S44 Diagnosis and Classi?cation Figure 1—Disorders of glycemia: etiologic types and stages. Even after presenting in ketoacidosis, these patients can brie?y 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. cellular-mediated autoimmune destruc- tion of the -cells of the pancreas. Mark- ers of the immune destruction of the -cell include islet cell autoantibodies, autoantibodies to insulin, autoantibodies to glutamic acid decarboxylase (GAD65), and autoantibodies to the tyrosine phos- phatases IA-2 and IA-2 . One and usually more of these autoantibodies are present in 85–90% of individuals when fasting hyperglycemia is initially detected. Also, the disease has strong HLA associations, with linkage to the DQA and DQB genes, and it is in?uenced by the DRB genes. These HLA-DR/DQ alleles can be either predisposing or protective. In this form of diabetes, the rate of -cell destruction is quite variable, being rapid in some individuals (mainly infants and children) and slow in others (mainly adults). Some patients, particularly chil- dren and adolescents, may present with ketoacidosis as the ?rst manifestation of the disease. Others have modest fasting hyperglycemia that can rapidly change to severe hyperglycemia and/or ketoacidosis in the presence of infection or other stress. Still others, particularly adults, may retain residual -cell function suf?cient to pre- vent ketoacidosis for many years; such in- dividuals eventually become dependent on insulin for survival and are at risk for ketoacidosis. At this latter stage of the dis- ease, there is little or no insulin secretion, as manifested by low or undetectable lev- els of plasma C-peptide. Immune- mediated diabetes commonly occurs in childhood and adolescence, but it can oc- cur at any age, even in the 8th and 9th decades of life. Autoimmune destruction of -cells has multiple genetic predispositions and is also related to environmental factors that are still poorly de?ned. Although pa- tients are rarely obese when they present with this type of diabetes, the presence of obesity is not incompatible with the diag- nosis. These patients are also prone to other autoimmune disorders such as Graves’ disease, Hashimoto’s thyroiditis, Addison’s disease, vitiligo, celiac sprue, autoimmune hepatitis, myasthenia gravis, and pernicious anemia. Idiopathic diabetes. Some forms of type 1 diabetes have no known etiologies. Some of these patients have permanent insulinopenia and are prone to ketoacido- sis, but have no evidence of autoimmu- nity. Although only a minority of patients with type 1 diabetes fall into this category, of those who do, most are of African or Asian ancestry. Individuals with this form of diabetes suffer from episodic ketoaci- dosis and exhibit varying degrees of insu- lin de?ciency between episodes. This form of diabetes is strongly inherited, lacks immunological evidence for -cell autoimmunity, and is not HLA associated. An absolute requirement for insulin re- placement therapy in affected patients may come and go. Type 2 diabetes (ranging from predominantly insulin resistance with relative insulin de?ciency to predominantly an insulin secretory defect with insulin resistance) This form of diabetes, which accounts for 90 –95% of those with diabetes, previ- ously referred to as non-insulin- dependent diabetes, type II diabetes, or adult-onset diabetes, encompasses indi- viduals who have insulin resistance and usually have relative (rather than abso- lute) insulin de?ciency At least initially, and often throughout their lifetime, these individuals do not need insulin treatment to survive. There are probably many dif- ferent causes of this form of diabetes. Al- though the speci?c etiologies are not known, autoimmune destruction of -cells does not occur, and patients do not have any of the other causes of diabe- tes listed above or below. Most patients with this form of diabe- tes are obese, and obesity itself causes some degree of insulin resistance. Patients who are not obese by traditional weight criteria may have an increased percentage of body fat distributed predominantly in the abdominal region. Ketoacidosis sel- dom occurs spontaneously in this type of diabetes; when seen, it usually arises in association with the stress of another ill- DIABETES CARE, VOLUME 29, SUPPLEMENT 1, JANUARY 2006
pathways. S45 Position Statement ness such as infection. This form of dia- betes frequently goes undiagnosed for many years because the hyperglycemia develops gradually and at earlier stages is often not severe enough for the patient to notice any of the classic symptoms of di- abetes. Nevertheless, such patients are at increased risk of developing macrovascu- lar and microvascular complications. Whereas patients with this form of diabe- tes may have insulin levels that appear normal or elevated, the higher blood glu- cose levels in these diabetic patients would be expected to result in even higher insulin values had their -cell function been normal. Thus, insulin se- cretion is defective in these patients and insuf?cient to compensate for insulin re- sistance. Insulin resistance may improve with weight reduction and/or pharmaco- logical treatment of hyperglycemia but is seldom restored to normal The risk of de- veloping this form of diabetes increases with age, obesity, and lack of physical ac- tivity. It occurs more frequently in women with prior GDM and in individu- als with hypertension or dyslipidemia, and its frequency varies in different racial/ ethnic subgroups. It is often associated with a strong genetic predisposition, more so than is the autoimmune form of type 1 diabetes. However, the genetics of this form of diabetes are complex and not clearly de?ned. Other speci?c types of diabetes Genetic defects of the -cell. Several forms of diabetes are associated with mo- nogenetic defects in -cell function. These forms of diabetes are frequently characterized by onset of hyperglycemia at an early age (generally before age 25 years). They are referred to as maturity- onset diabetes of the young (MODY) and are characterized by impaired insulin se- cretion with minimal or no defects in in- sulin action. They are inherited in an autosomal dominant pattern. Abnormali- ties at six genetic loci on different chro- mosomes have been identi?ed to date. The most common form is associated with mutations on chromosome 12 in a hepatic transcription factor referred to as hepatocyte nuclear factor (HNF)-1 . A second form is associated with mutations in the glucokinase gene on chromosome 7p and results in a defective glucokinase molecule. Glucokinase converts glucose to glucose-6-phosphate, the metabolism of which, in turn, stimulates insulin secre- tion by the -cell. Thus, glucokinase serves as the “glucose sensor” for the -cell. Because of defects in the glucoki- nase gene, increased plasma levels of glu- cose are necessary to elicit normal levels of insulin secretion. The less common forms result from mutations in other tran- scription factors, including HNF-4 , HNF-1 , insulin promoter factor (IPF)-1, and NeuroD1. Point mutations in mitochondrial DNA have been found to be associated with diabetes mellitus and deafness The most common mutation occurs at posi- tion 3243 in the tRNA leucine gene, lead- ing to an A-to-G transition. An identical lesion occurs in the MELAS syndrome (mitochondrial myopathy, encephalopa- thy, lactic acidosis, and stroke-like syn- drome); however, diabetes is not part of this syndrome, suggesting different phe- notypic expressions of this genetic lesion. Genetic abnormalities that result in the inability to convert proinsulin to in- sulin have been identi?ed in a few fami- lies, and such traits are inherited in an autosomal dominant pattern. The result- ant glucose intolerance is mild. Similarly, the production of mutant insulin mole- cules with resultant impaired receptor binding has also been identi?ed in a few families and is associated with an autoso- mal inheritance and only mildly impaired or even normal glucose metabolism. Genetic defects in insulin action. There are unusual causes of diabetes that result from genetically determined abnor- malities of insulin action. The metabolic abnormalities associated with mutations of the insulin receptor may range from hyperinsulinemia and modest hypergly- cemia to severe diabetes. Some individu- als with these mutations may have acanthosis nigricans. Women may be vir- ilized and have enlarged, cystic ovaries. In the past, this syndrome was termed type A insulin resistance. Leprechaunism and the Rabson-Mendenhall syndrome are two pediatric syndromes that have muta- tions in the insulin receptor gene with subsequent alterations in insulin receptor function and extreme insulin resistance. The former has characteristic facial fea- tures and is usually fatal in infancy, while the latter is associated with abnormalities of teeth and nails and pineal gland hyperplasia. Alterations in the structure and func- tion of the insulin receptor cannot be demonstrated in patients with insulin- resistant lipoatrophic diabetes. Therefore, it is assumed that the lesion(s) must reside in the postreceptor signal transduction Diseases of the exocrine pancreas. Any process that diffusely injures the pancreas can cause diabetes. Acquired processes include pancreatitis, trauma, infection, pancreatectomy, and pancreatic carci- noma. With the exception of that caused by cancer, damage to the pancreas must be extensive for diabetes to occur; adre- nocarcinomas that involve only a small portion of the pancreas have been associ- ated with diabetes. This implies a mecha- nism other than simple reduction in -cell mass. If extensive enough, cystic ?brosis and hemochromatosis will also damage -cells and impair insulin secre- tion. Fibrocalculous pancreatopathy may be accompanied by abdominal pain radi- ating to the back and pancreatic calci?ca- tions identi?ed on X-ray examination. Pancreatic ?brosis and calcium stones in the exocrine ducts have been found at autopsy. Endocrinopathies. Several hormones (e.g., growth hormone, cortisol, gluca- gon, epinephrine) antagonize insulin ac- tion. Excess amounts of these hormones (e.g., acromegaly, Cushing’s syndrome, glucagonoma, pheochromocytoma, re- spectively) can cause diabetes. This gen- erally occurs in individuals with preexisting defects in insulin secretion, and hyperglycemia typically resolves when the hormone excess is resolved. Somatostatinoma- and aldoster- onoma-induced hypokalemia can cause diabetes, at least in part, by inhibiting in- sulin secretion. Hyperglycemia generally resolves after successful removal of the tu- mor. Drug- or chemical-induced diabetes. Many drugs can impair insulin secretion. These drugs may not cause diabetes by themselves, but they may precipitate dia- betes in individuals with insulin resis- tance. In such cases, the classi?cation is unclear because the sequence or relative importance of -cell dysfunction and in- sulin resistance is unknown. Certain tox- ins such as Vacor (a rat poison) and intravenous pentamidine can perma- nently destroy pancreatic -cells. Such drug reactions fortunately are rare. There are also many drugs and hormones that can impair insulin action. Examples in- clude nicotinic acid and glucocorticoids. Patients receiving -interferon have been reported to develop diabetes associated with islet cell antibodies and, in certain instances, severe insulin de?ciency. The list shown in Table 1 is not all-inclusive, but re?ects the more commonly recog- DIABETES CARE, VOLUME 29, SUPPLEMENT 1, JANUARY 2006
S46 Diagnosis and Classi?cation nized drug-, hormone-, or toxin-induced Table 1—Etiologic classi?cation of diabetes mellitus I. Type 1 diabetes ( -cell destruction, usually leading to absolute insulin de?ciency) A. Immune mediated B. Idiopathic II. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin de?ciency to a predominantly secretory defect with insulin resistance) III. Other speci?c types A. Genetic defects of -cell function 1. Chromosome 12, HNF-1 (MODY3) 2. Chromosome 7, glucokinase (MODY2) 3. Chromosome 20, HNF-4 (MODY1) 4. Chromosome 13, insulin promoter factor-1 (IPF-1; MODY4) 5. Chromosome 17, HNF-1 (MODY5) 6. Chromosome 2, NeuroD1 (MODY6) 7. Mitochondrial DNA 8. Others B. Genetic defects in insulin action 1. Type A insulin resistance 2. Leprechaunism 3. Rabson-Mendenhall syndrome 4. Lipoatrophic diabetes 5. Others C. Diseases of the exocrine pancreas 1. Pancreatitis 2. Trauma/pancreatectomy 3. Neoplasia 4. Cystic ?brosis 5. Hemochromatosis 6. Fibrocalculous pancreatopathy 7. Others D. Endocrinopathies 1. Acromegaly 2. Cushing’s syndrome 3. Glucagonoma 4. Pheochromocytoma 5. Hyperthyroidism 6. Somatostatinoma 7. Aldosteronoma 8. Others E. Drug- or chemical-induced 1. Vacor 2. Pentamidine 3. Nicotinic acid 4. Glucocorticoids 5. Thyroid hormone 6. Diazoxide 7. -adrenergic agonists 8. Thiazides 9. Dilantin 10. -Interferon 11. Others F. Infections 1. Congenital rubella 2. Cytomegalovirus 3. Others G. Uncommon forms of immune-mediated diabetes 1. “Stiff-man” syndrome 2. Anti–insulin receptor antibodies 3. Others H. Other genetic syndromes sometimes associated with diabetes 1. Down’s syndrome 2. Klinefelter’s syndrome 3. Turner’s syndrome 4. Wolfram’s syndrome 5. Friedreich’s ataxia 6. Huntington’s chorea 7. Laurence-Moon-Biedl syndrome 8. Myotonic dystrophy 9. Porphyria 10. Prader-Willi syndrome 11. Others IV. Gestational diabetes mellitus (GDM) Patients with any form of diabetes may require insulin treatment at some stage of their disease. Such use of insulin does not, of itself, classify the patient. forms of diabetes. Infections. Certain viruses have been as- sociated with -cell destruction. Diabetes occurs in patients with congenital rubella, although most of these patients have HLA and immune markers characteristic of type 1 diabetes. In addition, coxsackievi- rus B, cytomegalovirus, adenovirus, and mumps have been implicated in inducing certain cases of the disease. Uncommon forms of immune-medi- ated diabetes. In this category, there are two known conditions, and others are likely to occur. The stiff-man syndrome is an autoimmune disorder of the central nervous system characterized by stiffness of the axial muscles with painful spasms. Patients usually have high titers of the GAD autoantibodies, and approximately one-third will develop diabetes. Anti–insulin receptor antibodies can cause diabetes by binding to the insulin receptor, thereby blocking the binding of insulin to its receptor in target tissues. However, in some cases, these antibodies can act as an insulin agonist after binding to the receptor and can thereby cause hy- poglycemia. Anti–insulin receptor anti- bodies are occasionally found in patients with systemic lupus erythematosus and other autoimmune diseases. As in other states of extreme insulin resistance, pa- tients with anti–insulin receptor antibod- ies often have acanthosis nigricans. In the past, this syndrome was termed type B insulin resistance. Other genetic syndromes sometimes associated with diabetes. Many genetic syndromes are accompanied by an in- creased incidence of diabetes mellitus. These include the chromosomal abnor- malities of Down’s syndrome, Klinefelter’s syndrome, and Turner’s syn- drome. Wolfram’s syndrome is an autoso- mal recessive disorder characterized by insulin-de?cient diabetes and the absence of -cells at autopsy. Additional manifes- tations include diabetes insipidus, hypo- gonadism, optic atrophy, and neural deafness. Other syndromes are listed in Table 1. Gestational diabetes mellitus (GDM) GDM is de?ned as any degree of glucose intolerance with onset or ?rst recognition during pregnancy. The de?nition applies regardless of whether insulin or only diet modi?cation is used for treatment or whether the condition persists after preg- nancy. It does not exclude the possibility that unrecognized glucose intolerance may DIABETES CARE, VOLUME 29, SUPPLEMENT 1, JANUARY 2006
2. FPG ? ? ? S47 Position Statement Table 2—Criteria for the diagnosis of diabetes mellitus 1. Symptoms of diabetes plus casual plasma glucose concentration 200 mg/dl (11.1 mmol/ l). Casual is de?ned as any time of day without regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss. OR 126 mg/dl (7.0 mmol/l). Fasting is de?ned as no caloric intake for at least 8 h. OR 3. 2-h postload glucose 200 mg/dl (11.1 mmol/l) during an OGTT. The test should be performed as described by WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water. In the absence of unequivocal hyperglycemia, these criteria should be con?rmed by repeat testing on a different day. The third measure (OGTT) is not recommended for routine clinical use. (A1C) for the diagnosis of diabetes is not recommended at this time. Diagnosis of GDM The criteria for abnormal glucose toler- ance in pregnancy are those of Carpenter and Coustan (3). Recommendations from the American Diabetes Association’s Fourth International Workshop- Conference on Gestational Diabetes Mel- litus held in March 1997 support the use of the Carpenter/Coustan diagnostic cri- teria as well as the alternative use of a di- agnostic 75-g 2-h OGTT. These criteria are summarized below. have antedated or begun concomitantly with the pregnancy. GDM complicates 4% of all pregnancies in the U.S., result- ing in 135,000 cases annually. The prev- alence may range from 1 to 14% of pregnancies, depending on the population studied. GDM represents nearly 90% of all pregnancies complicated by diabetes. Deterioration of glucose tolerance oc- curs normally during pregnancy, particu- larly in the 3rd trimester. Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) The Expert Committee (1,2) recognized an intermediate group of subjects whose glucose levels, although not meeting cri- teria for diabetes, are nevertheless too high to be considered normal. This group is de?ned as having fasting plasma glu- cose (FPG) levels 100 mg/dl (5.6 mmol/l) but 126 mg/dl (7.0 mmol/l) or 2-h values in the oral glucose tolerance test (OGTT) of 140 mg/dl (7.8 mmol/l) but 200 mg/dl (11.1 mmol/l). Thus, the categories of FPG values are as follows: ? FPG 100 mg/dl (5.6 mmol/l) nor- mal fasting glucose; ? FPG 100 –125 mg/dl (5.6 – 6.9 mmol/ l) IFG (impaired fasting glucose); ? FPG 126 mg/dl (7.0 mmol/l) pro- visional diagnosis of diabetes (the diag- nosis must be con?rmed, as described below). The corresponding categories when the OGTT is used are the following: 2-h postload glucose 140 mg/dl (7.8 mmol/l) normal glucose tolerance; 2-h postload glucose 140 –199 mg/dl abetes (the diagnosis must be con- ?rmed, as described below). Patients with IFG and/or IGT are now referred to as having “pre-diabetes” indi- cating the relatively high risk for develop- ment of diabetes in these patients. In the absence of pregnancy, IFG and IGT are not clinical entities in their own right but rather risk factors for future diabetes as well as cardiovascular disease. They can be observed as intermediate stages in any of the disease processes listed in Table 1. IFG and IGT are associated with the met- abolic syndrome, which includes obesity (especially abdominal or visceral obesity), dyslipidemia of the high-triglyceride and/or low-HDL type, and hypertension. It is worth mentioning that medical nutri- tion therapy aimed at producing 5–10% loss of body weight, exercise, and certain pharmacological agents have been vari- ably demonstrated to prevent or delay the development of diabetes in people with IGT; the potential impact of such inter- ventions to reduce cardiovascular risk has not been examined to date. Note that many individuals with IGT are euglycemic in their daily lives. Indi- viduals with IFG or IGT may have normal or near normal glycated hemoglobin lev- els. Individuals with IGT often manifest hyperglycemia only when challenged with the oral glucose load used in the standardized OGTT. DIAGNOSTIC CRITERIA FOR DIABETES MELLITUS — The cri- teria for the diagnosis of diabetes are shown in Table 2. Three ways to diagnose diabetes are possible, and each, in the ab- Testing for gestational diabetes. Previ- ous recommendations included screening for GDM performed in all pregnancies. However, there are certain factors that place women at lower risk for the devel- opment of glucose intolerance during pregnancy, and it is likely not cost- effective to screen such patients. Pregnant women who ful?ll all of these criteria need not be screened for GDM. This low-risk group comprises women who ? are 25 years of age ? are a normal body weight ? have no family history (i.e., ?rst-degree relative) of diabetes ? have no history of abnormal glucose metabolism ? have no history of poor obstetric out- come ? are not members of an ethnic/racial group with a high prevalence of diabe- tes (e.g., Hispanic American, Native American, Asian American, African American, Paci?c Islander) Risk assessment for GDM should be undertaken at the ?rst prenatal visit. Women with clinical characteristics con- sistent with a high risk of GDM (marked obesity, personal history of GDM, glyco- suria, or a strong family history of diabe- tes) should undergo glucose testing (see below) as soon as feasible. If they are found not to have GDM at that initial screening, they should be retested be- tween 24 and 28 weeks of gestation. Women of average risk should have test- ing undertaken at 24 –28 weeks of gestation. A fasting plasma glucose level 126 mg/dl (7.0 mmol/l) or a casual plasma (7.8 –11.1 mmol/l) IGT (impaired sence of unequivocal hyperglycemia, glucose 200 mg/dl (11.1 mmol/l) meets glucose tolerance); 2-h postload glucose 200 mg/dl (11.1 mmol/l) provisional diagnosis of di- must be con?rmed, on a subsequent day, by any one of the three methods given in Table 2. The use of the hemoglobin A1c the threshold for the diagnosis of diabe- tes. In the absence of unequivocal hyper- glycemia, the diagnosis must be DIABETES CARE, VOLUME 29, SUPPLEMENT 1, JANUARY 2006
mg/dl 95 5.3 S48 Diagnosis and Classi?cation Table 3—Diagnosis of GDM with a 100-g or 75-g glucose load mmol/l 100-g glucose load Fasting evaluation for GDM in women with aver- age or high-risk characteristics should fol- low one of two approaches. One-step approach. Perform a diagnos- tic OGTT without prior plasma or serum glucose screening. The one-step approach may be cost-effective in high-risk patients Mahan (4) modi?ed by Carpenter and Coustan (3) and are shown in the top of Table 3. Alternatively, the diagnosis can be made using a 75-g glucose load and the glucose threshold values listed for fasting, 1 h, and 2 h (Table 2, bottom); however, this test is not as well validated as the 1-h 2-h 180 155 10.0 8.6 or populations (e.g., some Native- American groups). 100-g OGTT. 3-h 140 7.8 75-g glucose load Fasting 95 5.3 1-h 180 10.0 2-h 155 8.6 Two or more of the venous plasma concentrations must be met or exceeded for a positive diagnosis. The test should be done in the morning after an overnight fast of between 8 and 14 h and after at least 3 days of unrestricted diet ( 150 g carbohydrate per day) and unlimited physical activity. The subject should remain seated and should not smoke throughout the test. con?rmed on a subsequent day. Con?r- mation of the diagnosis precludes the need for any glucose challenge. In the ab- sence of this degree of hyperglycemia, Two-step approach. Perform an initial screening by measuring the plasma or se- rum glucose concentration 1 h after a 50-g oral glucose load (glucose challenge test [GCT]) and perform a diagnostic OGTT on that subset of women exceeding the glucose threshold value on the GCT. When the two-step approach is used, a glucose threshold value 140 mg/dl (7.8 mmol/l) identi?es 80% of women with GDM, and the yield is further increased to 90% by using a cutoff of 130 mg/dl (7.2 mmol/l). With either approach, the diagnosis of GDM is based on an OGTT. Diagnostic criteria for the 100-g OGTT are derived from the original work of O’Sullivan and References 1. The Expert Committee on the Diagnosis and Classi?cation of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classi?cation of Diabetes Mellitus. Diabetes Care 20:1183–1197, 1997 2. The Expert Committee on the Diagnosis and Classi?cation of Diabetes Mellitus: Follow-up report on the diagnosis of dia- betes mellitus. Diabetes Care 26:3160 – 3167, 2003 3. Carpenter MW, Coustan DR: Criteria for screening tests for gestational diabetes. Am J Obstet Gynecol 144:768 –773, 1982 4. O’Sullivan JB, Mahan CM: Criteria for the oral glucose tolerance test in pregnancy. Diabetes 13:278, 1964 DIABETES CARE, VOLUME 29, SUPPLEMENT 1, JANUARY 2006
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