ADA 2013: 糖尿病的诊断和分类

Diagnosis and Classification of Diabetes Mellitus AMERICAN DIABETES ASSOCIATION DEFINITION AND DESCRIPTION OF DIABETES MELLITUSdDiabetes is a group of metabolic diseases characterized by hy- perglycemia resulting from defects in in- sulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dys- function, and failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels. Several pathogenic processes are in- volved in the development of diabetes. These range from autoimmune destruc- tion of the b-cells of the pancreas with consequent insulin deficiency to abnor- malities that result in resistance to insulin action. The basis of the abnormalities in carbohydrate, fat, and protein metabo- lism in diabetes is deficient action of in- sulin on target tissues. Deficient insulin action results from inadequate insulin se- cretion and/or diminished tissue respon- ses to insulin at one or more points in the complex pathways of hormone action. Impairment of insulin secretion and de- fects in insulin action frequently coexist in the same patient, and it is often unclear which abnormality, if either alone, is the primary cause of the hyperglycemia. Symptoms ofmarked hyperglycemia in- cludepolyuria,polydipsia,weight loss,some- times with polyphagia, and blurred vision. Impairment of growth and susceptibility to certain infections may also accompany chronic hyperglycemia. Acute, life-threaten- ing consequences of uncontrolled diabetes are hyperglycemia with ketoacidosis or the nonketotic hyperosmolar syndrome. Long-term complications of diabetes include retinopathy with potential loss of vision; nephropathy leading to renal failure; peripheral neuropathy with risk of foot ulcers, amputations, and Charcot joints; and autonomic neuropathy caus- ing gastrointestinal, genitourinary, and cardiovascular symptoms and sexual dys- function. Patients with diabetes have an increased incidence of atherosclerotic car- diovascular, peripheral arterial, and cere- brovascular disease. Hypertension and abnormalities of lipoprotein metabolism are often found in people with diabetes. The vast majority of cases of diabetes fall into two broad etiopathogenetic cate- gories (discussed in greater detail below). In one category, type 1 diabetes, the cause is an absolute deficiency of insulin secre- tion. Individuals at increased risk of de- veloping this type of diabetes can often be identified by serological evidence of an autoimmune pathologic process occurring in the pancreatic islets and by genetic markers. In the other, much more preva- lent category, type 2 diabetes, the cause is a combination of resistance to insulin action and an inadequate compensatory insulin secretory response. In the latter category, a degree of hyperglycemia sufficient to cause pathologic and functional changes in var- ious target tissues, but without clinical symptoms, may be present for a long period of time before diabetes is detected. During this asymptomatic period, it is possible to demonstrate an abnormality in carbohydrate metabolism by measurement of plasma glucose in the fasting state or after a challenge with an oral glucose load or by A1C. The degree of hyperglycemia (if any) may change over time, depending on the extent of the underlying disease process (Fig. 1). A disease process may be present but may not have progressed far enough to cause hyperglycemia. The same disease process can cause impaired fasting glu- cose (IFG) and/or impaired glucose toler- ance (IGT) without fulfilling the criteria for the diagnosis of diabetes. In some indi- viduals with diabetes, adequate glycemic control can be achieved with weight reduc- tion, exercise, and/or oral glucose-lowering agents. These individuals therefore do not require insulin. Other individuals who have some residual insulin secretion but require exogenous insulin for ade- quate glycemic control can survive with- out it. Individuals with extensive b-cell destruction and therefore no residual in- sulin secretion require insulin for survival. The severity of the metabolic abnormality can progress, regress, or stay the same. Thus, the degree of hyperglycemia reflects the severity of the underlying metabolic process and its treatment more than the nature of the process itself. CLASSIFICATION OF DIABETES MELLITUS AND OTHER CATEGORIES OF GLUCOSE REGULATIONdAssigning a type of diabetes to an individual often depends on the circumstances present at the time of diagnosis, and many diabetic individ- uals do not easily fit into a single class. For example, a person diagnosed with gesta- tional diabetes mellitus (GDM) may con- tinue to be hyperglycemic after delivery and may be determined to have, in fact, type 2 diabetes. Alternatively, a person who acquires diabetes because of large doses of exogenous steroids may become normoglycemic once the glucocorticoids are discontinued, but then may develop diabetes many years later after recurrent episodes of pancreatitis. Another example would be a person treated with thiazides who develops diabetes years later. Because thiazides in themselves seldomcause severe hyperglycemia, such individuals probably have type 2 diabetes that is exacerbated by the drug. Thus, for the clinician andpatient, it is less important to label the particular type of diabetes than it is to understand the pathogenesis of the hyperglycemia and to treat it effectively. Type 1 diabetes (b-cell destruction, usually leading to absolute insulin deficiency) Immune-mediated diabetes. This form of diabetes, which accounts for only 5–10% of those with diabetes, previously encompassed by the terms insulin- dependent diabetes or juvenile-onset di- abetes, results from a cellular-mediated autoimmune destruction of the b-cells of c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c Updated Fall 2012. DOI: 10.2337/dc13-S067 © 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and thework is not altered. See http://creativecommons.org/ licenses/by-nc-nd/3.0/ for details. care.diabetesjournals.org DIABETES CARE, VOLUME 36, SUPPLEMENT 1, JANUARY 2013 S67 P O S I T I O N S T A T E M E N T the pancreas. Markers of the immune de- struction of the b-cell include islet cell au- toantibodies, autoantibodies to insulin, autoantibodies toGAD (GAD65), and auto- antibodies to the tyrosine phosphatases IA-2 and IA-2b. One and usually more of these autoantibodies are present in 85– 90% of individuals when fasting hyper- glycemia is initially detected. Also, the disease has strong HLA associations, with linkage to the DQA and DQB genes, and it is influenced by the DRB genes. These HLA-DR/DQ alleles can be either predisposing or protective. In this form of diabetes, the rate of b-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 first manifestation of the disease. Others have modest fasting hyperglycemia that can rapidly change to severe hyperglycemia and/or ketoaci- dosis in the presence of infection or other stress. Still others, particularly adults, may retain residual b-cell function suffi- cient to prevent ketoacidosis for many years; such individuals eventually be- come dependent on insulin for survival and are at risk for ketoacidosis. At this latter stage of the disease, there is little or no insulin secretion, as manifested by low or undetectable levels of plasma C-peptide. Immune-mediated diabetes commonly occurs in childhood and ado- lescence, but it can occur at any age, even in the 8th and 9th decades of life. Autoimmune destruction of b-cells has multiple genetic predispositions and is also related to environmental factors that are still poorly defined. 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 ketoaci- dosis, but have no evidence of autoim- munity. Although only a minority of patients with type 1 diabetes fall into this category, of those who do, most are of African or Asian ancestry. Individuals with this form of diabetes suffer from episodic ketoacidosis and exhibit vary- ing degrees of insulin deficiency be- tween episodes. This form of diabetes is strongly inherited, lacks immunolog- ical evidence for b-cell autoimmunity, and is not HLA associated. An absolute requirement for insulin replacement therapy in affected patients may come and go. Type 2 diabetes (ranging from predominantly insulin resistance with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance) This form of diabetes, which accounts for ;90–95% of those with diabetes, previ- ously referred to as non–insulin-depen- dent diabetes, type 2 diabetes, or adult- onset diabetes, encompasses individuals who have insulin resistance and usually have relative (rather than absolute) insu- lin deficiency At least initially, and often throughout their lifetime, these individu- als do not need insulin treatment to sur- vive. There are probably many different causes of this form of diabetes. Although the specific etiologies are not known, au- toimmune destruction of b-cells does not occur, and patients do not have any of the other causes of diabetes listed above or below. Most patients with this form of di- abetes 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 illness such as infection. This form of diabetes frequently goes undiagnosed for many years because the hyperglycemia Figure 1dDisorders of glycemia: etiologic types and stages. *Even after presenting in ketoacidosis, these patients can briefly return to normo- glycemia 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. S68 DIABETES CARE, VOLUME 36, SUPPLEMENT 1, JANUARY 2013 care.diabetesjournals.org Position Statement develops gradually and at earlier stages is often not severe enough for the patient to notice any of the classic symptoms of diabetes. Nevertheless, such patients are at increased risk of developing macro- vascular and microvascular complica- tions. Whereas patients with this form of diabetes may have insulin levels that appear normal or elevated, the higher blood glucose levels in these diabetic patients would be expected to result in even higher insulin values had their b-cell function been normal. Thus, insulin se- cretion is defective in these patients and insufficient 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 developing 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 individuals with hypertension or dyslipidemia, and its fre- quency varies in different racial/ethnic sub- groups. It is often associated with a strong genetic predisposition, more so than is the autoimmune form of type 1 diabetes. How- ever, the genetics of this form of diabetes are complex and not fully defined. Other specific types of diabetes Genetic defects of the b-cell. Several forms of diabetes are associated with monogenetic defects in b-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 identified to date. The most common form is associated with mutations on chromosome 12 in a hepatic transcription factor referred to as hepatocyte nuclear factor (HNF)-1a. 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 b-cell. Thus, glucokinase serves as the “glucose sensor” for the b-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 frommutations in other tran- scription factors, including HNF-4a, HNF-1b, insulin promoter factor (IPF)- 1, and NeuroD1. Diabetes diagnosed in the first 6 months of life has been shown not to be typical autoimmune type 1 diabetes. This so-called neonatal diabetes can either be transient or permanent. The most com- mon genetic defect causing transient disease is a defect on ZAC/HYAMI im- printing, whereas permanent neonatal diabetes is most commonly a defect in the gene encoding the Kir6.2 subunit of the b-cell KATP channel. Diagnosing the latter has implications, since such children can be well managed with sulfonylureas. Point mutations in mitochondrial DNA have been found to be associated with diabetes and deafness The most common mutation occurs at position 3,243 in the tRNA leucine gene, leading to an A-to-G transition. An identical lesion occurs in the MELAS syndrome (mitochondrial myopathy, encephalop- athy, lactic acidosis, and stroke-like syn- drome); however, diabetes is not part of this syndrome, suggesting different phenotypic expressions of this genetic lesion. Genetic abnormalities that result in the inability to convert proinsulin to in- sulin have been identified in a few fami- lies, and such traits are inherited in an autosomal dominant pattern. The resul- tant glucose intolerance is mild. Similarly, the production of mutant insulin mole- cules with resultant impaired receptor binding has also been identified 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 abnormali- ties of insulin action. The metabolic ab- normalities associated with mutations of the insulin receptor may range from hyperinsulinemia and modest hyperglyce- mia to severe diabetes. Some individuals with these mutations may have acanthosis nigricans. Women may be virilized and have enlarged, cystic ovaries. In the past, this syndrome was termed type A insulin resistance. Leprechaunism and the Rabson- Mendenhall syndrome are two pediatric syndromes that have mutations in the insulin receptor gene with subsequent alterations in insulin receptor function and extreme insulin resistance. The former has characteristic facial features and is usually fatal in infancy, while the latter is associated with abnormalities of teeth and nails and pineal gland hyperplasia. Alterations in the structure and 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 pathways. Diseases of the exocrine pancreas. Any process that diffusely injures the pancreas can cause diabetes. Acquired processes include pancreatitis, trauma, infection, pan- createctomy, and pancreatic carcinoma. With the exception of that caused by cancer, damage to the pancreas must be extensive for diabetes to occur; adreno- carcinomas that involve only a small portion of the pancreas have been associ- ated with diabetes. This implies a mech- anism other than simple reduction in b-cell mass. If extensive enough, cystic fi- brosis and hemochromatosis will also damage b-cells and impair insulin secre- tion. Fibrocalculous pancreatopathy may be accompanied by abdominal pain radi- ating to the back and pancreatic calcifica- tions identified on X-ray examination. Pancreatic fibrosis 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. Somatostatinomas, and aldostero- noma-induced hypokalemia, can cause diabetes, at least in part, by inhibiting insulin secretion. Hyperglycemia gener- ally resolves after successful removal of the tumor. Drug- or chemical-induced diabetes. Many drugs can impair insulin secretion. These drugs may not cause diabetes by themselves, but they may precipitate di- abetes in individuals with insulin resis- tance. In such cases, the classification is unclear because the sequence or relative importance of b-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 b-cells. Such drug reactions fortunately are rare. There are also many drugs and hormones that care.diabetesjournals.org DIABETES CARE, VOLUME 36, SUPPLEMENT 1, JANUARY 2013 S69 Position Statement can impair insulin action. Examples in- clude nicotinic acid and glucocorticoids. Patients receiving a-interferon have been reported to develop diabetes associated with islet cell antibodies and, in certain instances, severe insulin deficiency. The list shown in Table 1 is not all-inclusive, but reflects the more commonly recog- nized drug-, hormone-, or toxin-induced forms of diabetes. Infections. Certain viruses have been as- sociated with b-cell destruction. Diabetes occurs in patients with congenital rubella, although most of these patients have HLA and immune markers characteristic of type 1 diabetes. In addition, coxsackievirus B, cytomegalovirus, adenovirus, and mumps have been implicated in inducing certain cases of the disease. Uncommon forms of immune-mediated diabetes. In this category, there are two known conditions, and others are likely to occur. The stiff-man syndrome is an autoimmune disorder of the central ner- vous 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 hypo- glycemia. Anti-insulin receptor antibodies are occasionally found in patients with systemic lupus erythematosus and other autoimmune diseases. As in other states of extreme insulin resistance, patients with anti-insulin receptor antibodies often have acanthosis nigricans. In the past, this syn-