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CLASSIFICATION AND DIAGNOSIS OF DIABETES MELLITUS

 

Charles Reasner, MD

Ralph A DeFronzo, MD

 

 

 

CLASSIFICATION OF DIABETES (Table 1) TYPE 1 DIABETES MELLITUS TYPE 2 DIABETES MELLLITUS GESTATIONAL DIABETES MELLITUS (GDM) SPECIFIC TYPES OF DIABETES Genetic Defects DISEASES OF THE EXOCRINE PANCREAS ENDOCRINOPATHIES INFECTIONS DRUGS DIAGNOSIS OF DIABETES

 

 

 

CLASSIFICATION OF DIABETES (Table 1)

Diabetes is a metabolic disorder characterized by resistance to the action of insulin, insufficient insulin secretion, or both^[1]. The major clinical manifestation of the diabetic state is hyperglycemia. However, insulin deficiency and/or insulin resistance also are associated with disturbances in lipid and protein metabolism. The vast majority of diabetic patients are classified into one of two broad categories: type 1 diabetes, which is caused by an absolute deficiency of insulin, and type 2 diabetes, which is characterized by the presence of insulin resistance with an inadequate compensatory increase in insulin secretion. In addition, women who develop diabetes during their pregnancy, are classified as having gestational diabetes. Finally, there are a variety of uncommon and diverse types of diabetes which are caused by infections, drugs, endocrinopathies, pancreatic destruction, and genetic defects. These unrelated forms of diabetes are classified separately.

 

TYPE 1 DIABETES MELLITUS

Type 1 diabetes results from autoimmune destruction of the pancreatic b-cells^[4][5]. Markers of immune destruction of the b-cell are present at the time of diagnosis in 90% of individuals and include antibodies to the islet cell (ICAs), to glutamic acid decarboxylase (GAD), and to insulin (IAAs). While this form of diabetes usually occurs in children and adolescents, it can occur at any age. Younger individuals typically have a rapid rate of b -cell destruction and present with ketoacidosis, while adults often maintain sufficient insulin secretion to prevent ketoacidosis for many years^[6]. The more indolent adult-onset variety has been referred to as latent autoimmune diabetes in adults (LADA). Eventually, all type 1 diabetic patients will require insulin therapy to maintain normglycemia.

 

TYPE 2 DIABETES MELLLITUS

Type 2 diabetes is characterized by insulin resistance and, at least initially, a relative deficiency of insulin secretion^[7][8]. In absolute terms, the plasma insulin concentration (both fasting and meal-stimulated) usually is increased, although "relative" to the severity of insulin resistance, the plasma insulin concentration is insufficient to maintain normal glucose homeostasis^[9][10]. With time, however, there is progressive beta cell failure and absolute insulin deficiency ensues. In a minority of type 2 diabetic individuals, severe insulinopenia is present at the time of diagnosis and insulin sensitivity is normal or near normal^[11]. Most individuals with type 2 diabetes exhibit intra (abdominal (visceral) obesity, which is closely related to the presence of insulin resistance^[12]. In addition, hypertension, dyslipidemia (high triglyceride and low HDL-cholesterol levels; postprandial hyperlipemia), and elevated PAI-1 levels often are present in these individuals. This clustering of abnormalities is referred to as the "insulin resistance syndrome" or the "metabolic syndrome" ^[13][14]. Because of these abnormalities, patients with type 2 diabetes are at increased risk of developing macrovascular complications (myocardial infarction and stroke). Type 2 diabetes has a strong genetic predisposition and is more common in minority ethnic groups, i.e. Mexican-Americans, Latinos, American Indians, Pacific Islanders, than in individuals of European ancestry. The genetic cause(s) of the common variety of type 2 diabetes is (are) not well defined and, at present, no specific genes have been identified in the pathogenesis of this common metabolic disorder ^[15][16].

 

GESTATIONAL DIABETES MELLITUS (GDM)

Gestational diabetes mellitus (GDM) is defined as glucose intolerance, which is first recognized during pregnancy. In most women who develop GDM, the disorder has its onset in the third trimester of pregnancy. At least 6 weeks after the pregnancy ends, the woman should receive an oral glucose tolerance test and be reclassified as having diabetes, normal glucose tolerance, impaired glucose tolerance, or impaired fasting glucose. Gestational diabetes complicates about 4% of all pregnancies ^[17]. Clinical detection is important, since therapy will reduce perinatal morbidity and mortality. Risk assessment for GDM should occur at the first prenatal visit. Women at high risk (positive family history, history of GDM, marked obesity, high risk ethnic group) should be screened as soon as feasible. If the initial screening is negative, they should undergo retesting at 24-48 weeks. Women of average risk should have the initial screen performed at 24-48 weeks. A fasting plasma glucose concentration greater than 126 mg/dl (7.0 mmol/l) or a postprandial glucose greater than 200 mg/dl (11.1 mmol/l) establishes the diagnosis of diabetes and obviates the need for more formal glucose tolerance testing. Women who require more formal testing should receive a 100 gram oral glucose load with plasma glucose levels determined at baseline, 1 hour, 2 hours, and 3 hours (Table 2). The diagnosis of GDM is made if two or more of the plasma glucose values in Table 2 are met or exceeded.

 

 

SPECIFIC TYPES OF DIABETES

Genetic Defects

Maturity Onset Diabetes of the Young (MODY) is characterized by impaired insulin secretion with minimal or no insulin resistance ^[18]. Patients typically exhibit mild hyperglycemia at an early age. The disease is inherited in an autosomal dominant pattern and, at present, six different genetic abnormalities have been identified ^[19].

 

Genetic inability to convert proinsulin to insulin results in mild hyperglycemia and is inherited an autosomal dominant pattern ^[20]. Similarly, the production of mutant insulin molecules has been identified in a few families and results in mild glucose intolerance ^[21].

 

Several genetic mutations have been described in the insulin receptor and are associated with insulin resistance ^[22]. Type A insulin resistance refers to the clinical syndrome of acanthosis nigricans, virilization in women, polycystic ovaries, and hyperinsulinemia ^[23]. Leprechaunism is a pediatric syndrome with specific facial features and severe insulin resistance that results from a defect in the insulin receptor ^[24]. Lipoatrophic diabetes results from postreceptor defects in insulin signaling ^[25].

 

A variety of genetic syndromes have been described in which diabetes mellitus occurs with increased frequency. The etiology of the disturbance in glucose homeostasis in these diverse and seemingly unrelated syndromes remains undefined.

 

DISEASES OF THE EXOCRINE PANCREAS

Damage of the pancreas must be extensive for diabetes to occur ^[26]. The most common causes are pancreatitis, trauma, and carcinoma. Cystic fibrosis and hemochromatosis also have been associated with impaired insulin secretion.

 

ENDOCRINOPATHIES

Since growth hormone, cortisol, glucagon, and epinephrine increase hepatic glucose production and induce insulin resistance in peripheral (muscle) tissues, excess production of these hormones can cause or exacerbate underlying diabetes ^[27][28][29]. Although the primary mechanism of action of these counter regulatory hormones is the induction of insulin resistance in muscle and liver, overt type 2 diabetes mellitus does not develop in the absence of beta cell failure.

 

INFECTIONS

A variety of infections have been etiologically related to the development of diabetes mellitus. Of these, the most clearly established is congenital rubella ^[30]. Approximately 20% of infants who are infected with the rubella virus at birth develop autoimmune type 2 diabetes later in life. These individuals have the typical type 1 susceptibility genotype, DR3/DR4.

 

DRUGS

A large number of commonly used drugs have been shown to induce insulin resistance and/or impair beta cell function and can lead to the development of diabetes mellitus in susceptible individuals. An extensive review of these drugs and their mechanism of action has been published ^[31].

 

 

DIAGNOSIS OF DIABETES

The diagnosis of diabetes requires the identification of a glycemic cutpoint which discriminates normal individuals from those with diabetes. The present cutpoints reflect the level of glucose above which microvascular complications have been shown to increase. Cross-sectional studies from Egypt, Pima Indians, and a representative sample from the United States have shown a consistent increase in the risk of developing retinopathy when the fasting plasma glucose concentration exceeds 108-116 mg/dl (6.0-6.4 mmol/l), when the 2 hour postprandial level rises above 185 mg/dl (10.3 mmol/l), and when the hemoglobin A1c is greater then 5.9-6.0% (Figure 1) ^[32][33][34]. Based upon these prospective epidemiologic studies relating glycemic control to the development of diabetic retinopathy, the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus of the ADA in 1997 revised the criteria for establishing the diagnosis of diabetes ^[35] (Table 3). To minimize the discrepancy between the fasting plasma glucose and 2-hour plasma glucose concentration measured during the OGTT, cut off values of ≥ 126 mg/dl and ≥ 200 mg/dl, respectively, were chosen. The WHO adopted this change in 1998 ^[36]. Although the ADA recommended use of the fasting plasma glucose concentration as the principal tool for the diagnosis of diabetes mellitus in non-pregnant adults, the recently published results of the Diabetes Prevention Program ^[37] have given renewed emphasis to the OGTT, since diet/exercise, as well as drug therapy (metformin and troglitazone), were shown to slow/prevent the progression of IGT to overt diabetes mellitus. The diagnosis of IGT only can be made from the 2-hour plasma glucose concentration (≥ 140 to 199 mg/dl) during the OGTT. In addition the Expert Committee defined a new category of glycemia, impaired fasting glucose (IFG). IFG is defined by a plasma glucose ≥ 110 mg/dl (6.1 mmol/l) but less than 126 mg/dl (7.0 mmol/l). This category was created to correspond to the category of impaired glucose tolerance (IGT), which is defined as a 2 hour glucose value ≥140 mg/dl (7.8 mmol/l) but less than 200 mg/dl (11.0 mmol/l) during an OGTT.

 

 

 

The fasting and postprandial glucose levels do not measure the same physiologic processes and, not surprisingly, they do not identify the same individuals as having diabetes. The fasting plasma glucose concentration is, in large part, determined by basal rate of hepatic glucose production ^[39][40] Thus, IFG primarily reflects hepatic resistance to the action of insulin. Under basal (postabsorptive) conditions, the majority of glucose is taken up by insulin-independent tissues (brain and liver) ^[41]; although tissue (muscle) glucose clearance is reduced in the postabsorptive state, in absolute terms the muscle is responsible for only a small amount of glucose uptake in the basal state and is unlikely to explain the rise in fasting glucose concentration in individuals with IFG ^[42][43]. Moreover, .basal insulin secretion is well preserved, even in individuals with overt type 2 diabetes mellitus ^[44], and, therefore, cannot explain the rise in fasting plasma glucose concentration in individuals with IFG. In contrast, the postprandial plasma glucose concentration primarily depends on insulin sensitivity in muscle and liver, as well as on insulin secretion by the pancreatic beta cells ^[45], and defects in both tissue (muscle) sensitivity to insulin and impaired insulin secretion are responsible for IGT. Although both IFG and IGT predict the future development of type 2 diabetes, IFG is a poor predictor of ASCVD, whereas IGT is a strong predictor of myocardial infarction and stroke ^[46]. This discordance most likely reflects the association of IGT with the metabolic syndrome and insulin resistance in muscle ^[47][48][49]. Although IFG and IGT are equally strong predictors of the development of future type 2 diabetes mellitus (32), the prevalence of IFG in the general population is significantly less than the prevalence of IGT ^[50]. In order to have similar prevalences of the two disorders (IGF and IGT) of glucose homeostasis, the cutpoint for IFG would have to be reduced to approximately 103-104 mg/dl.

 

The use of the fasting plasma glucose concentration (≥ 126 mg/dl), as opposed to the 2-hour plasma glucose concentration during the OGTT (≥ 200 mg/dl), also significantly underestimates the prevalence of diabetes in the general population ^[51][52]. In one study of U.S. adults between the ages of 40-74 years, the prevalence of undiagnosed diabetes was 6.4% using the OGTT and 4.4% based upon the fasting glucose measurement ^[53]. These differences have been reported to be even greater in some ethnic groups ^[54][55][56].

 

The American Diabetes Association recommends use of hemoglobin A1c (HbA1c or A1c) determinations to monitor glycemic control in known diabetic patients. Because there is not a "gold standard" assay and because many countries do not have ready access to the test, an A1c determination is not recommended for the diagnosis of diabetes mellitus. However, because the A1c accurately reflects the mean blood glucose concentration over a 1-3 month period and correlates well with the development of diabetic complications, it may in the future become established as a test for the diagnosis of diabetes ^[57]. The National Glycohemoglobin Standardization Program has established standard assays for A1c based on the results of the Diabetes Control and Complication Trials ^[58]. In 1999, 78% of laboratories were using standardized assays with inter-laboratory coefficients of variation of less than 5% ^[59][60]. An A1c level above ~6.5% correlates with the present diagnostic cutpoints for fasting and 2 hour postprandial plasma glucose levels.