Abstract 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): Table 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. Table 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. Figure 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. image 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): Table 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) (%). Table 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. Table 5 Disorders and conditions associated with low HbA1c values Anemia Liver disease Dialysis Major hemorrhage Blood transfusion Chronic malaria Hemoglobinopathy Others Table 6 Situations where a 75‐g oral glucose tolerance test is recommended Strongly recommended (suspicion of present diabetes mellitus cannot be ruled out)
Fasting plasma glucose level is 110–125 mg/dL (6.1–6.9 mmol/L)
Casual plasma glucose level is 140–199 mg/dL (7.8–11.0 mmol/L)
*HbA1c is 6.0–6.4% (excluding those having overt symptoms of diabetes mellitus) Testing is desirable (high risk of developing diabetes mellitus in the future;
Testing is especially advisable for patients with risk factors for arteriosclerosis such as hypertension, dyslipidemia and obesity.)
Fasting plasma glucose level is 100–109 mg/dL (5.5–6.0 mmol/L)
*HbA1c is 5.6–5.9%
Strong family history of diabetes mellitus or present obesity regardless of above criteria *The value for HbA1c (%) is indicated with 0.4% added to HbA1c (JDS) (%). Table 7 Definition and diagnostic criteria of gestational diabetes mellitus Definition of gestational diabetes mellitus
Glucose metabolism disorder with first recognition or onset during pregnancy, but that has not developed into diabetes mellitus Diagnostic criteria of gestational diabetes mellitus
Diagnosed if one or more of the following criteria is met in a 75 g OGTT
Fasting plasma glucose ≥92 mg/dL (5.1 mmol/L)
1‐h value ≥180 mg/dL (10.0 mmol/L)
2‐h value ≥153 mg/dL (8.5 mmol/L)
However, diabetes mellitus that is diagnosed according to ‘Clinical diagnosis’ outlined in Table 4 is excluded from gestational diabetes mellitus (IADPSG Consensus Panel, Reference 42, partly modified with permission of Diabetes Care). Figure 2 Flow chart outlining steps in the clinical diagnosis of diabetes mellitus. *The value for HbA1c (%) is indicated with 0.4% added to HbA1c (JDS) (%). image Categories of the State of Glycemia: Confirmation of chronic hyperglycemia is essential for the diagnosis of diabetes mellitus. When plasma glucose levels are used to determine the categories of glycemia, patients are classified as having a diabetic type if they meet one of the following criteria: (i) fasting plasma glucose level of ≥126 mg/dL (≥7.0 mmol/L); (ii) 2‐h value of ≥200 mg/dL (≥11.1 mmol/L) in 75 g oral glucose tolerance test (OGTT); or (iii) casual plasma glucose level of ≥200 mg/dL (≥11.1 mmol/L). Normal type is defined as fasting plasma glucose level of <110 mg/dL (<6.1 mmol/L) and 2‐h value of <140 mg/dL (<7.8 mmol/L) in OGTT. Borderline type (neither diabetic nor normal type) is defined as falling between the diabetic and normal values. According to the current revision, in addition to the earlier listed plasma glucose values, hemoglobin A1c (HbA1c) has been given a more prominent position as one of the diagnostic criteria. That is, (iv) HbA1c≥6.5% is now also considered to indicate diabetic type. The value of HbA1c, which is equivalent to the internationally used HbA1c (%) (HbA1c [NGSP]) defined by the NGSP (National Glycohemoglobin Standardization Program), is expressed by adding 0.4% to the HbA1c (JDS) (%) defined by the Japan Diabetes Society (JDS). Subjects with borderline type have a high rate of developing diabetes mellitus, and correspond to the combination of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) noted by the American Diabetes Association (ADA) and WHO. Although borderline cases show few of the specific complications of diabetes mellitus, the risk of arteriosclerosis is higher than those of normal type. When HbA1c is 6.0–6.4%, suspected diabetes mellitus cannot be excluded, and when HbA1c of 5.6–5.9% is included, it forms a group with a high risk for developing diabetes mellitus in the future, even if they do not have it currently. Clinical Diagnosis: 1 If any of the criteria for diabetic type (i) through to (iv) is observed at the initial examination, the patient is judged to be ‘diabetic type’. Re‐examination is conducted on another day, and if ‘diabetic type’ is reconfirmed, diabetes mellitus is diagnosed. However, a diagnosis cannot be made only by the re‐examination of HbA1c alone. Moreover, if the plasma glucose values (any of criteria [i], [ii], or [iii]) and the HbA1c (criterion [iv]) in the same blood sample both indicate diabetic type, diabetes mellitus is diagnosed based on the initial examination alone. If HbA1c is used, it is essential that the plasma glucose level (criteria [i], [ii] or [iii]) also indicates diabetic type for a diagnosis of diabetes mellitus. When diabetes mellitus is suspected, HbA1c should be measured at the same time as examination for plasma glucose. 2 If the plasma glucose level indicates diabetic type (any of [i], [ii], or [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 the above conditions 1 or 2 existed in the past, diabetes mellitus can be diagnosed or suspected regardless of the current test results. 4 If the diagnosis of diabetes cannot be established by these procedures, the patient is followed up and re‐examined after an appropriate interval. 5 The physician should assess not only the presence or absence of diabetes, but also its etiology and glycemic stage, and the presence and absence of diabetic complications or associated conditions. Epidemiological Study: For the purpose of estimating the frequency of diabetes mellitus, ‘diabetes mellitus’ can be substituted for the determination of ‘diabetic type’ from a single examination. In this case, HbA1c≥6.5% alone can be defined as ‘diabetes mellitus’. Health Screening: It is important not to misdiagnose diabetes mellitus, and thus clinical information such as family history and obesity should be referred to at the time of screening in addition to an index for plasma glucose level. Gestational Diabetes Mellitus: There are two hyperglycemic disorders in pregnancy: (i) gestational diabetes mellitus (GDM); and (ii) diabetes mellitus. GDM is diagnosed if one or more of the following criteria is met in a 75 g OGTT during pregnancy: 1 Fasting plasma glucose level of ≥92 mg/dL (5.1 mmol/L) 2 1‐h value of ≥180 mg/dL (10.0 mmol/L) 3 2‐h value of ≥153 mg/dL (8.5 mmol/L) However, diabetes mellitus that is diagnosed by the clinical diagnosis of diabetes mellitus defined earlier is excluded from GDM. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00074.x, 2010)
