashimotos thyroiditis, Addisons diabetes frequently goes undiagnosed chromosome 7p and results in a
disease, vitiligo, celiac sprue, for many years because the defective glucokinase molecule.
autoimmune hepatitis, myasthenia hyperglycemia develops gradually and Glucokinase converts glucose to
gravis, and pernicious anemia. at earlier stages is often not severe glucose-6-phosphate, the metabolism
enough for the patient to notice any of of which, in turn, stimulates insulin
Idiopathic Diabetes
the classic symptoms of diabetes. secretion by the b-cell. Thus,
Some forms of type 1 diabetes have no
Nevertheless, such patients are at glucokinase serves as the glucose
known etiologies. Some of these
increased risk of developing sensor for the b-cell. Because of
patients have permanent insulinopenia
macrovascular and microvascular defects in the glucokinase gene,
and are prone to ketoacidosis, but have
complications. Whereas patients with increased plasma levels of glucose are
no evidence of autoimmunity. Although
this form of diabetes may have insulin necessary to elicit normal levels of
only a minority of patients with type 1
levels that appear normal or elevated, insulin secretion. The less common
diabetes fall into this category, of those
the higher blood glucose levels in these forms result from mutations in other
who do, most are of African or Asian
diabetic patients would be expected to transcription factors, including
ancestry. Individuals with this form of
result in even higher insulin values had HNF-4a, HNF-1b, insulin promoter
diabetes suffer from episodic ketoacidosis
their b-cell function been normal. Thus, factor (IPF)-1, and NeuroD1.
and exhibit varying degrees of insulin
insulin secretion is defective in these
deciency between episodes. This form of Diabetes diagnosed in the rst 6 months
patients and insufcient to compensate
diabetes is strongly inherited, lacks of life has been shown not to be typical
for insulin resistance. Insulin resistance
immunological evidence for b-cell autoimmune type 1 diabetes. This so-
may improve with weight reduction
autoimmunity, and is not HLA associated. called neonatal diabetes can either be
and/or pharmacological treatment of
An absolute requirement for insulin transient or permanent. The most
hyperglycemia but is seldom restored to
replacement therapy in affected patients common genetic defect causing
normal. The risk of developing this form
may come and go. transient disease is a defect on ZAC/
of diabetes increases with age, obesity,
HYAMI imprinting, whereas permanent
Type 2 Diabetes (Ranging From and lack of physical activity. It occurs
neonatal diabetes is most commonly a
Predominantly Insulin Resistance With more frequently in women with prior
defect in the gene encoding the Kir6.2
GDM and in individuals with
Relative Insulin Deciency to subunit of the b-cell KATP channel.
Predominantly an Insulin Secretory hypertension or dyslipidemia, and its
Diagnosing the latter has implications,
Defect With Insulin Resistance) frequency varies in different racial/
since such children can be well managed
ethnic subgroups. It is often associated
This form of diabetes, which accounts with sulfonylureas.
with a strong genetic predisposition,
for ;9095% of those with diabetes, more so than is the autoimmune form Point mutations in mitochondrial DNA
previously referred to as noninsulin- of type 1 diabetes. However, the have been found to be associated with
dependent diabetes, type 2 diabetes, or genetics of this form of diabetes are diabetes and deafness. The most
adult-onset diabetes, encompasses complex and not fully dened. common mutation occurs at position
individuals who have insulin resistance 3,243 in the tRNA leucine gene, leading
and usually have relative (rather than Other Specic Types of Diabetes to an A-to-G transition. An identical
absolute) insulin deciency. At least Genetic Defects of the b-Cell lesion occurs in the MELAS syndrome
initially, and often throughout their Several forms of diabetes are associated (mitochondrial myopathy,
lifetime, these individuals do not need with monogenetic defects in b-cell encephalopathy, lactic acidosis, and
insulin treatment to survive. There are function. These forms of diabetes are stroke-like syndrome); however,
probably many different causes of this frequently characterized by onset of diabetes is not part of this syndrome,
form of diabetes. Although the specic hyperglycemia at an early age (generally suggesting different phenotypic
etiologies are not known, autoimmune before age 25 years). They are referred expressions of this genetic lesion.
destruction of b-cells does not occur, to as maturity-onset diabetes of the Genetic abnormalities that result in the
and patients do not have any of the other young (MODY) and are characterized inability to convert proinsulin to insulin
causes of diabetes listed above or below. by impaired insulin secretion with have been identied in a few families,
Most patients with this form of diabetes minimal or no defects in insulin action. and such traits are inherited in an
are obese, and obesity itself causes They are inherited in an autosomal autosomal dominant pattern. The
some degree of insulin resistance. dominant pattern. Abnormalities at resultant glucose intolerance is mild.
Patients who are not obese by six genetic loci on different Similarly, the production of mutant
traditional weight criteria may have an chromosomes have been identied to insulin molecules with resultant
increased percentage of body fat date. The most common form is impaired receptor binding has also been
distributed predominantly in the associated with mutations on identied in a few families and is
S84 Position Statement Diabetes Care Volume 37, Supplement 1, January 2014

associated with an autosomal Endocrinopathies occur. The stiff-man syndrome is an


inheritance and only mildly impaired or Several hormones (e.g., growth autoimmune disorder of the central
even normal glucose metabolism. hormone, cortisol, glucagon, nervous system characterized by
epinephrine) antagonize insulin action. stiffness of the axial muscles with
Genetic Defects in Insulin Action Excess amounts of these hormones painful spasms. Patients usually have
There are unusual causes of diabetes that (e.g., acromegaly, Cushings syndrome, high titers of the GAD autoantibodies,
result from genetically determined glucagonoma, pheochromocytoma, and approximately one-third will
abnormalities of insulin action. The respectively) can cause diabetes. This develop diabetes.
metabolic abnormalities associated with generally occurs in individuals with
Anti-insulin receptor antibodies can
mutations of the insulin receptor may preexisting defects in insulin secretion,
cause diabetes by binding to the insulin
range from hyperinsulinemia and modest and hyperglycemia typically resolves
receptor, thereby blocking the binding
hyperglycemia to severe diabetes. Some when the hormone excess is resolved.
of insulin to its receptor in target
individuals with these mutations may have
Somatostatinomas and aldosteronoma- tissues. However, in some cases, these
acanthosis nigricans. Women may be
induced hypokalemia can cause antibodies can act as an insulin agonist
virilized and have enlarged, cystic ovaries.
diabetes, at least in part, by inhibiting after binding to the receptor and can
In the past, this syndrome was termed
insulin secretion. Hyperglycemia thereby cause hypoglycemia. Anti-
type A insulin resistance. Leprechaunism
generally resolves after successful insulin receptor antibodies are
and the Rabson-Mendenhall syndrome
removal of the tumor. occasionally found in patients with
are two pediatric syndromes that have
systemic lupus erythematosus and
mutations in the insulin receptor gene Drug- or Chemical-Induced Diabetes
other autoimmune diseases. As in other
with subsequent alterations in insulin Many drugs can impair insulin secretion. states of extreme insulin resistance,
receptor function and extreme insulin These drugs may not cause diabetes by patients with anti-insulin receptor
resistance. The former has characteristic themselves, but they may precipitate antibodies often have acanthosis
facial features and is usually fatal in diabetes in individuals with insulin nigricans. In the past, this syndrome was
infancy, while the latter is associated with resistance. In such cases, the termed type B insulin resistance.
abnormalities of teeth and nails and pineal classication is unclear because the
gland hyperplasia. sequence or relative importance of Other Genetic Syndromes Sometimes

Alterations in the structure and function b-cell dysfunction and insulin resistance Associated With Diabetes
is unknown. Certain toxins such as Vacor Many genetic syndromes are
of the insulin receptor cannot be accompanied by an increased incidence
demonstrated in patients with insulin- (a rat poison) and intravenous
pentamidine can permanently destroy of diabetes. These include the
resistant lipoatrophic diabetes. chromosomal abnormalities of Down
Therefore, it is assumed that the lesion(s) pancreatic b-cells. Such drug reactions
fortunately are rare. There are also syndrome, Klinefelter syndrome, and
must reside in the postreceptor signal Turner syndrome. Wolfram syndrome is
transduction pathways. many drugs and hormones that can
impair insulin action. Examples include an autosomal recessive disorder
Diseases of the Exocrine Pancreas nicotinic acid and glucocorticoids. characterized by insulin-decient
Any process that diffusely injures the Patients receiving a-interferon have diabetes and the absence of b-cells at
pancreas can cause diabetes. Acquired been reported to develop diabetes autopsy. Additional manifestations
processes include pancreatitis, trauma, associated with islet cell antibodies and, include diabetes insipidus,
infection, pancreatectomy, and in certain instances, severe insulin hypogonadism, optic atrophy, and
pancreatic carcinoma. With the deciency. The list shown in Table 1 is neural deafness. Other syndromes are
exception of that caused by cancer, not all-inclusive, but reects the more listed in Table 1.
damage to the pancreas must be commonly recognized drug-, hormone-,
extensive for diabetes to occur; or toxin-induced forms of diabetes. GDM
adrenocarcinomas that involve only a For many years, GDM has been dened
Infections
small portion of the pancreas have been as any degree of glucose intolerance
Certain viruses have been associated with
associated with diabetes. This implies a with onset or rst recognition during
b-cell destruction. Diabetes occurs in
mechanism other than simple pregnancy. Although most cases resolve
patients with congenital rubella, although
reduction in b-cell mass. If extensive with delivery, the denition applied
most of these patients have HLA and
enough, cystic brosis and whether or not the condition persisted
immune markers characteristic of type 1
hemochromatosis will also damage after pregnancy and did not exclude the
diabetes. In addition, coxsackievirus B,
b-cells and impair insulin secretion. possibility that unrecognized glucose
cytomegalovirus, adenovirus, and mumps
Fibrocalculous pancreatopathy may be intolerance may have antedated or
have been implicated in inducing certain
accompanied by abdominal pain begun concomitantly with the
cases of the disease.
radiating to the back and pancreatic pregnancy. This denition facilitated a
calcications identied on X-ray Uncommon Forms of Immune-Mediated uniform strategy for detection and
examination. Pancreatic brosis and Diabetes classication of GDM, but its limitations
calcium stones in the exocrine ducts In this category, there are two known were recognized for many years. As the
have been found at autopsy. conditions, and others are likely to ongoing epidemic of obesity and
care.diabetesjournals.org Position Statement S85

Table 1Etiologic classication of diabetes mellitus diabetes has led to more type 2 diabetes
I. Type 1 diabetes (b-cell destruction, usually leading to absolute insulin deciency) in women of childbearing age, the
A. Immune mediated number of pregnant women with
B. Idiopathic undiagnosed type 2 diabetes has
II. Type 2 diabetes (may range from predominantly insulin resistance with relative
increased.
insulin deciency to a predominantly secretory defect with insulin resistance)
III. Other specic types After deliberations in 20082009, the
A. Genetic defects of b-cell function International Association of the
1. MODY 3 (Chromosome 12, HNF-1a)
2. MODY 1 (Chromosome 20, HNF-4a) Diabetes and Pregnancy Study Groups
3. MODY 2 (Chromosome 7, glucokinase) (IADPSG), an international consensus
4. Other very rare forms of MODY (e.g., MODY 4: Chromosome 13, insulin promoter factor-1; group with representatives from
MODY 6: Chromosome 2, NeuroD1; MODY 7: Chromosome 9, carboxyl ester lipase)
5. Transient neonatal diabetes (most commonly ZAC/HYAMI imprinting defect on 6q24) multiple obstetrical and diabetes
6. Permanent neonatal diabetes (most commonly KCNJ11 gene encoding Kir6.2 organizations, including the American
subunit of b-cell KATP channel) Diabetes Association (ADA),
7. Mitochondrial DNA
8. Others recommended that high-risk women
B. Genetic defects in insulin action found to have diabetes at their initial
1. Type A insulin resistance prenatal visit, using standard criteria
2. Leprechaunism
3. Rabson-Mendenhall syndrome (Table 3), receive a diagnosis of overt,
4. Lipoatrophic diabetes not gestational, diabetes. Based on
5. Others a recent National Institutes of Health
C. Diseases of the exocrine pancreas (NIH) consensus report, the ADA has
1. Pancreatitis
2. Trauma/pancreatectomy slightly modied the recommendations
3. Neoplasia for diagnosing GDM. Approximately 7%
4. Cystic brosis
5. Hemochromatosis
of all pregnancies (ranging from 1 to
6. Fibrocalculous pancreatopathy 14%, depending on the population
7. Others studied and the diagnostic tests employed)
D. Endocrinopathies are complicated by GDM, resulting in more
1. Acromegaly
2. Cushings syndrome than 200,000 cases annually.
3. Glucagonoma
4. Pheochromocytoma CATEGORIES OF INCREASED RISK
5. Hyperthyroidism
6. Somatostatinoma FOR DIABETES
7. Aldosteronoma In 1997 and 2003, the Expert Committee
8. Others
E. Drug or chemical induced
on Diagnosis and Classication of
1. Vacor Diabetes Mellitus (1,2) recognized an
2. Pentamidine intermediate group of individuals whose
3. Nicotinic acid
4. Glucocorticoids glucose levels do not meet criteria for
5. Thyroid hormone diabetes, yet are higher than those
6. Diazoxide considered normal. These people were
7. b-Adrenergic agonists
8. Thiazides dened as having impaired fasting
9. Dilantin glucose (IFG) [fasting plasma glucose
10. g-Interferon (FPG) levels 100 mg/dL (5.6 mmol/L) to
11. Others
125 mg/dL (6.9 mmol/L)], or impaired
F. Infections
1. Congenital rubella glucose tolerance (IGT) [2-h values in
2. Cytomegalovirus the oral glucose tolerance test (OGTT) of
3. Others
140 mg/dL (7.8 mmol/L) to 199 mg/dL
G. Uncommon forms of immune-mediated diabetes
1. Stiff-man syndrome (11.0 mmol/L)].
2. Anti-insulin receptor antibodies
3. Others
Individuals with IFG and/or IGT have
H. Other genetic syndromes sometimes associated with diabetes been referred to as having prediabetes,
1. Down syndrome indicating the relatively high risk for the
2. Klinefelter syndrome future development of diabetes. IFG and
3. Turner syndrome
4. Wolfram syndrome IGT should not be viewed as clinical
5. Friedreich ataxia entities in their own right but rather risk
6. Huntington chorea factors for diabetes as well as
7. Laurence-Moon-Biedl syndrome
8. Myotonic dystrophy cardiovascular disease. They can be
9. Porphyria observed as intermediate stages in any
10. Prader-Willi syndrome of the disease processes listed in
11. Others
IV. Gestational diabetes mellitus Table 1. IFG and IGT are associated with
obesity (especially abdominal or visceral
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. obesity), dyslipidemia with high
S86 Position Statement Diabetes Care Volume 37, Supplement 1, January 2014

triglycerides and/or low HDL linear regression analyses of these data consider an A1C range of 5.76.4% as
cholesterol, and hypertension. indicate that among the nondiabetic identifying individuals with high risk for
Structured lifestyle intervention, aimed adult population, an FPG of 110 mg/dL future diabetes, to whom the term
at increasing physical activity and (6.1 mmol/L) corresponds to an A1C of prediabetes may be applied.
producing 510% loss of body weight, 5.6%, while an FPG of 100 mg/dL (5.6
Individuals with an A1C of 5.76.4%
and certain pharmacological agents mmol/L) corresponds to an A1C of 5.4%
should be informed of their increased
have been demonstrated to prevent or (R.T. Ackerman, personal
risk for diabetes as well as
delay the development of diabetes in communication). Finally, evidence from
cardiovascular disease and counseled
people with IGT; the potential impact of the Diabetes Prevention Program (DPP),
about effective strategies, such as
such interventions to reduce mortality wherein the mean A1C was 5.9% (SD
weight loss and physical activity, to
or the incidence of cardiovascular 0.5%), indicates that preventive
lower their risks. As with glucose
disease has not been demonstrated to interventions are effective in groups of
measurements, the continuum of risk is
date. It should be noted that the 2003 people with A1C levels both below and
curvilinear, so that as A1C rises, the risk
ADA Expert Committee report reduced above 5.9% (9). For these reasons, the
of diabetes rises disproportionately.
the lower FPG cut point to dene IFG most appropriate A1C level above which
Accordingly, interventions should be
from 110 mg/dL (6.1 mmol/L) to 100 to initiate preventive interventions is likely
most intensive and follow-up should be
mg/dL (5.6 mmol/L), in part to ensure to be somewhere in the range of 5.56%.
particularly vigilant for those with A1C
that prevalence of IFG was similar to As was the case with FPG and 2-h PG, levels above 6.0%, who should be
that of IGT. However, the World Health dening a lower limit of an intermediate considered to be at very high risk.
Organization and many other diabetes category of A1C is somewhat arbitrary, However, just as an individual with a
organizations did not adopt this change as the risk of diabetes with any measure fasting glucose of 98 mg/dL (5.4 mmol/L)
in the denition of IFG. or surrogate of glycemia is a continuum, may not be at negligible risk for
As A1C is used more commonly to extending well into the normal ranges. diabetes, individuals with A1C levels
diagnose diabetes in individuals with To maximize equity and efciency of below 5.7% may still be at risk, depending
risk factors, it will also identify those at preventive interventions, such an A1C on level of A1C and presence of other risk
higher risk for developing diabetes in cut point should balance the costs of factors, such as obesity and family history.
the future. When recommending the false negatives (failing to identify those Table 2 summarizes the categories of
use of the A1C to diagnose diabetes in who are going to develop diabetes) against increased risk for diabetes. Evaluation of
its 2009 report, the International Expert the costs of false positives (falsely patients at risk should incorporate a
Committee (3) stressed the continuum identifying and then spending intervention global risk factor assessment for both
of risk for diabetes with all glycemic resources on those who were not going to diabetes and cardiovascular disease.
measures and did not formally identify develop diabetes anyway). Screening for and counseling about risk
an equivalent intermediate category for As is the case with the glucose of diabetes should always be in the
A1C. The group did note that those with measures, several prospective studies pragmatic context of the patients
A1C levels above the laboratory that used A1C to predict the progression comorbidities, life expectancy, personal
normal range but below the to diabetes demonstrated a strong, capacity to engage in lifestyle change,
diagnostic cut point for diabetes (6.0 to continuous association between A1C and overall health goals.
,6.5%) are at very high risk of and subsequent diabetes. In a DIAGNOSTIC CRITERIA FOR
developing diabetes. Indeed, incidence systematic review of 44,203 individuals DIABETES MELLITUS
of diabetes in people with A1C levels in from 16 cohort studies with a follow-up
this range is more than 10 times that of interval averaging 5.6 years (range 2.8 For decades, the diagnosis of diabetes
people with lower levels (47). 12 years), those with an A1C between has been based on glucose criteria,
However, the 6.0 to ,6.5% range fails to 5.5 and 6.0% had a substantially either the FPG or the 75-g OGTT. In
identify a substantial number of increased risk of diabetes with 5-year 1997, the rst Expert Committee on the
patients who have IFG and/or IGT. incidences ranging from 9 to 25%. An Diagnosis and Classication of Diabetes
Prospective studies indicate that people A1C range of 6.06.5% had a 5-year risk
within the A1C range of 5.56.0% have a of developing diabetes between 25 and
Table 2Categories of increased risk
5-year cumulative incidence of diabetes 50% and relative risk 20 times higher for diabetes (prediabetes)*
that ranges from 12 to 25% (47), which compared with an A1C of 5.0% (10). In a FPG 100 mg/dL (5.6 mmol/L) to
is appreciably (three- to eightfold) community-based study of black and 125 mg/dL (6.9 mmol/L) (IFG)
higher than incidence in the U.S. white adults without diabetes, baseline 2-h PG in the 75-g OGTT 140 mg/dL
population as a whole (8). Analyses of A1C was a stronger predictor of (7.8 mmol/L) to 199 mg/dL
nationally representative data from the subsequent diabetes and cardiovascular (11.0 mmol/L) (IGT)
National Health and Nutrition events than was fasting glucose (11). A1C 5.76.4%
Examination Survey (NHANES) indicate Other analyses suggest that an A1C of *For all three tests, risk is continuous,
that the A1C value that most accurately 5.7% is associated with similar diabetes extending below the lower limit of the range
identies people with IFG or IGT falls risk to the high-risk participants in the and becoming disproportionately greater at
higher ends of the range.
between 5.5 and 6.0%. In addition, DPP (12). Hence, it is reasonable to
care.diabetesjournals.org Position Statement S87

Mellitus revised the diagnostic criteria, point for retinopathy prevalence, as also measure an A1C test as part of the
using the observed association between are the diagnostic thresholds for FPG initial assessment of the severity of the
FPG levels and presence of retinopathy and 2-h PG (3). The diagnostic test diabetes and that it would (in most
as the key factor with which to identify should be performed using a method cases) be above the diagnostic cut point
threshold glucose level. The Committee that is certied by the National for diabetes. However, in rapidly
examined data from three cross- Glycohemoglobin Standardization evolving diabetes, such as the
sectional epidemiological studies that Program (NGSP) and standardized or development of type 1 diabetes in some
assessed retinopathy with fundus traceable to the Diabetes Control and children, A1C may not be signicantly
photography or direct ophthalmoscopy Complications Trial reference assay. elevated despite frank diabetes.
and measured glycemia as FPG, 2-h PG, Point-of-care A1C assays are not
Just as there is less than 100%
and A1C. These studies demonstrated sufciently accurate at this time to use
concordance between the FPG and 2-h
glycemic levels below which there was for diagnostic purposes.
little prevalent retinopathy and above PG tests, there is not full concordance
There is an inherent logic to using a between A1C and either glucose-based
which the prevalence of retinopathy
more chronic versus an acute marker of test. Analyses of NHANES data indicate
increased in an apparently linear
dysglycemia, particularly since the A1C that, assuming universal screening of
fashion. The deciles of the three
is already widely familiar to clinicians the undiagnosed, the A1C cut point of
measures at which retinopathy began to
increase were the same for each
as a marker of glycemic control. $6.5% identies one-third fewer cases
Moreover, the A1C has several of undiagnosed diabetes than a fasting
measure within each population.
Moreover, the glycemic values above
advantages to the FPG, including greater glucose cut point of $126 mg/dL (7.0
convenience, since fasting is not mmol/L) (www.cdc.gov/diabetes/pubs/
which retinopathy increased were
required, evidence to suggest greater factsheet11/tables1_2.htm). However,
similar among the populations. These
preanalytical stability, and less day-to- in practice, a large portion of the
analyses conrmed the long-standing
day perturbations during periods of population with type 2 diabetes remains
diagnostic 2-h PG value of $200 mg/dL
stress and illness. These advantages, unaware of their condition. Thus, it is
(11.1 mmol/L). However, the older FPG
however, must be balanced by greater conceivable that the lower sensitivity of
diagnostic cut point of 140 mg/dL (7.8
cost, the limited availability of A1C A1C at the designated cut point will be
mmol/L) was noted to identify far fewer
testing in certain regions of the offset by the tests greater practicality,
individuals with diabetes than the 2-h
developing world, and the incomplete and that wider application of a more
PG cut point. The FPG diagnostic cut point
correlation between A1C and average convenient test (A1C) may actually
was reduced to $126 mg/dL (7.0 mmol/L).
glucose in certain individuals. In increase the number of diagnoses made.
A1C is a widely used marker of chronic addition, the A1C can be misleading in
glycemia, reecting average blood patients with certain forms of anemia Further research is needed to better
glucose levels over a 2- to 3-month and hemoglobinopathies, which may characterize those patients whose
period of time. The test plays a critical also have unique ethnic or geographic glycemic status might be categorized
role in the management of the patient distributions. For patients with a differently by two different tests (e.g.,
with diabetes, since it correlates well hemoglobinopathy but normal red cell FPG and A1C), obtained in close
with both microvascular and, to a turnover, such as sickle cell trait, an A1C temporal approximation. Such
lesser extent, macrovascular assay without interference from discordance may arise from
complications and is widely used as the abnormal hemoglobins should be used measurement variability, change over
standard biomarker for the adequacy (an updated list is available at http:// time, or because A1C, FPG, and
of glycemic management. Prior Expert www.ngsp.org/interf.asp). For postchallenge glucose each measure
Committees have not recommended conditions with abnormal red cell different physiological processes. In the
use of the A1C for diagnosis of turnover, such as anemias from setting of an elevated A1C but
diabetes, in part due to lack of hemolysis and iron deciency, the nondiabetic FPG, the likelihood of
standardization of the assay. However, diagnosis of diabetes must employ greater postprandial glucose levels or
A1C assays are now highly glucose criteria exclusively. increased glycation rates for a given
standardized so that their results can degree of hyperglycemia may be present.
The established glucose criteria for the In the opposite scenario (high FPG yet A1C
be uniformly applied both temporally
diagnosis of diabetes remain valid.
and across populations. In their recent below the diabetes cut point), augmented
These include the FPG and 2-h PG.
report (3), an International Expert hepatic glucose production or reduced
Additionally, patients with severe
Committee, after an extensive review glycation rates may be present.
hyperglycemia such as those who
of both established and emerging present with severe classic As with most diagnostic tests, a test
epidemiological evidence, hyperglycemic symptoms or result diagnostic of diabetes should be
recommended the use of the A1C test hyperglycemic crisis can continue to be repeated to rule out laboratory error,
to diagnose diabetes, with a threshold diagnosed when a random (or casual) unless the diagnosis is clear on clinical
of $6.5%, and ADA afrms this plasma glucose of $200 mg/dL (11.1 grounds, such as a patient with classic
decision. The diagnostic A1C cut point mmol/L) is found. It is likely that in such symptoms of hyperglycemia or
of 6.5% is associated with an inection cases the health care professional would hyperglycemic crisis. It is preferable that
S88 Position Statement Diabetes Care Volume 37, Supplement 1, January 2014

the same test be repeated for The decision about which test to use to diagnostic criteria will identify different
conrmation, since there will be a assess a specic patient for diabetes magnitudes of maternal hyperglycemia
greater likelihood of concurrence in this should be at the discretion of the health and maternal/fetal risk.
case. For example, if the A1C is 7.0% care professional, taking into account
In the 2011 Standards of Care (14), ADA
and a repeat result is 6.8%, the diagnosis the availability and practicality of testing
for the rst time recommended that all
of diabetes is conrmed. However, an individual patient or groups of
pregnant women not known to have
there are scenarios in which results of patients. Perhaps more important than
prior diabetes undergo a 75-g OGTT at
two different tests (e.g., FPG and A1C) are which diagnostic test is used, is that the
2428 weeks of gestation based on an
available for the same patient. In this testing for diabetes be performed when
IADPSG consensus meeting (15).
situation, if the two different tests are indicated. There is discouraging
Diagnostic cut points for the fasting, 1-h,
both above the diagnostic thresholds, the evidence indicating that many at-risk
and 2-h PG measurements were dened
diagnosis of diabetes is conrmed. patients still do not receive adequate
testing and counseling for this that conveyed an odds ratio for adverse
On the other hand, when two different outcomes of at least 1.75 compared
tests are available in an individual and increasingly common disease, or for its
frequently accompanying with women with the mean glucose
the results are discordant, the test levels in the HAPO study, a strategy
whose result is above the diagnostic cut cardiovascular risk factors. The current
diagnostic criteria for diabetes are anticipated to signicantly increase the
point should be repeated, and the prevalence of GDM (from 56% to
diagnosis is made on the basis of the summarized in Table 3.
;1520%), primarily because only one
conrmed test. That is, if a patient Diagnosis of GDM abnormal value, not two, is sufcient to
meets the diabetes criterion of the A1C GDM carries risks for the mother and make the diagnosis. The ADA recognized
(two results $6.5%) but not the FPG neonate. Not all adverse outcomes are that the anticipated increase in the
(,126 mg/dL or 7.0 mmol/L), or vice of equal clinical importance. The incidence of GDM diagnosed by these
versa, that person should be considered Hyperglycemia and Adverse Pregnancy criteria would have signicant impact on
to have diabetes. Admittedly, in most Outcome (HAPO) study (13), a large- the costs, medical infrastructure
circumstance the nondiabetic test is scale (;25,000 pregnant women) capacity, and potential for increased
likely to be in a range very close to the multinational epidemiological study, medicalization of pregnancies
threshold that denes diabetes. demonstrated that risk of adverse previously categorized as normal, but
Since there is preanalytic and analytic maternal, fetal, and neonatal outcomes recommended these diagnostic criteria
variability of all the tests, it is also continuously increased as a function of changes in the context of worrisome
possible that when a test whose result maternal glycemia at 2428 weeks, even worldwide increases in obesity and
was above the diagnostic threshold is within ranges previously considered diabetes rates with the intent of
repeated, the second value will be normal for pregnancy. For most optimizing gestational outcomes for
below the diagnostic cut point. This is complications, there was no threshold women and their babies. It is important
least likely for A1C, somewhat more for risk. These results have led to careful to note that 8090% of women in both
likely for FPG, and most likely for the reconsideration of the diagnostic of the mild GDM studies (whose glucose
2-h PG. Barring a laboratory error, criteria for GDM. GDM screening can be values overlapped with the thresholds
such patients are likely to have test accomplished with either of two recommended herein) could be
results near the margins of the strategies: the one-step 2-h 75-g managed with lifestyle therapy alone.
threshold for a diagnosis. The health OGTT or the two-step approach with a The expected benets to these
care professional might opt to follow 1-h 50-g (nonfasting) screen followed pregnancies and offspring are inferred
the patient closely and repeat the by a 3-h 100-g OGTT for those who from intervention trials that focused on
testing in 36 months. screen positive (Table 4). Different women with lower levels of
hyperglycemia than identied using
Table 3Criteria for the diagnosis of diabetes older GDM diagnostic criteria and that
A1C $6.5%. The test should be performed in a laboratory using a method that is found modest benets including
NGSP certied and standardized to the DCCT assay.* reduced rates of large-for-gestational-
OR age (LGA) births (16,17). However, while
FPG $126 mg/dL (7.0 mmol/L). Fasting is dened as no caloric intake for at least 8 h.* treatment of lower threshold
OR hyperglycemia can reduce LGA, it has
Two-hour plasma glucose $200 mg/dL (11.1 mmol/L) during an OGTT. The test not been shown to reduce primary
should be performed as described by the World Health Organization, using cesarean delivery rates. Data are lacking
a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in
on how treatment of lower threshold
water.*
hyperglycemia impacts prognosis of
OR
future diabetes for the mother, or on
In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis,
a random plasma glucose $200 mg/dL (11.1 mmol/L). future obesity, diabetes risk, or other
metabolic consequences for the
*In the absence of unequivocal hyperglycemia, criteria 13 should be conrmed by repeat
testing.
offspring. The frequency of follow-up
and blood glucose monitoring for these
care.diabetesjournals.org Position Statement S89

Table 4Screening for and diagnosis of GDM 2. The decision of which strategy to
One-step (IADPSG consensus) implement must therefore be
Perform a 75-g OGTT, with plasma glucose measurement fasting and at 1 and 2 h, at made based on the relative values
2428 weeks of gestation in women not previously diagnosed with overt diabetes. placed on currently unmeasured
The OGTT should be performed in the morning after an overnight fast of at least 8 h. factors (e.g., cost-benet
The diagnosis of GDM is made when any of the following plasma glucose values are estimation, willingness to change
exceeded: practice based on correlation
c Fasting: $92 mg/dL (5.1 mmol/L) studies rather than clinical
c 1 h: $180 mg/dL (10.0 mmol/L) intervention trial results, relative
c 2 h: $153 mg/dL (8.5 mmol/L)
role of cost considerations, and
Two-step (NIH consensus) available infrastructure).
Perform a 50-g GLT (nonfasting), with plasma glucose measurement at 1 h (Step 1), at 3. Further research is needed to
2428 weeks of gestation in women not previously diagnosed with overt diabetes. resolve these uncertainties.
If the plasma glucose level measured 1 h after the load is $140 mg/dL* (7.8 mmol/L),
proceed to 100-g OGTT (Step 2). The 100-g OGTT should be performed when the
There remains strong consensus that
patient is fasting.
The diagnosis of GDM is made when at least two of the following four plasma glucose establishing a uniform approach to
levels (measured fasting, 1 h, 2 h, 3 h after the OGTT) are met or exceeded: diagnosing GDM will have extensive
Carpenter/Coustan or NDDG benets for patients, caregivers, and
policymakers. Longer-term outcome
c Fasting 95 mg/dL (5.3 mmol/L) 105 mg/dL (5.8 mmol/L) studies are currently under way.
c 1h 180 mg/dL (10.0 mmol/L) 190 mg/dL (10.6 mmol/L) Because some cases of GDM may
c 2h 155 mg/dL (8.6 mmol/L) 165 mg/dL (9.2 mmol/L)
c 3h 140 mg/dL (7.8 mmol/L) 145 mg/dL (8.0 mmol/L) represent preexisting undiagnosed type
2 diabetes, women with a history
NDDG, National Diabetes Data Group. *The American College of Obstetricians and of GDM should be screened for diabetes
Gynecologists (ACOG) recommends a lower threshold of 135 mg/dL (7.5 mmol/L) in high-risk
ethnic minorities with higher prevalence of GDM; some experts also recommend 130 mg/dL 612 weeks postpartum, using
(7.2 mmol/L). nonpregnant OGTT criteria. Because of
their antepartum treatment for
hyperglycemia, A1C for diagnosis of
women has also not yet been standardized, LGA, and shoulder dystocia, without
persistent diabetes at the postpartum
but is likely to be less intensive than for increasing small-for-gestational-age
visit is not recommended (20). Women
women diagnosed by the older criteria. births (19).
with a history of GDM have a greatly
Since this initial IADPSG How do two different groups of experts increased subsequent diabetes risk (21)
recommendation, the NIH completed a arrive at different GDM screening and and should be followed up with
consensus development conference diagnosis recommendations? Because subsequent screening for the
involving a 15-member panel with glycemic dysregulation exists on a development of diabetes or
representatives from obstetrics/ continuum, the decision to pick a single prediabetes, as outlined in Section II
gynecology, maternal-fetal medicine, binary threshold for diagnosis requires (22). Lifestyle interventions or
pediatrics, diabetes research, balancing the harms and benets metformin should be offered to women
biostatistics, and other related elds associated with greater versus lesser with a history of GDM who develop
(18). Reviewing the same available data, sensitivity. While data from the HAPO prediabetes, as discussed in Section IV
the NIH consensus panel recommended study demonstrated a correlation (22). In the prospective Nurses Health
continuation of the two-step between increased fasting glucose Study II, subsequent diabetes risk after a
approach of screening with a 1-h 50-g levels identied through the one-step history of GDM was signicantly lower
glucose load test (GLT) followed by a 3-h strategy with increased odds for adverse in women who followed healthy eating
100-g OGTT for those who screen positive, pregnancy outcomes, this large patterns. Adjusting for BMI moderately,
a strategy commonly used in the U.S. observational study was not designed to but not completely, attenuated this
Key factors reported in the NIH panels determine the benet of intervention. association (23).
decision-making process were the lack of Moreover, there are no available cost-
clinical trial interventions demonstrating effective analyses to examine the balance
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