Report of the Committee on the Classification and Diagnostic Criteria of Diabetes Mellitus

• Published in: Journal of diabetes investigation Vol. 1; no. 5; pp. 212 - 228
• Main Authors: Seino, Yutaka, Nanjo, Kishio, Tajima, Naoko, Kadowaki, Takashi, Kashiwagi, Atsunori, Araki, Eiichi, Ito, Chikako, Inagaki, Nobuya, Iwamoto, Yasuhiko, Kasuga, Masato, Hanafusa, Toshiaki, Haneda, Masakazu, Ueki, Kohjiro
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.10.2010
• Subjects: Clinical diagnosis; Diabetes mellitus; HbA1c; Special Report; Clinical diagnosis; HbA1c; Diabetes mellitus
• ISSN: 2040-1116; 2040-1124
• DOI: 10.1111/j.2040-1124.2010.00074.x

Concept of Diabetes Mellitus: Diabetes mellitus is a group of diseases associated with various metabolic disorders, the main feature of which is chronic hyperglycemia due to insufficient insulin action. Its pathogenesis involves both genetic and environmental factors. The long‐term persistence of metabolic disorders can cause susceptibility to specific complications and also foster arteriosclerosis. Diabetes mellitus is associated with a broad range of clinical presentations, from being asymptomatic to ketoacidosis or coma, depending on the degree of metabolic disorder. Classification (Tables 1 and 2, and Figure 1): 1  Etiological classification of diabetes mellitus and glucose metabolism disorders I. Type 1 (destruction of pancreatic β‐cells, usually leading to absolute insulin deficiency)  A. Autoimmune  B. Idiopathic II. Type 2 (ranging from predominantly insulin secretory defect, to predominantly insulin resistance with varying degrees of insulin secretory defect) III. Due to other specific mechanisms or diseases (see Table 2 for details)  A. Those in which specific mutations have been identified as a cause  of genetic susceptibility   (1) Genetic abnormalities of pancreatic β‐cell function   (2) Genetic abnormalities of insulin action  B. Those associated with other diseases or conditions   (1) Diseases of exocrine pancreas   (2) Endocrine diseases   (3) Liver disease   (4) Drug‐ or chemical‐induced   (5) Infections   (6) Rare forms of immune‐mediated diabetes   (7) Various genetic syndromes often associated with diabetes IV. Gestational diabetes mellitus Note: Those that cannot at present be classified as any of the above are called unclassifiable. The occurrence of diabetes‐specific complications has not been confirmed in some of these conditions. 2  Diabetes mellitus and glucose metabolism disorders due to other specific mechanisms and diseases A. Those in which specific mutations have been identified as a cause of genetic susceptibility B. Those associated with other diseases or conditions (1) Genetic abnormalities of pancreatic β‐cell function
Insulin gene (abnormal insulinemia, abnormal proinsulinemia, neonatal diabetes mellitus) 
HNF 4α gene (MODY1) 
Glucokinase gene (MODY2) 
HNF 1α gene (MODY3) 
IPF‐1 gene (MODY4) 
HNF 1β gene (MODY5) 
Mitochondria DNA (MIDD) 
NeuroD1 gene (MODY6) 
Kir6.2 gene (neonatal diabetes mellitus) 
SUR1 gene (neonatal diabetes mellitus) 
Amylin
Others
(2) Genetic abnormalities of insulin action
Insulin receptor gene (type A insulin resistance, leprechaunism, Rabson–Mendenhall syndrome etc.) 
Others (1) Diseases of exocrine pancreas
Pancreatitis
Trauma/pancreatectomy
Neoplasm
Hemochromatosis
Others
(2) Endocrine diseases
Cushing’s syndrome
Acromegaly
Pheochromocytoma
Glucagonoma
Aldosteronism
Hyperthyroidism
Somatostatinoma
Others
(3) Liver disease
Chronic hepatitis
Liver cirrhosis 
Others
(4) Drug‐ or chemical‐induced
Glucocorticoids
Interferon
Others
(5) Infections
Congenital rubella
Cytomegalovirus
Others
(6) Rare forms of immune‐mediated diabetes
Anti‐insulin receptor antibodies
Stiffman syndrome
Insulin autoimmune syndrome
Others
(7) Various genetic syndromes often associated with diabetes
Down syndrome
Prader‐Willi syndrome
Turner syndrome
Klinefelter syndrome
Werner syndrome
Wolfram syndrome
Ceruloplasmin deficiency
Lipoatrophic diabetes mellitus
Myotonic dystrophy
Friedreich ataxia
Laurence‐Moon‐Biedl syndrome
Others The occurrence of diabetes‐specific complications has not been confirmed in some of these conditions. 1  A scheme of the relationship between etiology (mechanism) and patho‐physiological stages (states) of diabetes mellitus. Arrows pointing right represent worsening of glucose metabolism disorders (including onset of diabetes mellitus). Among the arrow lines, indicates the condition classified as ‘diabetes mellitus’. Arrows pointing left represent improvement in the glucose metabolism disorder. The broken lines indicate events of low frequency. For example, in type 2 diabetes mellitus, infection can lead to ketoacidosis and require temporary insulin treatment for survival. Also, once diabetes mellitus has developed, it is treated as diabetes mellitus regardless of improvement in glucose metabolism, therefore, the arrow lines pointing left are filled in black. In such cases, a broken line is used, because complete normalization of glucose metabolism is rare. The classification of glucose metabolism disorders is principally derived from etiology, and includes staging of pathophysiology based on the degree of deficiency of insulin action. These disorders are classified into four groups: (i) type 1 diabetes mellitus; (ii) type 2 diabetes mellitus; (iii) diabetes mellitus due to other specific mechanisms or diseases; and (iv) gestational diabetes mellitus. Type 1 diabetes is characterized by destruction of pancreatic β‐cells. Type 2 diabetes is characterized by combinations of decreased insulin secretion and decreased insulin sensitivity (insulin resistance). Glucose metabolism disorders in category (iii) are divided into two subgroups; subgroup A is diabetes in which a genetic abnormality has been identified, and subgroup B is diabetes associated with other pathologic disorders or clinical conditions. The staging of glucose metabolism includes normal, borderline and diabetic stages depending on the degree of hyperglycemia occurring as a result of the lack of insulin action or clinical condition. The diabetic stage is then subdivided into three substages: non‐insulin‐ requiring, insulin‐requiring for glycemic control, and insulin‐dependent for survival. The two former conditions are called non‐insulin‐dependent diabetes and the latter is known as insulin‐dependent diabetes. In each individual, these stages may vary according to the deterioration or the improvement of the metabolic state, either spontaneously or by treatment. Diagnosis (Tables 3–7 and Figure 2): 3  Criteria of fasting plasma glucose levels and 75 g oral glucose tolerance test 2‐h value Normal range Diabetic range Fasting value <110 mg/dL (6.1 mmol/L) ≥126 mg/dL (7.0 mmol/L) 75 g OGTT 2‐h value <140 mg/dL (7.8 mmol/L) ≥200 mg/dL (11.1 mmol/L) Evaluation of OGTT Normal type: If both values belong to normal range *Diabetic type: If any of the two values falls into diabetic range Borderline type
Neither normal nor diabetic types *Casual plasma glucose ≥200 mg/dL (≥11.1 mmol/L) and HbA1c≥6.5% are also regarded as to indicate diabetic type. Even for normal type, if 1‐h value is 180 mg/dL (10.0 mmol/L), the risk of progression to diabetes mellitus is greater than for <180 mg/dL (10.0 mmol/L) and should be treated as with borderline type (follow‐up observation, etc.). Fasting plasma glucose level of 100–109 mg/dL (5.5–6.0 mmol/L) is called ‘high‐normal’: within the range of normal fasting plasma glucose. Plasma glucose level after glucose load in oral glucose tolerance test (OGTT) is not included in casual plasma glucose levels. The value for HbA1c (%) is indicated with 0.4% added to HbA1c (JDS) (%). 4  Procedures for diagnosing diabetes mellitus Clinical diagnosis
 (1) At initial examination, a ‘diabetic type’ is diagnosed if any of the following criteria are met: (i) fasting plasma glucose level ≥126 mg/dL (7.0 mmol/L), (ii) 75 g OGTT 2‐h value ≥200 mg/dL (11.1 mmol/L), (iii) casual plasma glucose level ≥200 mg/dL (11.1 mmol/L) or (iv) *HbA1c≥6.5%. Re‐examination is carried out at another date and diabetes mellitus is diagnosed if ‘diabetic type’ is confirmed again**. However, diagnosis cannot be made on the basis of a repeated HbA1c test alone. If the same blood sample is confirmed to be diabetic type by both plasma glucose and HbA1c levels (any of [i] to [iii] plus [iv]), then diabetes mellitus can be diagnosed from the initial test  (2) If plasma glucose level shows diabetic type (any of [i] to [iii]) and either of the following conditions exists, diabetes mellitus can be diagnosed immediately at the initial examination
• The presence of typical symptoms of diabetes mellitus (thirst, polydipsia, polyuria, weight loss)
• The presence of definite diabetic retinopathy  (3) If it can be confirmed that either of the above conditions 1 or 2 existed in the past, diabetes mellitus must be diagnosed or suspected even if present test values do not meet the above conditions  (4) If diabetes mellitus is suspected but the diagnosis cannot be made by the above (1) to (3), the patient should be followed‐up  (5) The following points should be kept in mind when selecting the method of determination in initial examination and re‐examination
• If HbA1c is used at initial examination, another method of determination is required for diagnosis at re‐examination. As a rule, both plasma  glucose level and HbA1c should be measured
• If casual plasma glucose level is ≥200 mg/dL (11.1 mmol/L) at the initial test, a different test method is desirable for re‐examination
• In the case of disorders and conditions in which HbA1c may be inappropriately low, plasma glucose level should be used for diagnosis (Table 5) Epidemiological study
 For the purpose of estimating the frequency of diabetes mellitus, determination of ‘diabetic type’ from a single test can be considered to represent ‘diabetes mellitus’. Whenever possible, the criteria to be used are HbA1c≥6.5% or OGTT 2‐h value ≥200 mg/dL (11.1 mmol/L) Health screening
 It is important to detect diabetes mellitus and identify high risk groups without overlooking anyone. Therefore, besides measuring plasma glucose and HbA1c, clinical information such as family history and obesity should be referred *The value for HbA1c (%) is indicated with 0.4% added to HbA1c (JDS) (%). **Hyperglycemia must be confirmed in a non‐stressful condition. OGTT, oral glucose tolerance test. 5  Disorders and conditions associated with low HbA1c values Anemia Liver disease Dialysis Major hemorrhage Blood transfusion Chronic malaria Hemoglobinopathy Others 6  Situations where a 75‐g oral glucose toler