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P O S I T I O N S T A T E M E N T

Diagnosis and Classification of Diabetes


Mellitus
AMERICAN DIABETES ASSOCIATION fore do not require insulin. Other
individuals who have some residual insu-
lin secretion but require exogenous insu-
DEFINITION AND cardiovascular symptoms and sexual dys- lin for adequate glycemic control can
DESCRIPTION OF DIABETES function. Patients with diabetes have an in- survive without it. Individuals with ex-
MELLITUS — Diabetes is a group of creased incidence of atherosclerotic tensive ␤-cell destruction and therefore
metabolic diseases characterized by hy- cardiovascular, peripheral arterial, and ce- no residual insulin secretion require insu-
perglycemia resulting from defects in in- rebrovascular disease. Hypertension and lin for survival. The severity of the meta-
sulin secretion, insulin action, or both. abnormalities of lipoprotein metabolism are bolic abnormality can progress, regress,
The chronic hyperglycemia of diabetes is often found in people with diabetes. or stay the same. Thus, the degree of hy-
associated with long-term damage, dys- The vast majority of cases of diabetes perglycemia reflects the severity of the un-
function, and failure of differentorgans, fall into two broad etiopathogenetic cate- derlying metabolic process and its
especially the eyes, kidneys, nerves, heart, gories (discussed in greater detail below). treatment more than the nature of the
and blood vessels. In one category, type 1 diabetes, the cause process itself.
Several pathogenic processes are in- is an absolute deficiency of insulin secre-
volved in the development of diabetes. tion. Individuals at increased risk of de- CLASSIFICATION OF
These range from autoimmune destruc- veloping this type of diabetes can often be DIABETES MELLITUS AND
tion of the ␤-cells of the pancreas with identified by serological evidence of an OTHER CATEGORIES
consequent insulin deficiency to abnor- autoimmune pathologic process occur- OF GLUCOSE
malities that result in resistance to insulin ring in the pancreatic islets and by genetic REGULATION — Assigning a type of
action. The basis of the abnormalities in markers. In the other, much more preva- diabetes to an individual often depends
carbohydrate, fat, and protein metabo- lent category, type 2 diabetes, the cause is on the circumstances present at the time
lism in diabetes is deficient action of in- a combination of resistance to insulin ac- of diagnosis, and many diabetic individu-
sulin on target tissues. Deficient insulin tion and an inadequate compensatory in- als do not easily fit into a single class. For
action results from inadequate insulin se- sulin secretory response. In the latter example, a person with gestational diabe-
cretion and/or diminished tissue re- category, a degree of hyperglycemia suffi- tes mellitus (GDM) may continue to be
sponses to insulin at one or more points in cient to cause pathologic and functional hyperglycemic after delivery and may be
the complex pathways of hormone action. changes in various target tissues, but determined to have, in fact, type 2 diabe-
Impairment of insulin secretion and de- without clinical symptoms, may be tes. Alternatively, a person who acquires
fects in insulin action frequently coexist present for a long period of time before diabetes because of large doses of exoge-
in the same patient, and it is often unclear diabetes is detected. During this asymp- nous steroids may become normoglyce-
which abnormality, if either alone, is the tomatic period, it is possible to demon- mic once the glucocorticoids are
primary cause of the hyperglycemia. strate an abnormality in carbohydrate discontinued, but then may develop dia-
Symptoms of marked hyperglycemia metabolism by measurement of plasma betes many years later after recurrent ep-
include polyuria, polydipsia, weight loss, glucose in the fasting state or after a chal- isodes of pancreatitis. Another example
sometimes with polyphagia, and blurred lenge with an oral glucose load. would be a person treated with thiazides
vision. Impairment of growth and suscep- The degree of hyperglycemia (if any) who develops diabetes years later. Because
tibility to certain infections may also ac- may change over time, depending on the thiazides in themselves seldom cause severe
company chronic hyperglycemia. Acute, extent of the underlying disease process hyperglycemia, such individuals probably
life-threatening consequences of uncon- (Fig. 1). A disease process may be present have type 2 diabetes that is exacerbated by
trolled diabetes are hyperglycemia with but may not have progressed far enough the drug. Thus, for the clinician and patient,
ketoacidosis or the nonketotic hyperos- to cause hyperglycemia. The same disease it is less important to label the particular
molar syndrome. process can cause impaired fasting glu- type of diabetes than it is to understand the
Long-term complications of diabetes cose (IFG) and/or impaired glucose toler- pathogenesis of the hyperglycemia and to
include retinopathy with potential loss of ance (IGT) without fulfilling the criteria treat it effectively.
vision; nephropathy leading to renal fail- for the diagnosis of diabetes. In some in-
ure; peripheral neuropathy with risk of dividuals with diabetes, adequate glyce- Type 1 diabetes (␤-cell destruction,
foot ulcers, amputations, and Charcot mic control can be achieved with weight usually leading to absolute insulin
joints; and autonomic neuropathy caus- reduction, exercise, and/or oral glucose- deficiency)
ing gastrointestinal, genitourinary, and lowering agents. These individuals there- Immune-mediated diabetes. This form
of diabetes, which accounts for only
● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
5–10% of those with diabetes, previously
Section on gestational diabetes diagnosis revised Fall 2010. encompassed by the terms insulin-
DOI: 10.2337/dc11-S062
© 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly dependent diabetes, type 1 diabetes, or
cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons. juvenile-onset diabetes, results from a cel-
org/licenses/by-nc-nd/3.0/ for details. lular-mediated autoimmune destruction

S62 DIABETES CARE, VOLUME 34, SUPPLEMENT 1, JANUARY 2011 care.diabetesjournals.org


Position Statement

Figure 1—Disorders of glycemia: etiologic types and stages. *Even after presenting in ketoacidosis, these patients can briefly return to normogly-
cemia 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.

of the ␤-cells of the pancreas. Markers of childhood and adolescence, but it can oc- Type 2 diabetes (ranging from
the immune destruction of the ␤-cell in- cur at any age, even in the 8th and 9th predominantly insulin resistance
clude islet cell autoantibodies, autoanti- decades of life. with relative insulin deficiency to
bodies to insulin, autoantibodies to GAD Autoimmune destruction of ␤-cells predominantly an insulin secretory
(GAD65), and autoantibodies to the ty- has multiple genetic predispositions and defect with insulin resistance)
rosine phosphatases IA-2 and IA-2␤. One is also related to environmental factors This form of diabetes, which accounts for
and usually more of these autoantibodies that are still poorly defined. Although pa- ⬃90 –95% of those with diabetes, previ-
are present in 85–90% of individuals tients are rarely obese when they present ously referred to as non–insulin-
when fasting hyperglycemia is initially with this type of diabetes, the presence of dependent diabetes, type 2 diabetes, or
detected. Also, the disease has strong HLA obesity is not incompatible with the diag- adult-onset diabetes, encompasses indi-
associations, with linkage to the DQA and nosis. These patients are also prone to viduals who have insulin resistance and
DQB genes, and it is influenced by the other autoimmune disorders such as usually have relative (rather than abso-
DRB genes. These HLA-DR/DQ alleles can Graves’ disease, Hashimoto’s thyroiditis, lute) insulin deficiency At least initially,
be either predisposing or protective. Addison’s disease, vitiligo, celiac sprue, and often throughout their lifetime, these
In this form of diabetes, the rate of autoimmune hepatitis, myasthenia gravis, individuals do not need insulin treatment
␤-cell destruction is quite variable, being to survive. There are probably many dif-
and pernicious anemia.
rapid in some individuals (mainly infants ferent causes of this form of diabetes. Al-
Idiopathic diabetes. Some forms of type
and children) and slow in others (mainly though the specific etiologies are not
1 diabetes have no known etiologies.
adults). Some patients, particularly chil- known, autoimmune destruction of
dren and adolescents, may present with Some of these patients have permanent ␤-cells does not occur, and patients do
ketoacidosis as the first manifestation of insulinopenia and are prone to ketoacido- not have any of the other causes of diabe-
the disease. Others have modest fasting sis, but have no evidence of autoimmu- tes listed above or below.
hyperglycemia that can rapidly change to nity. Although only a minority of patients Most patients with this form of diabe-
severe hyperglycemia and/or ketoacidosis with type 1 diabetes fall into this category, tes are obese, and obesity itself causes
in the presence of infection or other stress. of those who do, most are of African or some degree of insulin resistance. Patients
Still others, particularly adults, may retain Asian ancestry. Individuals with this form who are not obese by traditional weight
residual ␤-cell function sufficient to pre- of diabetes suffer from episodic ketoaci- criteria may have an increased percentage
vent ketoacidosis for many years; such in- dosis and exhibit varying degrees of insu- of body fat distributed predominantly in
dividuals eventually become dependent lin deficiency between episodes. This the abdominal region. Ketoacidosis sel-
on insulin for survival and are at risk for form of diabetes is strongly inherited, dom occurs spontaneously in this type of
ketoacidosis. At this latter stage of the dis- lacks immunological evidence for ␤-cell diabetes; when seen, it usually arises in
ease, there is little or no insulin secretion, autoimmunity, and is not HLA associated. association with the stress of another ill-
as manifested by low or undetectable lev- An absolute requirement for insulin re- ness such as infection. This form of dia-
els of plasma C-peptide. Immune- placement therapy in affected patients betes frequently goes undiagnosed for
mediated diabetes commonly occurs in may come and go. many years because the hyperglycemia

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Diagnosis and Classification

develops gradually and at earlier stages is of insulin secretion. The less common noma. With the exception of that caused
often not severe enough for the patient to forms result from mutations in other tran- by cancer, damage to the pancreas must
notice any of the classic symptoms of di- scription factors, including HNF-4␣, be extensive for diabetes to occur; adre-
abetes. Nevertheless, such patients are at HNF-1␤, insulin promoter factor (IPF)-1, nocarcinomas that involve only a small
increased risk of developing macrovascu- and NeuroD1. portion of the pancreas have been associ-
lar and microvascular complications. Point mutations in mitochondrial ated with diabetes. This implies a mecha-
Whereas patients with this form of diabe- DNA have been found to be associated nism other than simple reduction in
tes may have insulin levels that appear with diabetes and deafness The most ␤-cell mass. If extensive enough, cystic
normal or elevated, the higher blood glu- common mutation occurs at position fibrosis and hemochromatosis will also
cose levels in these diabetic patients 3,243 in the tRNA leucine gene, leading damage ␤-cells and impair insulin secre-
would be expected to result in even to an A-to-G transition. An identical le- tion. Fibrocalculous pancreatopathy may
higher insulin values had their ␤-cell sion occurs in the MELAS syndrome (mi- be accompanied by abdominal pain radi-
function been normal. Thus, insulin se- tochondrial myopathy, encephalopathy, ating to the back and pancreatic calcifica-
cretion is defective in these patients and lactic acidosis, and stroke-like syn- tions identified on X-ray examination.
insufficient to compensate for insulin re- drome); however, diabetes is not part of Pancreatic fibrosis and calcium stones in
sistance. Insulin resistance may improve this syndrome, suggesting different phe- the exocrine ducts have been found at
with weight reduction and/or pharmaco- notypic expressions of this genetic lesion. autopsy.
logical treatment of hyperglycemia but is Genetic abnormalities that result in Endocrinopathies. Several hormones
seldom restored to normal. The risk of the inability to convert proinsulin to in- (e.g., growth hormone, cortisol, gluca-
developing this form of diabetes increases sulin have been identified in a few fami- gon, epinephrine) antagonize insulin ac-
with age, obesity, and lack of physical ac- lies, and such traits are inherited in an tion. Excess amounts of these hormones
tivity. It occurs more frequently in autosomal dominant pattern. The result- (e.g., acromegaly, Cushing’s syndrome,
women with prior GDM and in individu- ant glucose intolerance is mild. Similarly, glucagonoma, pheochromocytoma, re-
als with hypertension or dyslipidemia, the production of mutant insulin mole- spectively) can cause diabetes. This gen-
and its frequency varies in different racial/ cules with resultant impaired receptor erally occurs in individuals with
ethnic subgroups. It is often associated binding has also been identified in a few preexisting defects in insulin secretion,
with a strong genetic predisposition, families and is associated with an autoso- and hyperglycemia typically resolves
more so than is the autoimmune form of mal inheritance and only mildly impaired when the hormone excess is resolved.
type 1 diabetes. However, the genetics of or even normal glucose metabolism. Somatostatinoma- and aldoster-
this form of diabetes are complex and not Genetic defects in insulin action. There onoma-induced hypokalemia can cause
clearly defined. are unusual causes of diabetes that result diabetes, at least in part, by inhibiting in-
from genetically determined abnormali- sulin secretion. Hyperglycemia generally
Other specific types of diabetes ties of insulin action. The metabolic ab- resolves after successful removal of the
Genetic defects of the ␤-cell. Several normalities associated with mutations of tumor.
forms of diabetes are associated with mo- the insulin receptor may range from hy- Drug- or chemical-induced diabetes.
nogenetic defects in ␤-cell function. perinsulinemia and modest hyperglyce- Many drugs can impair insulin secretion.
These forms of diabetes are frequently mia to severe diabetes. Some individuals These drugs may not cause diabetes by
characterized by onset of hyperglycemia with these mutations may have acanthosis themselves, but they may precipitate dia-
at an early age (generally before age 25 nigricans. Women may be virilized and betes in individuals with insulin resis-
years). They are referred to as maturity- have enlarged, cystic ovaries. In the past, tance. In such cases, the classification is
onset diabetes of the young (MODY) and this syndrome was termed type A insulin unclear because the sequence or relative
are characterized by impaired insulin se- resistance. Leprechaunism and the Rabson- importance of ␤-cell dysfunction and in-
cretion with minimal or no defects in in- Mendenhall syndrome are two pediatric sulin resistance is unknown. Certain tox-
sulin action. They are inherited in an syndromes that have mutations in the insu- ins such as Vacor (a rat poison) and
autosomal dominant pattern. Abnormali- lin receptor gene with subsequent alter- intravenous pentamidine can perma-
ties at six genetic loci on different chro- ations in insulin receptor function and nently destroy pancreatic ␤-cells. Such
mosomes have been identified to date. extreme insulin resistance. The former has drug reactions fortunately are rare. There
The most common form is associated characteristic facial features and is usually are also many drugs and hormones that
with mutations on chromosome 12 in a fatal in infancy, while the latter is associated can impair insulin action. Examples in-
hepatic transcription factor referred to as with abnormalities of teeth and nails and clude nicotinic acid and glucocorticoids.
hepatocyte nuclear factor (HNF)-1␣. A pineal gland hyperplasia. Patients receiving ␣-interferon have been
second form is associated with mutations Alterations in the structure and func- reported to develop diabetes associated
in the glucokinase gene on chromosome tion of the insulin receptor cannot be dem- with islet cell antibodies and, in certain
7p and results in a defective glucokinase onstrated in patients with insulin-resistant instances, severe insulin deficiency. The
molecule. Glucokinase converts glucose lipoatrophic diabetes. Therefore, it is as- list shown in Table 1 is not all-inclusive,
to glucose-6-phosphate, the metabolism sumed that the lesion(s) must reside in the but reflects the more commonly recog-
of which, in turn, stimulates insulin secre- postreceptor signal transduction pathways. nized drug-, hormone-, or toxin-induced
tion by the ␤-cell. Thus, glucokinase Diseases of the exocrine pancreas. Any forms of diabetes.
serves as the “glucose sensor” for the process that diffusely injures the pancreas Infections. Certain viruses have been as-
␤-cell. Because of defects in the glucoki- can cause diabetes. Acquired processes sociated with ␤-cell destruction. Diabetes
nase gene, increased plasma levels of glu- include pancreatitis, trauma, infection, occurs in patients with congenital rubella,
cose are necessary to elicit normal levels pancreatectomy, and pancreatic carci- although most of these patients have HLA

S64 DIABETES CARE, VOLUME 34, SUPPLEMENT 1, JANUARY 2011 care.diabetesjournals.org


Position Statement

Table 1—Etiologic classification of diabetes mellitus and immune markers characteristic of


I. Type 1 diabetes (␤-cell destruction, usually leading to absolute insulin deficiency) type 1 diabetes. In addition, coxsackievi-
A. Immune mediated rus B, cytomegalovirus, adenovirus, and
B. Idiopathic mumps have been implicated in inducing
II. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency
to a predominantly secretory defect with insulin resistance)
certain cases of the disease.
III. Other specific types Uncommon forms of immune-medi-
A. Genetic defects of ␤-cell function ated diabetes. In this category, there are
1. Chromosome 12, HNF-1␣ (MODY3) two known conditions, and others are
2. Chromosome 7, glucokinase (MODY2)
3. Chromosome 20, HNF-4␣ (MODY1)
likely to occur. The stiff-man syndrome is
4. Chromosome 13, insulin promoter factor-1 (IPF-1; MODY4) an autoimmune disorder of the central
5. Chromosome 17, HNF-1␤ (MODY5) nervous system characterized by stiffness
6. Chromosome 2, NeuroD1 (MODY6) of the axial muscles with painful spasms.
7. Mitochondrial DNA
8. Others
Patients usually have high titers of the
B. Genetic defects in insulin action GAD autoantibodies, and approximately
1. Type A insulin resistance one-third will develop diabetes.
2. Leprechaunism Anti-insulin receptor antibodies can
3. Rabson-Mendenhall syndrome
4. Lipoatrophic diabetes cause diabetes by binding to the insulin
5. Others receptor, thereby blocking the binding of
C. Diseases of the exocrine pancreas insulin to its receptor in target tissues.
1. Pancreatitis However, in some cases, these antibodies
2. Trauma/pancreatectomy
3. Neoplasia can act as an insulin agonist after binding
4. Cystic fibrosis to the receptor and can thereby cause hy-
5. Hemochromatosis poglycemia. Anti-insulin receptor anti-
6. Fibrocalculous pancreatopathy bodies are occasionally found in patients
7. Others
D. Endocrinopathies with systemic lupus erythematosus and
1. Acromegaly other autoimmune diseases. As in other
2. Cushing’s syndrome states of extreme insulin resistance, pa-
3. Glucagonoma tients with anti-insulin receptor antibod-
4. Pheochromocytoma
5. Hyperthyroidism ies often have acanthosis nigricans. In the
6. Somatostatinoma past, this syndrome was termed type B
7. Aldosteronoma insulin resistance.
8. Others Other genetic syndromes sometimes
E. Drug or chemical induced
1. Vacor associated with diabetes. Many genetic
2. Pentamidine syndromes are accompanied by an in-
3. Nicotinic acid creased incidence of diabetes. These in-
4. Glucocorticoids clude the chromosomal abnormalities of
5. Thyroid hormone
6. Diazoxide Down syndrome, Klinefelter syndrome,
7. ␤-adrenergic agonists and Turner syndrome. Wolfram’s syn-
8. Thiazides drome is an autosomal recessive disorder
9. Dilantin characterized by insulin-deficient diabe-
10. ␥-Interferon
11. Others tes and the absence of ␤-cells at autopsy.
F. Infections Additional manifestations include diabe-
1. Congenital rubella tes insipidus, hypogonadism, optic atro-
2. Cytomegalovirus phy, and neural deafness. Other
3. Others
G. Uncommon forms of immune-mediated diabetes syndromes are listed in Table 1.
1. “Stiff-man” syndrome
2. Anti-insulin receptor antibodies Gestational diabetes mellitus
3. Others For many years, GDM has been defined as
H. Other genetic syndromes sometimes associated with diabetes
1. Down syndrome any degree of glucose intolerance with on-
2. Klinefelter syndrome set or first recognition during pregnancy.
3. Turner syndrome Although most cases resolve with deliv-
4. Wolfram syndrome ery, the definition applied whether or not
5. Friedreich ataxia
6. Huntington chorea the condition persisted after pregnancy
7. Laurence-Moon-Biedl syndrome and did not exclude the possibility that
8. Myotonic dystrophy unrecognized glucose intolerance may
9. Porphyria have antedated or begun concomitantly
10. Prader-Willi syndrome
11. Others with the pregnancy. This definition facil-
IV. Gestational diabetes mellitus itated a uniform strategy for detection and
Patients with any form of diabetes may require insulin treatment at some stage of their disease. Such use of classification of GDM, but its limitations
insulin does not, of itself, classify the patient. were recognized for many years. As the
ongoing epidemic of obesity and diabetes
has led to more type 2 diabetes in women

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Diagnosis and Classification

Table 2—Categories of increased risk for dominal or visceral obesity), dyslipidemia nication). Finally, evidence from the Dia-
diabetes* with high triglycerides and/or low HDL betes Prevention Program (DPP), wherein
FPG 100 mg/dl (5.6 mmol/l) to 125 mg/dl cholesterol, and hypertension. Structured the mean A1C was 5.9% (SD 0.5%), indi-
(6.9 mmol/l) 关IFG兴 lifestyle intervention, aimed at increasing cates that preventive interventions are ef-
2-h PG in the 75-g OGTT 140 mg/dl (7.8 physical activity and producing 5–10% fective in groups of people with A1C
mmol/l) to 199 mg/dl (11.0 mmol/l) 关IGT兴 loss of body weight, and certain pharma- levels both below and above 5.9% (9). For
A1C 5.7–6.4% cological agents have been demonstrated these reasons, the most appropriate A1C
to prevent or delay the development of level above which to initiate preventive
*For all three tests, risk is continuous, extending
below the lower limit of the range and becoming diabetes in people with IGT; the potential interventions is likely to be somewhere in
disproportionately greater at higher ends of the impact of such interventions to reduce the range of 5.5– 6%.
range. mortality or the incidence of cardiovascu- As was the case with FPG and 2-h PG,
lar disease has not been demonstrated to defining a lower limit of an intermediate
date. It should be noted that the 2003 category of A1C is somewhat arbitrary, as
of childbearing age, the number of preg- ADA Expert Committee report reduced the risk of diabetes with any measure or
nant women with undiagnosed type 2 di- the lower FPG cut point to define IFG surrogate of glycemia is a continuum, ex-
abetes has increased. from 110 mg/dl (6.1 mmol/l) to 100 tending well into the normal ranges. To
After deliberations in 2008 –2009, mg/dl (5.6 mmol/l), in part to ensure that maximize equity and efficiency of preven-
the International Association of Diabetes prevalence of IFG was similar to that of tive interventions, such an A1C cut point
and Pregnancy Study Groups (IADPSG), IGT. However, the World Health Organi- should balance the costs of “false nega-
an international consensus group with zation (WHO) and many other diabetes tives” (failing to identify those who are
representatives from multiple obstetrical organizations did not adopt this change in going to develop diabetes) against the
and diabetes organizations, including the the definition of IFG. costs of “false positives” (falsely identify-
American Diabetes Association (ADA), As A1C is used more commonly to ing and then spending intervention re-
recommended that high-risk women diagnose diabetes in individuals with risk sources on those who were not going to
found to have diabetes at their initial pre- factors, it will also identify those at higher develop diabetes anyway).
natal visit, using standard criteria (Table risk for developing diabetes in the future. Compared to the fasting glucose cut-
3), receive a diagnosis of overt, not gesta- When recommending the use of the A1C point of 100 mg/dl (5.6 mmol/l), an A1C
tional, diabetes. Approximately 7% of all to diagnose diabetes in its 2009 report, cutpoint of 5.7% is less sensitive but more
pregnancies (ranging from 1 to 14%, de- the International Expert Committee (3) specific and has a higher positive predic-
pending on the population studied and stressed the continuum of risk for diabe- tive value to identify people at risk for
the diagnostic tests employed) are com- tes with all glycemic measures and did not later development of diabetes. A large
plicated by GDM, resulting in more than formally identify an equivalent intermedi- prospective study found that a 5.7% cut-
200,000 cases annually. ate category for A1C. The group did note point has a sensitivity of 66% and speci-
that those with A1C levels above the lab- ficity of 88% for the identification of
CATEGORIES OF oratory “normal” range but below the di- subsequent 6-year diabetes incidence
INCREASED RISK FOR agnostic cut point for diabetes (6.0 to (10). Receiver operating curve analyses
DIABETES — In 1997 and 2003, The ⬍6.5%) are at very high risk of develop- of nationally representative U.S. data
Expert Committee on Diagnosis and Clas- ing diabetes. Indeed, incidence of diabe- (NHANES 1999-2006) indicate that an
sification of Diabetes Mellitus (1,2) recog- tes in people with A1C levels in this range A1C value of 5.7% has modest sensitivity
nized an intermediate group of is more than 10 times that of people with (39-45%) but high specificity (81-91%)
individuals whose glucose levels do not lower levels (4 –7). However, the 6.0 to to identify cases of IFP (FPG ⬎100 mg/dl)
meet criteria for diabetes, yet are higher ⬍6.5% range fails to identify a substantial (5.6 mmol/l) or IGT (2-h glucose ⬎ 140
than those considered normal. These peo- number of patients who have IFG and/or mg/dl) (R.T. Ackerman, personal com-
ple were defined as having impaired fast- IGT. Prospective studies indicate that munication). Other analyses suggest that
ing glucose (IFG) [fasting plasma glucose people within the A1C range of 5.5– 6.0% an A1C of 5.7% is associated with diabe-
(FPG) levels 100 mg/dl (5.6 mmol/l) to have a 5-year cumulative incidence of di- tes risk similar to the high-risk partici-
125 mg/dl (6.9 mmol/l)], or impaired glu- abetes that ranges from 12 to 25% (4 –7), pants in the DPP (R.T. Ackerman,
cose tolerance (IGT) [2-h values in the which is appreciably (three- to eightfold) personal communication). Hence, it is
oral glucose tolerance test (OGTT) of 140 higher than incidence in the U.S. popula- reasonable to consider an A1C range of
mg/dl (7.8 mmol/l) to 199 mg/dl (11.0 tion as a whole (8). Analyses of nationally 5.7 to 6.4% as identifying individuals
mmol/l)]. representative data from the National with high risk for future diabetes and to
Individuals with IFG and/or IGT have Health and Nutrition Examination Survey whom the term pre-diabetes may be ap-
been referred to as having pre-diabetes, (NHANES) indicate that the A1C value plied if desired.
indicating the relatively high risk for the that most accurately identifies people Individuals with an A1C of 5.7– 6.4%
future development of diabetes. IFG and with IFG or IGT falls between 5.5 and should be informed of their increased risk
IGT should not be viewed as clinical en- 6.0%. In addition, linear regression anal- for diabetes as well as cardiovascular dis-
tities in their own right but rather risk yses of these data indicate that among the ease and counseled about effective strate-
factors for diabetes as well as cardiovas- nondiabetic adult population, an FPG of gies, such as weight loss and physical
cular disease. They can be observed as in- 110 mg/dl (6.1 mmol/l) corresponds to an activity, to lower their risks. As with glu-
termediate stages in any of the disease A1C of 5.6%, while an FPG of 100 mg/dl cose measurements, the continuum of
processes listed in Table 1. IFG and IGT (5.6 mmol/l) corresponds to an A1C of risk is curvilinear, so that as A1C rises, the
are associated with obesity (especially ab- 5.4% (R.T. Ackerman, personal commu- risk of diabetes rises disproportionately.

S66 DIABETES CARE, VOLUME 34, SUPPLEMENT 1, JANUARY 2011 care.diabetesjournals.org


Position Statement

Accordingly, interventions should be Table 3—Criteria for the diagnosis of diabetes


most intensive and follow-up should be A1C ⱖ6.5%. The test should be performed in a laboratory using a method that is NGSP
particularly vigilant for those with A1C certified and standardized to the DCCT assay.*
levels above 6.0%, who should be consid- OR
ered to be at very high risk. However, just FPG ⱖ126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.*
as an individual with a fasting glucose of OR
98 mg/dl (5.4 mmol/l) may not be at neg- 2-h plasma glucose ⱖ200 mg/dl (11.1 mmol/l) during an OGTT. The test should be
ligible risk for diabetes, individuals with performed as described by the World Health Organization, using a glucose load containing
A1C levels below 5.7% may still be at risk, the equivalent of 75 g anhydrous glucose dissolved in water.*
depending on level of A1C and presence OR
of other risk factors, such as obesity and In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random
family history. plasma glucose ⱖ200 mg/dl (11.1 mmol/l).
Table 2 summarizes the categories of
*In the absence of unequivocal hyperglycemia, criteria 1–3 should be confirmed by repeat testing.
increased risk for diabetes. Evaluation of
patients at risk should incorporate a
global risk factor assessment for both di- abetes, since it correlates well with both glucose in certain individuals. In addi-
abetes and cardiovascular disease. microvascular and, to a lesser extent, ma- tion, the A1C can be misleading in pa-
Screening for and counseling about risk of crovascular complications and is widely tients with certain forms of anemia and
diabetes should always be in the prag- used as the standard biomarker for the hemoglobinopathies, which may also
matic context of the patient’s comorbidi- adequacy of glycemic management. Prior have unique ethnic or geographic distri-
ties, life expectancy, personal capacity to Expert Committees have not recom- butions. For patients with a hemoglobi-
engage in lifestyle change, and overall mended use of the A1C for diagnosis of nopathy but normal red cell turnover,
health goals. diabetes, in part due to lack of standard- such as sickle cell trait, an A1C assay
ization of the assay. However, A1C assays without interference from abnormal he-
are now highly standardized so that their moglobins should be used (an updated
DIAGNOSTIC CRITERIA FOR results can be uniformly applied both list is available at www.ngsp.org/prog/
DIABETES MELLITUS — For de- temporally and across populations. In index3.html). For conditions with abnor-
cades, the diagnosis of diabetes has been their recent report (3), an International mal red cell turnover, such as anemias
based on glucose criteria, either the FPG Expert Committee, after an extensive re- from hemolysis and iron deficiency, the
or the 75-g OGTT. In 1997, the first Ex- view of both established and emerging ep- diagnosis of diabetes must employ glu-
pert Committee on the Diagnosis and idemiological evidence, recommended cose criteria exclusively.
Classification of Diabetes Mellitus revised the use of the A1C test to diagnose diabe- The established glucose criteria for
the diagnostic criteria, using the observed tes, with a threshold of ⱖ6.5%, and ADA the diagnosis of diabetes remain valid.
association between FPG levels and pres- affirms this decision. The diagnostic A1C These include the FPG and 2-h PG. Addi-
ence of retinopathy as the key factor with cut point of 6.5% is associated with an tionally, patients with severe hyperglyce-
which to identify threshold glucose level. inflection point for retinopathy preva- mia such as those who present with severe
The Committee examined data from three lence, as are the diagnostic thresholds for classic hyperglycemic symptoms or hy-
cross-sectional epidemiologic studies that FPG and 2-h PG (3). The diagnostic test perglycemic crisis can continue to be di-
assessed retinopathy with fundus photog- should be performed using a method that agnosed when a random (or casual)
raphy or direct ophthalmoscopy and is certified by the National Glycohemo- plasma glucose of ⱖ200 mg/dl (11.1
measured glycemia as FPG, 2-h PG, and globin Standardization Program (NGSP) mmol/l) is found. It is likely that in such
A1C. These studies demonstrated glyce- and standardized or traceable to the Dia- cases the health care professional would
mic levels below which there was little betes Control and Complications Trial also measure an A1C test as part of the
prevalent retinopathy and above which reference assay. Point-of-care A1C assays initial assessment of the severity of the di-
the prevalence of retinopathy increased in are not sufficiently accurate at this time to abetes and that it would (in most cases) be
an apparently linear fashion. The deciles use for diagnostic purposes. above the diagnostic cut point for diabe-
of the three measures at which retinopa- There is an inherent logic to using a tes. However, in rapidly evolving diabe-
thy began to increase were the same for more chronic versus an acute marker of tes, such as the development of type 1
each measure within each population. dysglycemia, particularly since the A1C is diabetes in some children, A1C may not
Moreover, the glycemic values above already widely familiar to clinicians as a be significantly elevated despite frank
which retinopathy increased were similar marker of glycemic control. Moreover, diabetes.
among the populations. These analyses the A1C has several advantages to the Just as there is less than 100% con-
helped to inform a new diagnostic cut FPG, including greater convenience, cordance between the FPG and 2-h PG
point of ⱖ126 mg/dl (7.0 mmol/l) for since fasting is not required, evidence to tests, there is not full concordance be-
FPG and confirmed the long-standing di- suggest greater preanalytical stability, and tween A1C and either glucose-based test.
agnostic 2-h PG value of ⱖ200 mg/dl less day-to-day perturbations during pe- Analyses of NHANES data indicate that,
(11.1 mmol/l). riods of stress and illness. These advan- assuming universal screening of the undi-
A1C is a widely used marker of tages, however, must be balanced by agnosed, the A1C cut point of ⱖ6.5%
chronic glycemia, reflecting average greater cost, the limited availability of identifies one-third fewer cases of undiag-
blood glucose levels over a 2- to 3-month A1C testing in certain regions of the de- nosed diabetes than a fasting glucose cut
period of time. The test plays a critical role veloping world, and the incomplete cor- point of ⱖ126 mg/dl (7.0 mmol/l) (cdc
in the management of the patient with di- relation between A1C and average website tbd). However, in practice, a large

care.diabetesjournals.org DIABETES CARE, VOLUME 34, SUPPLEMENT 1, JANUARY 2011 S67


Diagnosis and Classification

portion of the population with type 2 di- that when a test whose result was above Table 4 —Screening for and diagnosis of
abetes remains unaware of their condi- the diagnostic threshold is repeated, the GDM
tion. Thus, it is conceivable that the lower second value will be below the diagnostic Perform a 75-g OGTT, with plasma glucose
sensitivity of A1C at the designated cut cut point. This is least likely for A1C, measurement fasting and at 1 and 2 h, at
point will be offset by the test’s greater somewhat more likely for FPG, and most 24-28 of weeks gestation in women not
practicality, and that wider application of likely for the 2-h PG. Barring a laboratory previously diagnosed with overt diabetes.
a more convenient test (A1C) may actu- error, such patients are likely to have test The OGTT should be performed in the
ally increase the number of diagnoses results near the margins of the threshold morning after an overnight fast of at least
made. for a diagnosis. The healthcare profes- 8 h.
Further research is needed to better sional might opt to follow the patient The diagnosis of GDM is made when any of
characterize those patients whose glyce- closely and repeat the testing in 3– 6 the following plasma glucose values are
mic status might be categorized differ- months. exceeded
ently by two different tests (e.g., FPG and The decision about which test to use ● Fasting: ⱖ92 mg/dl (5.1 mmol/l)
A1C), obtained in close temporal approx- to assess a specific patient for diabetes ● 1 h: ⱖ180 mg/dl (10.0 mmol/l)
imation. Such discordance may arise from should be at the discretion of the health ● 2 h: ⱖ153 mg/dl (8.5 mmol/l)
measurement variability, change over care professional, taking into account the
time, or because A1C, FPG, and postchal- availability and practicality of testing an
lenge glucose each measure different individual patient or groups of patients.
physiological processes. In the setting of Perhaps more important than which diag- These new criteria will significantly
an elevated A1C but “nondiabetic” FPG, nostic test is used, is that the testing for increase the prevalence of GDM, primar-
the likelihood of greater postprandial glu- diabetes be performed when indicated. ily because only one abnormal value, not
cose levels or increased glycation rates for There is discouraging evidence indicating two, is sufficient to make the diagnosis.
a given degree of hyperglycemia may be that many at-risk patients still do not receive The ADA recognizes the anticipated sig-
present. In the opposite scenario (high adequate testing and counseling for this in- nificant increase in the incidence of GDM
FPG yet A1C below the diabetes cut creasingly common disease, or for its fre- to be diagnosed by these criteria and is
point), augmented hepatic glucose pro- quently accompanying cardiovascular risk sensitive to concerns about the “medical-
duction or reduced glycation rates may be factors. The current diagnostic criteria for ization” of pregnancies previously catego-
present. diabetes are summarized in Table 3. rized as normal. These diagnostic criteria
As with most diagnostic tests, a test changes are being made in the context of
result diagnostic of diabetes should be re- Diagnosis of gestational diabetes worrisome worldwide increases in obe-
peated to rule out laboratory error, unless GDM carries risks for the mother and ne- sity and diabetes rates, with the intent of
the diagnosis is clear on clinical grounds, onate. The Hyperglycemia and Adverse optimizing gestational outcomes for
such as a patient with classic symptoms of Pregnancy Outcomes (HAPO) study (11), women and their babies.
hyperglycemia or hyperglycemic crisis. It a large-scale (⬃25,000 pregnant women) Admittedly, there are few data from
is preferable that the same test be repeated multinational epidemiologic study, dem- randomized clinical trials regarding ther-
for confirmation, since there will be a onstrated that risk of adverse maternal, apeutic interventions in women who will
greater likelihood of concurrence in this fetal, and neonatal outcomes continu- now be diagnosed with GDM based on
case. For example, if the A1C is 7.0% and ously increased as a function of maternal only one blood glucose value above the
a repeat result is 6.8%, the diagnosis of glycemia at 24-28 weeks, even within
specified cutpoints (in contrast to the
diabetes is confirmed. However, there are ranges previously considered normal for
older criteria that stipulated at least two
scenarios in which results of two different pregnancy. For most complications, there
abnormal values). Expected benefits to
tests (e.g., FPG and A1C) are available for was no threshold for risk. These results
the same patient. In this situation, if the have led to careful reconsideration of the their pregnancies and offspring is inferred
two different tests are both above the di- diagnostic criteria for GDM. After delib- from intervention trials that focused on
agnostic thresholds, the diagnosis of dia- erations in 2008-2009, the IADPSG, an women with more mild hyperglycemia
betes is confirmed. international consensus group with rep- than identified using older GDM diagnos-
On the other hand, when two differ- resentatives from multiple obstetrical and tic criteria and that found modest benefits
ent tests are available in an individual and diabetes organizations, including ADA, (13,14). The frequency of their follow-up
the results are discordant, the test whose developed revised recommendations for and blood glucose monitoring is not yet
result is above the diagnostic cut point diagnosing GDM. The group recom- clear but likely to be less intensive than
should be repeated, and the diagnosis is mended that all women not known to women diagnosed by the older criteria.
made on the basis of the confirmed test. have diabetes undergo a 75-g OGTT at Additional well-designed clinical studies
That is, if a patient meets the diabetes cri- 24-28 weeks of gestation. Additionally, are needed to determine the optimal in-
terion of the A1C (two results ⱖ6.5%) but the group developed diagnostic cutpoints tensity of monitoring and treatment of
not the FPG (⬍126 mg/dl or 7.0 mmol/l), for the fasting, 1-h, and 2-h plasma glu- women with GDM diagnosed by the new
or vice versa, that person should be con- cose measurements that conveyed an criteria (that would not have met the prior
sidered to have diabetes. Admittedly, in odds ratio for adverse outcomes of at least definition of GDM). It is important to note
most circumstance the “nondiabetic” test 1.75 compared with women with mean that 80-90% of women in both of the mild
is likely to be in a range very close to the glucose levels in the HAPO study. Cur- GDM studies (whose glucose values over-
threshold that defines diabetes. rent screening and diagnostic strategies, lapped with the thresholds recommended
Since there is preanalytic and analytic based on the IADPSG statement (12), are herein) could be managed with lifestyle
variability of all the tests, it is also possible outlined in Table 4. therapy alone.

S68 DIABETES CARE, VOLUME 34, SUPPLEMENT 1, JANUARY 2011 care.diabetesjournals.org


Position Statement

6. Sato KK, Hayashi T, Harita N, Yoneda T, 29:1619 –1625.


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