Glucagonoma

Diabetes mellitus is a group of metabolic disorders with one common manifestation: hyperglycemia. Chronic hyperglycemia causes damage to the eyes, kidneys, nerves, heart and blood vessels. The etiology and pathophysiology leading to the hyperglycemia, however, are markedly different among patients with diabetes mellitus, dictating different prevention strategies, diagnostic screening methods and treatments. The adverse impact of hyperglycemia and the rationale for aggressive treatment have recently been reviewed.[1]

In June 1997, an international expert committee released a report with new recommendations for the classification and diagnosis of diabetes mellitus.[2] These new recommendations were the result of more than two years of collaboration among experts from the American Diabetes Association and the World Health Organization (WHO). The use of classification systems and standardized diagnostic criteria facilitates a common language among patients, physicians, other health care professionals and scientists.

Previous Classification

In 1979, the National Diabetes Data Group produced a consensus document standardizing the nomenclature and definitions for diabetes mellitus.[3] This document was endorsed one year later by WHO.[4,5] The two major types of diabetes mellitus were given names descriptive of their clinical presentation: "insulin-dependent diabetes mellitus" (IDDM) and "non-insulin-dependent diabetes mellitus" (NIDDM). However, as treatment recommendations evolved, correct classification of the type of diabetes mellitus became confusing. For example, it was difficult to correctly classify persons with NIDDM who were being treated with insulin. This confusion led to the incorrect classification of a large number of patients with diabetes mellitus, complicating epidemiologic evaluation and clinical management. The discovery of other types of diabetes with specific pathophysiology that did not fit into this classification system further complicated the situation. These difficulties, along with new insights into the mechanisms of diabetes mellitus, provided a major impetus for the development of a new classification system.

The National Diabetes Data Group also established the oral glucose tolerance test, (using a glucose load of 75 g) as the preferred diagnostic test for diabetes mellitus.[3] However, this test has poor reproducibility, lacks physiologic relevance and is a weaker indicator of long-term complications compared with other measures of hyperglycemia.[6] Furthermore, many high-risk patients are unwilling to undergo this time-consuming test on a repeat basis. The new diagnostic criteria also address this issue.

Changes in the Classification System

The new classification system identifies four types of diabetes mellitus: type 1, type 2, "other specific types" and gestational diabetes. Arabic numerals are specifically used in the new system to minimize the occasional confusion of type "II" as the number "11" Each of the types of diabetes mellitus identified extends across a clinical continuum of hyperglycemia and insulin requirements.

Type 1 diabetes mellitus (formerly called type I, IDDM or juvenile diabetes) is characterized by beta cell destruction caused by an autoimmune process, usually leading to absolute insulin deficiency.[2,7] The onset is usually acute, developing over a period of a few days to weeks. Over 95 percent of persons with type 1 diabetes mellitus develop the disease before the age of 25, with an equal incidence in both sexes and an increased prevalence in the white population. A family history of type 1 diabetes mellitus, gluten enteropathy (celiac disease) or other endocrine disease is often found. Most of these patients have the "immune-mediated form" of type 1 diabetes mellitus with islet cell antibodies and often have other autoimmune disorders such as Hashimoto's thyroidiris, Addison's disease, vitiligo or pernicious anemia. A few patients, usually those of African or Asian origin, have no antibodies but have a similar clinical presentation; consequently, they are included in this classification and their disease is called the "idiopathic form" of type 1 diabetes mellitus.[2,7]

Type 2 diabetes mellitus (formerly called NIDDM, type II or adult-onset) is characterized by insulin resistance in peripheral tissue and an insulin secretory defect of the beta cell.[2,7] This is the most common form of diabetes mellitus and is highly associated with a family history of diabetes, older age, obesity and lack of exercise. It is more common in women, especially women with a history of gestational diabetes, and in blacks, Hispanics and Native Americans. Insulin resistance and hyperinsulinemia eventually lead to impaired glucose tolerance. Defective beta cells become exhausted, further fueling the cycle of glucose intolerance and hyperglycemia. The etiology of type 2 diabetes mellitus is multifactorial and probably genetically based, but it also has strong behavioral components.

Types of diabetes mellitus of various known etiologies are grouped together to form the classification called "other specific types." This group includes persons with genetic defects of beta-cell function (this type of diabetes was formerly called MODY or maturity-onset diabetes in youth) or with defects of insulin action; persons with diseases of the exocrine pancreas, such as pancreatitis or cystic fibrosis; persons with dysfunction associated with other endocrinopathies (e.g., acromegaly); and persons with pancreatic dysfunction caused by drugs, chemicals or infections.[2,7] The etiologic classifications of diabetes mellitus are listed in Table 1.[2]

TABLE 1 Etiologic Classifications of Diabetes Mellitus

Type 1 diabetes mellitus(*)

Type 2 diabetes mellitus(*)

Other specific types:

Genetic defects of beta-cell function Genetic defects in insulin action

Diseases of the exocrine pancreas

Pancreatitis Trauma/pancreatectomy Neoplasia Cystic fibrosis Hemochromatosis Others

Endocrinopathies

Acromegaly Cushing's syndrome Glucagonoma Pheochromocytoma Hyperthyroidism Somatostatinoma Aldosteronoma Others

Drug- or chemical-induced

Vacor([dagger]) Pentamidine Nicotinic acid Glucocorticoids Thyroid hormone Diazoxide Beta-adrenergic agonists Thiazides Phenytoin Alfa-interferon Others

Infections

Congenital rubella Cytomegalovirus Others

Uncommon forms of immune- mediated diabetes

Other genetic syndromes sometimes associated with diabetes

Down syndrome Klinefelter's syndrome Turner's syndrome Wolfram syndrome Friedreich's ataxia Huntington's chorea Lawrence-Moon Beidel syndrome Myotonic dystrophy Porphyria Prader-Willi syndrome Others

Gestational diabetes mellitus

(*) Patients with any form of diabetes may require insulin treatment at some stage of the disease. Use of insulin does not, of itself, classify the patient.

([dagger]) -- Vacor is an acute rodenticide that was released in 1975 but withdrawn as a general-use pesticide in 1979 because of severe toxicity. Exposure produces destruction of the beta cells of the pancreas, causing diabetes mellitus in survivors.

Adapted with permission from Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20:1183-97.

The definition and diagnosis of gestational diabetes mellitus was not altered in these new recommendations.[2] Gestational diabetes mellitus is an operational classification (rather than a pathophysiologic condition) identifying women who develop diabetes mellitus during gestation.[7] (Women with diabetes mellitus before pregnancy are said to have "pregestational diabetes" and are not included in this group.) Women who develop type 1 diabetes mellitus during pregnancy and women with undiagnosed asymptomatic type 2 diabetes mellitus that is discovered during pregnancy are classified with gestational diabetes mellitus. However, most women classified with gestational diabetes mellitus have normal glucose homeostasis during the first half of the pregnancy and develop a relative insulin deficiency during the last half of the pregnancy, leading to hyperglycemia. The hyperglycemia resolves in most women after delivery but places them at increased risk of developing type 2 diabetes mellitus later in life.

New Diagnostic Criteria for Diabetes Mellitus

The new diagnostic criteria for diabetes mellitus have been greatly simplified (Table 2).[2]

TABLE 2 Criteria for the Diagnosis of Diabetes Mellitus and Impaired Glucose Homeostasis

Diabetes mellitus--positive findings from any two of the following tests on different days:

Symptoms of diabetes mellitus(*) plus casual([dagger]) plasma glucose concentration

[is greater than or equal to] 200 mg per dL (11.1 mmol per L) or

FPG [is greater than or equal to] 126 mg per dL (7.0 mmol per L) or

2hrPPG [is greater than or equal to] 200 mg per dL (11.1 mmol per L) after a 75-g glucose load

Impaired glucose homeostasis

Impaired fasting glucose: FPG from 110 to < 126 (6.1 to 7.0 mmol per L)

Impaired glucose tolerance: 2hrPPG from 140 to < 200 (7.75 to < 11.1 mmol per L)

Normal

FPG < 110 mg per dL (6.1 mmol per L)

2hrPPG < 140 mg per dL (7.75 mmol per L)

FPG = fasting plasma glucose; 2hrPPG = two-hour postprandial glucose.

(*)--Symptoms include polyuria, polydipsia or unexplained weight loss.

([dagger])--Casual is defined as any time of day without regard to time since last meal.

Adapted with permission from Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997; 20:1183-97.

The oral glucose tolerance test previously recommended by the National Diabetes Data Group has been replaced with the recommendation that the diagnosis of diabetes mellitus be based on two fasting plasma glucose levels of 126 mg per dL (7.0 mmol per L) or higher. Other options for diagnosis include two two-hour postprandial plasma glucose (2hrPPG) readings of 200 mg per dL (11.1 mmol per L) or higher after a glucose load of 75 g (essentially, the criterion recommended by WHO) or two casual glucose readings of 200 mg per dL (11.1 mmol per L) or higher. Measurement of the fasting plasma glucose level is the preferred diagnostic test, but any combination of two abnormal test results can be used. Fasting plasma glucose was selected as the primary diagnostic test because it predicts adverse outcomes (e.g., retinopathy) as well as the 2hrPPG test but is much more reproducible than the oral glucose tolerance test or the 2hrPPG test and easier to perform in a clinical setting.

The choice of the new cutoff point for fasting plasma glucose levels is based on strong evidence from a number of populations linking the risk of various complications to the glycemic status of the patient. Figure 1 shows the risk of diabetic retinopathy based on the glycemic status of 40- to 74-year-old participants in the National Health and Nutritional Epidemiologic Survey (NHANES III).[2] The risk of retinopathy greatly increases when the patient's fasting plasma glucose level is higher than 109 to 116 mg per dL (6.05 to 6.45 mmol per L) or when the result of a 2hrPPG test is higher than 150 to 180 mg per dL (8.3 to 10.0 mmol per L). However, the committee decided to maintain the cutoff point for the 2hrPPG test at 200 mg per dL (11.1 mmol per L) because so much literature has already been published using this criterion. They selected a cutoff point for fasting plasma glucose of 126 mg per dL (7.0 mmol per L) or higher. This point corresponded best with the 2hrPPG level of 200 mg per dL (11.1 mmol per L). The risk of other complications also increases dramatically at the same cutoff points.

[Figure 1 ILLUSTRATION OMITTED]

A normal fasting plasma glucose level is less than 110 mg per dL (6.1 mmol per L) and normal 2hrPPG levels are less than 140 mg per dL (7.75 mmol per L). Blood glucose levels above the normal level but below the criterion established for diabetes mellitus indicate impaired glucose homeostasis. Persons with fasting plasma glucose levels ranging from 110 to 126 mg per dL (6.1 to 7.0 mmol per L) are said to have impaired fasting glucose, while those with a 2hrPPG level between 140 mg per dL (7.75 mmol per L) and 200 mg per dL (11.1 mmol per L) are said to have impaired glucose tolerance. Both impaired fasting glucose and impaired glucose tolerance are associated with an increased risk of developing type 2 diabetes mellitus. Lifestyle changes, such as weight loss and exercise, are warranted in these patients.

The committee chose not to address the current controversies surrounding the diagnosis of gestational diabetes mellitus and did not alter the diagnostic criteria in this area. Screening for gestational diabetes mellitus is generally accomplished with administration of a 50-g glucose load one hour before determining a plasma glucose level. A positive screen (defined as a plasma glucose level of 140 mg per dL [7.75 mmol per L] or higher) should prompt a diagnostic test: fasting plasma glucose levels should be measured after a 100-g glucose load at baseline and at one, two and three hours after the glucose load. Two of the four values must be abnormal (105 mg per dL [5.8 mmol per L] or higher; 190 mg per dL [10.5 mmol per L] or higher; 165 mg per dL [9.15 mmol per L] or higher; and 145 mg per dL [8.05 mmol per L] or higher) for a patient to be diagnosed with gestational diabetes mellitus. The WHO criteria use a glucose load of 75 g with a test two hours after the glucose load, using the same criterion for the diagnosis of gestational diabetes mellitus.

Glycated Hemoglobin

Measurements of glycated hemoglobin have commonly been used to monitor the glycemic control of persons already diagnosed with diabetes mellitus. Measurements of this hemoglobin, also called glycosylated hemoglobin, glycohemoglobin, hemoglobin [A.sub.1c] or hemoglobin A1, aid in the evaluation of the stable linkage of glucose to minor hemoglobin components. There is currently no agreement on standardization, so a variety of measurement methods and normal ranges are being used.

Some experts argue that a glycated hemoglobin test could be used for the diagnosis of diabetes mellitus.[8,9] Glycated hemoglobin levels are as highly correlated to adverse clinical outcomes (e.g., retinopathy) as are fasting plasma glucose or postprandial plasma glucose levels and are as reproducible as fasting plasma glucose levels. The major advantage of measuring glycated hemoglobin is that the specimen can be collected without regard to when the patient last ate.

The expert committee, however, did not include glycated hemoglobin measurement in the recommendations for international standards for the diagnosis of diabetes mellitus.[2] They noted the lack of standardization and normal ranges among the various tests, making it difficult to dictate a standard cutoff point. The test for measuring glycated hemoglobin is not widely available in developing countries; consequently, it was not favored for use as an international criterion. There is also some overlap in the levels of glycated hemoglobin in patients with diabetes mellitus and those without it.

Although it was not specifically recommended by the National Diabetes Data Group as a diagnostic test for diabetes mellitus, glycated hemoglobin may, in some cases, be used to diagnose diabetes mellitus. The diagnosis of diabetes mellitus is made in the following fashion.[8,9] A glycated hemoglobin level of 1 percent above the reference laboratory's upper range of normal is consistent with diabetes mellitus and has a specificity of 98 percent.[8] People with normal glycated hemoglobin levels (i.e., within the laboratory's published normal range) either do not have diabetes mellitus or have well-controlled diabetes mellitus (i.e., a false-negative test). However, incorrectly diagnosing these persons as normal would not alter their treatment because exercise and diet are adequately controlling their blood glucose levels. People who are not diagnosed with diabetes mellitus and who have near-normal glycated hemoglobin levels (less than 1 percent above the normal range) may be advised of the high probability that they have diabetes mellitus and may be offered the same treatment as a person with mild diabetes mellitus (i.e., dietary and exercise counseling), followed by repeat testing of glycated hemoglobin several months later. This method of screening and counseling high-risk persons is easier for many patients and clinicians because the blood specimen can be drawn at the time of the patient visit.

Impact of the New Diagnostic Criteria

Physicians may be concerned that the new diagnostic criteria for diabetes mellitus, including the lower cutoff for fasting plasma glucose levels, may greatly increase the number of people who are diagnosed with diabetes mellitus in their practices. Concerns about overdiagnosis include the harm created by anxiety, the risks and costs of unnecessary treatment, and possible insurance discrimination, especially if the condition that is being diagnosed is relatively benign or if no effective treatment is available. On the other hand, underdiagnosing a condition is harmful if early treatment can make a difference in patient outcome, especially if the treatment is relatively benign and inexpensive.

It is true that a rigorous screening program will increase the number of persons who are diagnosed with diabetes mellitus. However, currently one half of the people who have diabetes mellitus according to the old criteria have not been diagnosed and may remain undiagnosed for up to 10 years.[10] People who are asymptomatic and undiagnosed continue to develop the complications of diabetes mellitus.[1]

Screening Recommendations

The expert committee provided guidelines governing the selection of patients to be tested for diabetes and the frequency of that testing (Table 3).[2] Testing should be considered for all persons who are 45 years or older and should be repeated at three-year intervals.

TABLE 3 Recommendations for Diabetes Screening of Asymtomatic Persons

Timing of first test and repeat tests

Test at age 45; repeat every three years: Patients 45 years of age or older

Test before age 45; repeat more frequently than every three years if patient has one or more of the following risk factors:

Obesity: [is greater than or equal to] 120% of desirable body weight or BMI [is greater than or equal to] 27 kg per [m.sup.2]

First-degree relative with diabetes mellitus

Member of high risk-ethnic group (black, Hispanic, Native American, Asian)

History of gestational diabetes mellitus or delivering a baby weighing more than 4,032 g (9 lb)

Hypertensive ([is greater than or equal to]140/90 mm Hg)

HDL cholesterol level [is less than or equal to] 35 mg per dL (0.90 mmol per L) and/or triglyceride level [is greeter than or equal to] 250 mg per dL (2.83 mmol per L)

History of IGT or IFG on prior testing

BMI = body mass index; HDL = high density lipoprotein; IGT = impaired glucose tolerance;

IFG = impaired fasting glucose.

Adapted with permission from Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20:1183-97.

Testing should be considered at a younger age and be performed more frequently in persons who are obese (120 percent of desirable body weight or greater or a body mass index of 27 kg per [m.sup.2] or greater); who have a first-degree relative with diabetes mellitus; who are black, Hispanic or Native American; who have delivered a baby weighing more than 4,032 g (9 lb), or who were diagnosed with gestational diabetes mellitus during pregnancy; are hypertensive; or have a high-density lipoprotein level of 35 mg per dL (0.90 mmol per L) or lower and/or a triglyceride level of 250 mg per dL (2.83 mmol per L) or higher. In addition, any patient with impaired glucohomeostasis should be reevaluated on a more frequent basis.

The expert committee recommended that screening for gestational diabetes mellitus be reserved for use in women who meet one or more of the following criteria: 25 years of age or older, obese (defined as more than 120 percent above their desirable body weight), a family history of a first-degree relative with diabetes mellitus, and belong to a high-risk ethnic population.

Final Comment

The changes recommended by the expert committee for the diagnosis of diabetes mellitus should prove beneficial to patients. Measurement Of fasting plasma glucose levels should be more acceptable to patients than the oral glucose tolerance test and can be readily incorporated with fasting lipid determinations. Identifying asymptomatic persons earlier in the disease process will allow earlier institution of lifestyle changes and medical therapy that may decrease the complications of hyperglycemia. The National Diabetes Data Group emphasizes that these changes in diagnostic criteria have not changed the treatment goals in patients with diabetes mellitus. These goals include maintaining a fasting plasma glucose level of less than 120 mg per dL (6.65 mmol per L) and a glucose hemoglobin measurement of less than 7.0 percent.

Figure 1 adapted with permission from Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20: 1183-97.

REFERENCES

[1.] Susman JL, Helseth LD. Reducing the complications of type II diabetes: a patient-centered approach. Am Fam Physician 1997;56:471-80.

[2.] Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20:1183-97.

[3.] Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. National Diabetes Data Group. Diabetes 1979;28: 1039-57.

[4.] WHO Expert Committee on Diabetes Mellitus: second report. World Health Organ Tech Rep Ser 1980;646:1-80.

[5.] Diabetes mellitus: Report of a WHO Study Group. World Health Organ Tech Rep Ser 1985;727:1-113.

[6.] McCance DR, Hanson RL, Pettitt DJ, Bennett PH, Hadden DR, Knowler WC. Diagnosing diabetes mellitus: do we need new criteria? Diabetologia 1997;40:247-55.

[7.] National Diabetes Data Group. Diabetes in America. 2d ed. Bethesda, Md.: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 1995; NIH publication no. 95-1468.

[8.] McCance DR, Hanson RL, Charles MA, Jacobsson LT, Pettitt DJ, Bennett PH, et al. Which test for diagnosing diabetes? Diabetes Care 1995;18:1042-4.

[9.] Davidson MB, Peters AL, Schriger DL. An alternative approach to the diagnosis of diabetes with a review of the literature. Diabetes Care 1995; 8:1065-71.

[10.] Harris MI, Hadden WC, Knowler WC, Bennett PH. Prevalence of diabetes and impaired glucose tolerance and plasma glucose levels in U.S. population aged 20-74 yr. Diabetes 1987;36:523-34.

RELATED ARTICLE:

Diabetes mellitus that is characterized by absolute insulin deficiency and acute onset, usually before 25 years of age, should now be reffered to as type 1 (not type I, IDDM or juvenile) diabetes mellitus.

Any patient with two fasting plasma glucose levels of 126 mg per dL (7.0 mmol per L) or greater is considered to have diabetes mellitus.

Glycated hemoglobin (also known as glycohemoglobin, glycosylated hemoglobin or [HbA.sub.1c]) is used to monitor treatment in patients with diabetes mellitus; however, it is not recommended for routine diagnosis of this condition because of a lack of standardization of tests and results.

JENNIFER MAYFIELD, M.D., M.P.H., is associate professor of family medicine at Bowen Research Center, Indiana University, Indianapolis. She received a medical degree from Loma Linda (Calif.) School of Medicine and completed a residency in family medicine at the University of Minnesota Medical School, Minneapolis. Dr. Mayfield has served as chair of the Council on Foot Care for the American Diabetes Association for the past two years and was previously the epidemiologist for the Indian Health Service Diabetes Program.

Address correspondence to Jennifer Mayfield, M.D., M.P.H., Bowen Research Center, Department of Family Practice, Indiana University, 1110 West Michigan St., Long Hospital Room 200, Indianapolis, IN 46202. Reprints are not available from the author.

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