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Ada diganosis and clasification dm .full

  1. 1. P O S I T I O N S T A T E M E N TDiagnosis and Classification of DiabetesMellitusAMERICAN 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 canDESCRIPTION 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 thereforemetabolic 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 itsespecially the eyes, kidneys, nerves, heart, gories (discussed in greater detail below). treatment more than the nature of theand 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 OFThese range from autoimmune destruc- veloping this type of diabetes can often be DIABETES MELLITUS ANDtion of the ␤-cells of the pancreas with identified by serological evidence of an OTHER CATEGORIESconsequent insulin deficiency to abnor- autoimmune pathologic process occur- OF GLUCOSEmalities that result in resistance to insulin ring in the pancreatic islets and by genetic REGULATION — Assigning a type ofaction. The basis of the abnormalities in markers. In the other, much more preva- diabetes to an individual often dependscarbohydrate, fat, and protein metabo- lent category, type 2 diabetes, the cause is on the circumstances present at the timelism 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. Foraction 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 besponses to insulin at one or more points in cient to cause pathologic and functional hyperglycemic after delivery and may bethe 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 acquiresfects 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 areprimary 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 examplesometimes with polyphagia, and blurred lenge with an oral glucose load. would be a person treated with thiazidesvision. Impairment of growth and suscep- The degree of hyperglycemia (if any) who develops diabetes years later. Becausetibility to certain infections may also ac- may change over time, depending on the thiazides in themselves seldom cause severecompany chronic hyperglycemia. Acute, extent of the underlying disease process hyperglycemia, such individuals probablylife-threatening consequences of uncon- (Fig. 1). A disease process may be present have type 2 diabetes that is exacerbated bytrolled 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 particularmolar 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 toinclude retinopathy with potential loss of ance (IGT) without fulfilling the criteria treat it; 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 insulinjoints; 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, previouslySections on diagnosis revised Fall 2009. encompassed by the terms insulin-DOI: 10.2337/dc10-S062© 2010 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 destructionS62 DIABETES CARE, VOLUME 33, SUPPLEMENT 1, JANUARY 2010
  2. 2. Position StatementFigure 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, type1 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 fromthe immune destruction of the ␤-cell in- cur at any age, even in the 8th and 9th predominantly insulin resistanceclude islet cell autoantibodies, autoanti- decades of life. with relative insulin deficiency tobodies 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 forand usually more of these autoantibodies that are still poorly defined. Although pa- ϳ90 –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, ordetected. 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 andDQB 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 typeand 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 ofdren and adolescents, may present with Some of these patients have permanent ␤-cells does not occur, and patients doketoacidosis 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 causesin the presence of infection or other stress. of those who do, most are of African or some degree of insulin resistance. PatientsStill others, particularly adults, may retain Asian ancestry. Individuals with this form who are not obese by traditional weightresidual ␤-cell function sufficient to pre- of diabetes suffer from episodic ketoaci- criteria may have an increased percentagevent ketoacidosis for many years; such in- dosis and exhibit varying degrees of insu- of body fat distributed predominantly individuals 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 ofketoacidosis. At this latter stage of the dis- lacks immunological evidence for ␤-cell diabetes; when seen, it usually arises inease, 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 formediated diabetes commonly occurs in may come and go. many years because the DIABETES CARE, VOLUME 33, SUPPLEMENT 1, JANUARY 2010 S63
  3. 3. Diagnosis and Classificationdevelops gradually and at earlier stages is of insulin secretion. The less common noma. With the exception of that causedoften not severe enough for the patient to forms result from mutations in other tran- by cancer, damage to the pancreas mustnotice 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 smallincreased 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 intes may have insulin levels that appear with diabetes and deafness The most ␤-cell mass. If extensive enough, cysticnormal or elevated, the higher blood glu- common mutation occurs at position fibrosis and hemochromatosis will alsocose 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 mayhigher 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 insistance. Insulin resistance may improve this syndrome, suggesting different phe- the exocrine ducts have been found atwith 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 hormonesseldom 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 hormonestivity. 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 withethnic 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 resolvesmore 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 causeclearly defined. are unusual causes of diabetes that result diabetes, at least in part, by inhibiting in- from genetically determined abnormali- sulin secretion. Hyperglycemia generallyOther specific types of diabetes ties of insulin action. The metabolic ab- resolves after successful removal of theGenetic 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 bycharacterized 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 isonset diabetes of the young (MODY) and this syndrome was termed type A insulin unclear because the sequence or relativeare 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) andautosomal 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. Suchmosomes have been identified to date. extreme insulin resistance. The former has drug reactions fortunately are rare. ThereThe most common form is associated characteristic facial features and is usually are also many drugs and hormones thatwith 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 beensecond form is associated with mutations Alterations in the structure and func- reported to develop diabetes associatedin the glucokinase gene on chromosome tion of the insulin receptor cannot be dem- with islet cell antibodies and, in certain7p and results in a defective glucokinase onstrated in patients with insulin-resistant instances, severe insulin deficiency. Themolecule. 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-inducedtion 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. Diabetesnase 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 HLAS64 DIABETES CARE, VOLUME 33, SUPPLEMENT 1, JANUARY 2010
  4. 4. Position StatementTable 1—Etiologic classification of diabetes mellitus and immune markers characteristic ofI. 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 inducingII. 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 andPatients with any form of diabetes may require insulin treatment at some stage of their disease. Such use of classification of GDM, but its limitationsinsulin 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 DIABETES CARE, VOLUME 33, SUPPLEMENT 1, JANUARY 2010 S65
  5. 5. Diagnosis and ClassificationTable 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), whereinFPG 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) ͓IFG͔ 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) ͓IGT͔ loss of body weight, and certain pharma- levels both below and above 5.9% (9). ForA1C 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, extendingbelow the lower limit of the range and becoming diabetes in people with IGT; the potential interventions is likely to be somewhere indisproportionately 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, asof childbearing age, the number of preg- ADA Expert Committee report reduced the risk of diabetes with any measure ornant 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 pointand 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 arerepresentatives from multiple obstetrical organizations did not adopt this change in going to develop diabetes) against theand 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 tofound 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 A1Ctional, diabetes. Approximately 7% of all to diagnose diabetes in its 2009 report, cutpoint of 5.7% is less sensitive but morepregnancies (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 forthe diagnostic tests employed) are com- tes with all glycemic measures and did not later development of diabetes. A largeplicated 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 ofCATEGORIES OF oratory “normal” range but below the di- subsequent 6-year diabetes incidenceINCREASED RISK FOR agnostic cut point for diabetes (6.0 to (10). Receiver operating curve analysesDIABETES — In 1997 and 2003, The Ͻ6.5%) are at very high risk of develop- of nationally representative U.S. dataExpert Committee on Diagnosis and Clas- ing diabetes. Indeed, incidence of diabe- (NHANES 1999-2006) indicate that ansification of Diabetes Mellitus (1,2) recog- tes in people with A1C levels in this range A1C value of 5.7% has modest sensitivitynized 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 Ͼ100 mg/dl)meet criteria for diabetes, yet are higher Ͻ6.5% range fails to identify a substantial (5.6 mmol/l) or IGT (2-h glucose Ͼ 140than 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 thating 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 isoral glucose tolerance test (OGTT) of 140 higher than incidence in the U.S. popula- reasonable to consider an A1C range ofmg/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 individualsmmol/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 riskIGT 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 physicalcular 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 ofprocesses listed in Table 1. IFG and IGT (5.6 mmol/l) corresponds to an A1C of risk is curvilinear, so that as A1C rises, theare associated with obesity (especially ab- 5.4% (R.T. Ackerman, personal commu- risk of diabetes rises disproportionately.S66 DIABETES CARE, VOLUME 33, SUPPLEMENT 1, JANUARY 2010
  6. 6. Position StatementAccordingly, interventions should be Table 3—Criteria for the diagnosis of diabetesmost intensive and follow-up should be 1. A1C Ն6.5%. The test should be performed in a laboratory using a method that is NGSPparticularly vigilant for those with A1C certified and standardized to the DCCT assay.*levels above 6.0%, who should be consid- ORered to be at very high risk. However, just 2. FPG Ն126 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 OR98 mg/dl (5.4 mmol/l) may not be at neg- 3. 2-h plasma glucose Ն200 mg/dl (11.1 mmol/l) during an OGTT. The test should beligible risk for diabetes, individuals with performed as described by the World Health Organization, using a glucose load containingA1C 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 ORof other risk factors, such as obesity and 4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a randomfamily history. plasma glucose Ն200 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 ofpatients at risk should incorporate aglobal risk factor assessment for both di- microvascular and, to a lesser extent, ma- tion, the A1C can be misleading in pa-abetes and cardiovascular disease. crovascular complications and is widely tients with certain forms of anemia andScreening for and counseling about risk of used as the standard biomarker for the hemoglobinopathies, which may alsodiabetes should always be in the prag- adequacy of glycemic management. Prior have unique ethnic or geographic distri-matic context of the patient’s comorbidi- Expert Committees have not recom- butions. For patients with a hemoglobi-ties, life expectancy, personal capacity to mended use of the A1C for diagnosis of nopathy but normal red cell turnover,engage in lifestyle change, and overall diabetes, in part due to lack of standard- such as sickle cell trait, an A1C assayhealth goals. ization of the assay. However, A1C assays without interference from abnormal he- are now highly standardized so that their moglobins should be used (an updatedDIAGNOSTIC CRITERIA FOR results can be uniformly applied both list is available at 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 anemiasbased on glucose criteria, either the FPG Expert Committee, after an extensive re- from hemolysis and iron deficiency, theor 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 forthe diagnostic criteria, using the observed tes, with a threshold of Ն6.5%, 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 severeThe 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 Ն200 mg/dl (11.1measured glycemia as FPG, 2-h PG, and globin Standardization Program (NGSP) mmol/l) is found. It is likely that in suchA1C. These studies demonstrated glyce- and standardized or traceable to the Dia- cases the health care professional wouldmic levels below which there was little betes Control and Complications Trial also measure an A1C test as part of theprevalent 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) bean 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 1each measure within each population. dysglycemia, particularly since the A1C is diabetes in some children, A1C may notMoreover, the glycemic values above already widely familiar to clinicians as a be significantly elevated despite frankwhich 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 PGpoint of Ն126 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 Ն200 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 Ն6.5%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 cutperiod of time. The test plays a critical role veloping world, and the incomplete cor- point of Ն126 mg/dl (7.0 mmol/l) (cdcin the management of the patient with di- relation between A1C and average website tbd). However, in practice, a largeabetes, since it correlates well with both glucose in certain individuals. In addi- portion of the population with type 2 DIABETES CARE, VOLUME 33, SUPPLEMENT 1, JANUARY 2010 S67
  7. 7. Diagnosis and Classificationabetes remains unaware of their condi- the diagnostic threshold is repeated, the group with a high prevalence of diabe-tion. Thus, it is conceivable that the lower second value will be below the diagnostic tes (e.g., Hispanic American, Nativesensitivity of A1C at the designated cut cut point. This is least likely for A1C, American, Asian American, Africanpoint will be offset by the test’s greater somewhat more likely for FPG, and most American, Pacific Islander)practicality, and that wider application of likely for the 2-h PG. Barring a laboratorya more convenient test (A1C) may actu- error, such patients are likely to have test Risk assessment for GDM should beally increase the number of diagnoses results near the margins of the thresholdmade. for a diagnosis. The healthcare profes- undertaken at the first prenatal visit. Further research is needed to better sional might opt to follow the patient Women with clinical characteristics con-characterize those patients whose glyce- closely and repeat the testing in 3– 6 sistent with a high risk of GDM (markedmic status might be categorized differ- months. obesity, personal history of GDM, glyco-ently by two different tests (e.g., FPG and The decision about which test to use suria, or a strong family history of diabe-A1C), obtained in close temporal approx- to assess a specific patient for diabetes tes) should undergo glucose testing (seeimation. Such discordance may arise from should be at the discretion of the health below) as soon as feasible. If they aremeasurement variability, change over care professional, taking into account the found not to have GDM at that initialtime, or because A1C, FPG, and postchal- availability and practicality of testing an screening, they should be retested be-lenge glucose each measure different individual patient or groups of patients. tween 24 and 28 weeks of gestation.physiological processes. In the setting of Perhaps more important than which diag- Women of average risk should have test-an elevated A1C but “nondiabetic” FPG, nostic test is used, is that the testing for ing undertaken at 24 –28 weeks ofthe likelihood of greater postprandial glu- diabetes be performed when indicated. gestation.cose levels or increased glycation rates for There is discouraging evidence indicating An FPG level Ͼ126 mg/dl (7.0a given degree of hyperglycemia may be that many at-risk patients still do not receive mmol/l) or a casual plasma glucose Ͼ200present. In the opposite scenario (high adequate testing and counseling for this in- mg/dl (11.1 mmol/l) meets the thresholdFPG yet A1C below the diabetes cut creasingly common disease, or for its fre- for the diagnosis of diabetes. In the ab-point), augmented hepatic glucose pro- quently accompanying cardiovascular risk sence of unequivocal hyperglycemia, theduction or reduced glycation rates may be factors. The current diagnostic criteria for diagnosis must be confirmed on a subse-present. diabetes are summarized in Table 3. quent day. Confirmation of the diagnosis As with most diagnostic tests, a test precludes the need for any glucose chal-result diagnostic of diabetes should be re- Diagnosis of GDM lenge. In the absence of this degree of hy-peated to rule out laboratory error, unless At the time of publication of this state- perglycemia, evaluation for GDM inthe diagnosis is clear on clinical grounds, ment, the criteria for abnormal glucose women with average or high-risk charac-such as a patient with classic symptoms of tolerance in pregnancy are those of Car- teristics should follow one of twohyperglycemia or hyperglycemic crisis. It penter and Coustan (11). Recommenda- preferable that the same test be repeated tions from ADA’s Fourth International One-step approach. Perform a diagnos-for confirmation, since there will be a Workshop-Conference on Gestational tic OGTT without prior plasma or serumgreater likelihood of concurrence in this Diabetes Mellitus held in March 1997 glucose screening. The one-step approachcase. For example, if the A1C is 7.0% and support the use of the Carpenter/Coustan may be cost-effective in high-risk patientsa repeat result is 6.8%, the diagnosis of diagnostic criteria as well as the alterna- or populations (e.g., some Native-diabetes is confirmed. However, there are tive use of a diagnostic 75-g 2-h OGTT. American groups).scenarios in which results of two different These criteria are summarized below. Two-step approach. Perform an initialtests (e.g., FPG and A1C) are available for Testing for gestational diabetes. Previ- screening by measuring the plasma or se-the same patient. In this situation, if the ous recommendations included screening rum glucose concentration 1 h after atwo different tests are both above the di- for GDM performed in all pregnancies. 50-g oral glucose load (glucose challengeagnostic thresholds, the diagnosis of dia- However, there are certain factors that test [GCT]) and perform a diagnosticbetes is confirmed. place women at lower risk for the devel- OGTT on that subset of women exceeding On the other hand, when two differ- opment of glucose intolerance during the glucose threshold value on the GCT.ent tests are available in an individual and pregnancy, and it is likely not cost- When the two-step approach is used, athe results are discordant, the test whose effective to screen such patients. Pregnant glucose threshold value Ͼ140 mg/dl (7.8result is above the diagnostic cut point women who fulfill all of these criteria mmol/l) identifies ϳ80% of women withshould be repeated, and the diagnosis is need not be screened for GDM. GDM, and the yield is further increased tomade on the basis of the confirmed test. This low-risk group comprises 90% by using a cutoff of Ͼ130 mg/dl (7.2That is, if a patient meets the diabetes cri- women who: mmol/l).terion of the A1C (two results Ն6.5%) but With either approach, the diagnosisnot the FPG (Ͻ126 mg/dl or 7.0 mmol/l), ● are Ͻ25 years of age of GDM is based on an OGTT. Diagnosticor vice versa, that person should be con- ● are a normal body weight criteria for the 100-g OGTT are derivedsidered to have diabetes. Admittedly, in ● have no family history (i.e., first-degree from the original work of O’Sullivan andmost circumstance the “nondiabetic” test relative) of diabetes Mahan (12) modified by Carpenter andis likely to be in a range very close to the ● have no history of abnormal glucose Coustan (11) and are shown at the top ofthreshold that defines diabetes. metabolism Table 4. Alternatively, the diagnosis can Since there is preanalytic and analytic ● have no history of poor obstetric be made using a 75-g glucose load and thevariability of all the tests, it is also possible outcome glucose threshold values listed for fasting,that when a test whose result was above ● are not members of an ethnic/racial 1 h, and 2 h (Table 4, bottom); however,S68 DIABETES CARE, VOLUME 33, SUPPLEMENT 1, JANUARY 2010
  8. 8. Position StatementTable 4—Diagnosis of GDM with a 100-g or obstetrical organizations to consider cose and A1C is effective for the75-g glucose load adoption of the IADPSG diagnostic crite- prediction of type 2 diabetes: the Kansai ria and to discuss the implications of this Healthcare Study. Diabetes Care 2009;32: change. While this change will signifi- 644 – 646 mg/dl mmol/l 7. Shimazaki T, Kadowaki T, Ohyama Y, cantly increase the prevalence of GDM, Ohe K, Kubota K. Hemoglobin A1c100-g glucose load there is mounting evidence that treating (HbA1c) predicts future drug treatment Fasting 95 5.3 even mild GDM reduces morbidity for for diabetes mellitus: a follow-up study 1-h 180 10.0 both mother and baby (14). using routine clinical data in a Japanese 2-h 155 8.6 university hospital. Translational Re- 3-h 140 7.8 search 2007;149:196 –20475-g glucose load Acknowledgments — The American Diabe- 8. Geiss LS, Pan L, Cadwell B, Gregg EW, Ben- Fasting 95 5.3 tes Association thanks the following volunteer jamin SM, Engelgau MM. Changes in inci- 1-h 180 10.0 members of the writing group for the updated dence of diabetes in U.S. adults, 1997– 2-h 155 8.6 sections on diagnosis and categories of in- 2003. Am J Prev Med 2006;30:371–377 creased risk: Silvio Inzucchi, MD; Richard Ber- 9. Knowler WC, Barrett-Connor E, FowlerTwo or more of the venous plasma concentrations genstal, MD; Vivian Fonseca, MD; Edwardmust be met or exceeded for a positive diagnosis. SE, Hamman RF, Lachin JM, Walker EA, Gregg, PhD; Beth Mayer-Davis, MSPH, PhD, Nathan DM, Diabetes Prevention Pro-The test should be done in the morning after anovernight fast of between 8 and 14 h and after at least RD; Geralyn Spollett, MSN, CDE, ANP; and gram Research Group. Reduction in the3 days of unrestricted diet (Ն150 g carbohydrate per Richard Wender, MD. incidence of type 2 diabetes with lifestyleday) and unlimited physical activity. The subject intervention or metformin. N Engl J Medshould remain seated and should not smoke 2002;346:393– 403throughout the test. References 10. Droumaguet C, Balkau B, Simon D, Caces 1. Expert Committee on the Diagnosis and E, Tichet J, Charles MA, Eschwege E, the Classification of Diabetes Mellitus. Report of DESIR Study Group. Use of HbA1c in pre-this test is not as well validated as the the Expert Committee on the Diagnosis and dicting progression to diabetes in French100-g OGTT. Classification of Diabetes Mellitus. Diabetes men and women: data from an Epidemi- Care 1997;20:1183–1197 ological Study on the Insulin Resistance Results of the Hyperglycemia and 2. Genuth S, Alberti KG, Bennett P, Buse J, Syndrome (DESIR) Diabetes Care 2006;Adverse Pregnancy Outcomes study Defronzo R, Kahn R, Kitzmiller J, Knowler 29:1619 –1625.(13), a large-scale (ϳ25,000 pregnant WC, Lebovitz H, Lernmark A, Nathan D, 11. Carpenter MW, Coustan DR. Criteria forwomen) multinational epidemiologic Palmer J, Rizza R, Saudek C, Shaw J, Ste- screening tests for gestational diabetes. Am Jstudy, demonstrated that risk of adverse ffes M, Stern M, Tuomilehto J, Zimmet P, Obstet Gynecol 1982;144:768 –773maternal, fetal, and neonatal outcomes Expert Committee on the Diagnosis and 12. O’Sullivan JB, Mahan CM. Criteria for thecontinuously increased as a function of Classification of Diabetes Mellitus2, the oral glucose tolerance test in pregnancy.maternal glycemia at 24 –28 weeks, Expert Committee on the Diagnosis and Diabetes 1964;13:278even within ranges previously consid- Classification of Diabetes Mellitus. Fol- 13. HAPO Study Cooperative Researchered normal for pregnancy. For most low-up report on the diagnosis of dia- Group, Metzger BE, Lowe LP, Dyer AR, betes mellitus. Diabetes Care 2003;26: Trimble ER, Chaovarindr U, Coustan DR,complications, there was no threshold 3160 –3167 Hadden DR, McCance DR, Hod M, McIn-for risk. These results have led to careful 3. International Expert Committee. Interna- tyre HD, Oats JJ, Persson B, Rogers MS,reconsideration of the diagnostic crite- tional Expert Committee report on the Sacks DA. Hyperglycemia and adverseria for GDM. The IADPSG recom- role of the A1C assay in the diagnosis pregnancy outcomes. N Engl J Med 2008;mended that all women not known to of diabetes. Diabetes Care 2009;32:1327– 358:1991–2002have prior diabetes undergo a 75-g 1334 14. Landon MB, Spong CY, Thom E, Carpen-OGTT at 24 –28 weeks of gestation. The 4. Edelman D, Olsen MK, Dudley TK, Harris ter MW, Ramin SM, Casey B, Wapner RJ,group developed diagnostic cut points AC, Oddone EZ. Utility of hemoglobin Varner MW, Rouse DJ, Thorp JM Jr,for the fasting, 1-h, and 2-h plasma glu- A1c in predicting diabetes risk. J Gen In- Sciscione A, Catalano P, Harper M, Saadecose measurements that conveyed an tern Med 2004;19:1175–1180 G, Lain KY, Sorokin Y, Peaceman AM, To- 5. Pradhan AD, Rifai N, Buring JE, Ridker PM. losa JE, Anderson GB, Eunice Kennedyodds ratio for adverse outcomes of at Hemoglobin A1c predicts diabetes but not Shriver National Institute of Child Healthleast 1.75 compared with women with cardiovascular disease in nondiabetic and Human Development Maternal-Fetalthe mean glucose levels in the HAPO women. Am J Med 2007;120:720 –727 Medicine Units Network. A multicenter,study. 6. Sato KK, Hayashi T, Harita N, Yoneda T, randomized trial of treatment for mild At the time of publication of this up- Nakamura Y, Endo G, Kambe H. Com- gestational diabetes. N Engl J Med 2009;date, ADA is planning to work with U.S. bined measurement of fasting plasma glu- 361:1339 – DIABETES CARE, VOLUME 33, SUPPLEMENT 1, JANUARY 2010 S69