Classification and Diagnosis of Diabetes Mellitus

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Chapter 13

Classification and Diagnosis of Diabetes Mellitus

Definition

The term diabetes mellitus does not represent a single disease entity but rather a set of disease states that share certain characteristics. Foremost among these is the presence of elevated plasma glucose levels. As is discussed below, the presence of hyperglycemia in a patient is used both to diagnose diabetes and to guide management decisions, which are directed largely toward avoiding hyperglycemia. The hyperglycemia itself results from a combination of defects in insulin secretion, insulin action, or both.1 An important characteristic of the various disease states that are labeled as diabetes is the development of end-organ damage in vital organs of the body, including the retina, the renal glomerulus, and peripheral nerves. Damage results, at least in part, from the long-term effects of hyperglycemia and are mediated through glycation of tissue proteins, increased activity of the polyol pathway, or other, as yet unrecognized, mechanisms.2 Individual patients vary in their predisposition to develop these so-called microvascular complications. Because of this and because of the length of time they take to develop (frequently decades), the complications of diabetes cannot be used to classify or diagnose the disease. People with diabetes are at considerably greater risk for developing atherosclerotic disease affecting the coronary, cerebrovascular, peripheral arterial, or other parts of the circulation. A cause-and-effect relationship between chronic hyperglycemia and these so-called macrovascular complications of diabetes has not been as clearly established, although evidence linking the two is accumulating.3 Any definition of diabetes that refers only to carbohydrate metabolism is incomplete. Oskar Minkowski is reputed to have first made the association between the insulin-deficient pancreatectomized state of his laboratory dogs and the sweet taste of their urine. It has been suggested that if Minkowski had lacked a sense of taste but possessed a keen sense of smell, he might have smelled the ketones on the breath of his animals and thereby directed diabetes research toward the study of fat metabolism.4 Disordered fat and protein metabolism must be included in a complete definition of the disease, although an emphasis on the pathogenesis of hyperglycemia continues to this day. To define a disease purely in biochemical terms is to diminish the component of the disease that leads to much physical, mental, and psychosocial distress for the many millions of people around the world who live with it every day. Chronic rheumatic diseases such as rheumatoid arthritis are not associated with any biochemical hallmark, and their definition is based largely on patient-derived symptoms and signs. Therefore, it is important to try to include the patient’s perspective in any definition of the chronic disease referred to as diabetes.

Classification

Before 1979, a classification system for diabetes was not well established, and many different terms were used to describe essentially the same clinical entity. Following publication that year of the report of the National Diabetes Data Group (NDDG),5 some order was brought to bear in this area. The recommendations of the NDDG were subsequently endorsed by the World Health Organization (WHO) in a publication in 1980, and minor modifications were later made in a document published in 1985.6 This classification in large part was based on pharmacologic treatment of the disease. Insulin-dependent diabetes mellitus (IDDM) and non–insulin-dependent diabetes mellitus (NIDDM) were the two major forms of diabetes that had been identified. The term insulin-dependent diabetes mellitus was used to describe patients who typically were lean at presentation, were prone to ketosis, and required insulin for survival. The term non–insulin-dependent diabetes mellitus was used to describe patients who typically were overweight or obese at presentation, were not prone to ketosis, and did not require insulin for survival. The NDDG also had categories for gestational diabetes, malnutrition-related diabetes mellitus (MRDM), and a category labeled “other types,” which included certain forms of diabetes for which a cause had been suggested at that time. As the terms IDDM and NIDDM became widely used during the 1980s and 1990s, several problems became apparent. The main problem arose from the fact that many patients with NIDDM ended up at some point in the course of their disease being treated with insulin and being misclassified as IDDM or having the rather confusing term insulin-requiring NIDDM applied to them. In addition, as more information became available on the causes of the various forms of diabetes, it became apparent that a classification based on therapy was not always consistent with new insights into the pathogenesis of the various forms of diabetes. For this reason, the American Diabetes Association (ADA) convened an expert panel in 1995 to address the issue of classification. This panel published its recommendations in 1997,7 and these were subsequently endorsed by a WHO consultation group in a 1998 report.8 The main thrust of this proposal was to move away from a classification based on therapy and toward one based on pathogenesis. Four major categories were proposed: type 1 diabetes, type 2 diabetes, other specific types of diabetes (including categories for which a cause has been established), and gestational diabetes. The details of this system, which are outlined in Table 13-1, are discussed in the following sections.

Table 13-1

Classification of Diabetes Mellitus

1. Type 1 diabetes

2. Type 2 diabetes

3. Other specific types

Genetic defects in β cell function

Genetic defects in insulin action

Diseases of the exocrine pancreas

Endocrinopathies

Drug or chemical induced

Infections

Uncommon forms of immune-mediated diabetes

Other genetic syndromes sometimes associated with diabetes

4. Gestational diabetes mellitus

HNF, Hepatocyte nuclear factor; IPF, insulin promoter factor; MODY, maturity-onset diabetes of the young.

From the Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, Diabetes Care 20(7):1183–1197, 1997.

Type 1 Diabetes

Type 1 diabetes is characterized by the development of a state of complete insulin deficiency. In its fully developed form, patients, if deprived of insulin, will develop ketoacidosis, coma, and death. Biochemical testing reveals the absence of circulating C-peptide (a marker of insulin secretion) despite hyperglycemia. The incidence of type 1 diabetes in the United States is estimated to be approximately 30,000 new cases per year.9 Although the peak incidence occurs in childhood and early adolescence, this form of diabetes can occur at any age. The incidence of the disease shows marked regional variation, with the highest worldwide incidence reported in Scandinavia.10 Epidemiologic and immunologic research has led to the recognition of two major forms of type 1 diabetes based on the presence or absence of certain immunologic markers.

Autoimmune Type 1 Diabetes

Autoimmune type 1 diabetes is a prototypic organ-specific autoimmune disorder. Individuals who develop this form of diabetes are born with a genetic predisposition to autoimmune dysfunction, which may manifest in the development of other autoimmune conditions such as Addison’s disease or Hashimoto’s thyroiditis. The genetic predisposition is not well understood but is known to be linked to the major histocompatibility locus on chromosome 6.11 The presence of certain human lymphocyte antigen (HLA) haplotypes appears to predispose the individual to the disease, but other HLA haplotypes appear to be protective. In predisposed individuals, a poorly understood environmental trigger sets off a series of immunologic events that culminate in selective T cell–mediated destruction of the β cells of the pancreatic islet. Many antigens have been investigated as potential triggers for the disease. These include certain viral antigens12 as well as an antigen contained in cow’s milk protein.13 The rate at which β cell destruction occurs varies from individual to individual and may be very brief, as is seen when type 1 diabetes presents in the neonatal period, or may be prolonged, as is seen in what has been called latent autoimmune diabetes in adults.14 Antibodies appear in the circulation early in the process of β cell destruction.15 These autoantibodies are believed to be markers (rather than true instigators) of the immune response. Their presence can help to classify a newly diagnosed patient with diabetes. In several studies, screening for these autoantibodies has led to recognition of autoimmune type 1 diabetes in individuals who otherwise might have been labeled as having type 2 diabetes16,17 (see later). Islet cell antibodies, the first autoantibodies to be discovered, are directed against a range of islet antigens. The best characterized autoantibodies are those directed against glutamic acid decarboxylase (GAD), an enzyme that is involved in γ-aminobutyric acid synthesis.18 Isoforms of GAD are found in the central nervous system and in β cells of the pancreatic islet. Other autoantibodies include antibodies directed against IA-2 and IA-2β, as well as antibodies directed against insulin itself (anti-insulin antibodies). Childhood-onset type 1 diabetes is associated with higher levels of autoantibody in serum. Testing for these autoantibodies is still restricted to a limited number of laboratories. Greater standardization of assays is required before they can be used widely in clinical practice.

Idiopathic Type 1 Diabetes

The term idiopathic type 1 diabetes is used to describe a small subset of individuals with type 1 diabetes who appear not to have an autoimmune basis for their β cell destruction.19 Other features of this subtype include its occurrence predominantly in individuals of African American ethnicity, its lack of HLA association, and its intermittent proneness to ketosis. A number of different terms, including atypical diabetes, Flatbush diabetes, and type 1.5 diabetes, have been used to describe this form of diabetes. The preferred term in the recent literature appears to be ketosis-prone type 2 diabetes.20

Type 2 Diabetes

Type 2 diabetes represents the most common form of diabetes. Current estimates for the U.S. population indicate that almost 20 million people have type 2 diabetes.21 The condition is characterized by hyperglycemia that results from a combination of defects in insulin secretion and insulin action. In any given individual, the degree to which these defects contribute to hyperglycemia may vary. The disease usually has its onset after age 40, although type 2 diabetes is being seen increasingly in young adults and adolescents.22 Although progressive β cell failure is believed by many to be an important part of the natural history of this form of diabetes,23 the β cell destruction is not autoimmune mediated1 and does not progress to the point at which the patient becomes dependent on insulin for survival. Ketoacidosis is unusual in this form of diabetes, and when it occurs, it usually does so in the setting of a major intercurrent illness such as myocardial infarction or stroke, or when treatment with glucocorticoids is provided. Individuals with type 2 diabetes are not at increased risk for autoimmune disease but have a higher prevalence of metabolic abnormalities, including obesity, hypertension, and a typical dyslipidemia that is characterized by hypertriglyceridemia and low levels of high-density lipoprotein cholesterol. This combination of metabolic derangements is associated with a marked increase in risk for atherosclerotic disease. In fact, the prevalence of atherosclerotic disease in people with type 2 diabetes has led to the suggestion that, rather than one leading to the other, the two conditions may share common antecedents.3 Insulin resistance may be an important predisposing factor for both conditions.

The cause of type 2 diabetes remains to be determined. Any pathogenetic model of the disease must include both genetic and environmental factors. Challenges in establishing the cause of type 2 diabetes include the following: (1) The disease lacks an easy-to-define phenotype and instead is characterized by considerable heterogeneity across different ethnic groups; this heterogeneity often is represented by a spectrum ranging from a predominant defect in insulin secretion on the one hand to a predominant defect in insulin action on the other. (2) The relatively late age of onset makes it difficult to establish large kindreds and therefore limits genetic studies. (3) No easy-to-apply methods are available for screening populations for insulin resistance and defective insulin secretion. (4) The pathways that are involved in mediating insulin action are complex and are not fully understood; most authors believe that a single genetic defect will explain only a subset of the disease; it is much more likely that type 2 diabetes represents a set of disorders. Evidence to support a genetic component of the disease comes from the strong concordance for the disease that is seen among monozygotic twins.24 On the other hand, the dramatic increase in incidence and prevalence of type 2 diabetes that accompanies the change to a so-called Westernized lifestyle strongly supports an environmental component as well.25