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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #1: Classification of Diabetes Mellitus and Other Categories of Glucose Intolerance Part 1 of 6

DeFronzoCoverIntroduction

A critical requirement for orderly epidemiologic, genetic and clinical research, and indeed for the management of diabetes mellitus and other forms of glucose intolerance is an appropriate classification system. Furthermore, a hallmark in the process of understanding the etiology of a disease and studying its natural history is the ability to identify and differentiate its various forms and place them into a rational etiopathologic framework.

While there have been a number of sets of nomenclature and diagnostic criteria proposed for diabetes, no systematic categorization existed until the mid 1960s [1]. Now diabetes mellitus is recognized as being a syndrome, a collection of disorders that have hyperglycemia and glucose intolerance as their hallmark, due either to insulin deficiency or to impaired effectiveness of insulin’s action, or to a combination of these.

Historical perspective and current classifications

Previous classifications

In 1965, an Expert Committee on Diabetes Mellitus published the first World Health Organization (WHO) report on diabetes classification [1]. The report includes one of the first attempts at international consensus on a classification. They decided to classify diabetes: “… based on the age of recognized onset, which seemed to be the only reliable means of classification for universal use.”

The report also recognized certain specific types of diabetes including brittle, insulin-resistant, gestational, pancreatic, endocrine, and iatrogenic diabetes. Since then, several pathogenic mechanisms have been described and long-term studies have shown different courses and outcomes of different types of diabetes.

A revised classification of glucose intolerance, was formulated by the National Diabetes Data Group (NDDG) [2]. This was amended and adopted in the second report of the WHO Expert Committee in 1980 [3] and in a modified form in 1985. The 1980 Expert Committee proposed two major classes of diabetes mellitus and named them insulin-dependent diabetes mellitus (IDDM) or type 1, and non-insulin-dependent diabetes mellitus (NIDDM) or type 2 [3]. In the 1985 Study Group Report, the terms type 1 and type 2 were omitted, but the classes IDDM and NIDDM were retained and a new class of malnutrition-related diabetes mellitus (MRDM) was introduced [4]. The 1985 WHO classification was essentially based on clinical descriptions, with a specific focus on the pharmacologic management of patients (i.e., insulin-dependent, non-insulin-dependent, gestational). The question as to whether certain clinical forms of diabetes (such as the so-called “tropical diabetes”) had been given adequate priority to correct hierarchic order that was raised many years before probably led to the introduction of MRDM, although more precise epidemiologic data and a better assessment were needed, and called for.

Both the 1980 and 1985 reports included other types of diabetes and impaired glucose tolerance (IGT) as well as gestational diabetes mellitus (GDM). The 1985 classification was widely accepted and used internationally, and represented a compromise between clinical and etiological classifications.

Furthermore, it permitted classification of individual patients in a clinically useful manner even when the specific etiology was unknown. The 2011 American Diabetes Association (ADA) [5] classifications or staging of diabetes still include clinical descriptive criteria but a complementary classification according to etiology is recommended by both organizations.

In 1999, the WHO incorporated an approach developed by Kuzuya and Matsuda [6], which clearly separated the criteria related to etiology from those related to the degree of deficiency of insulin or insulin action, and defined each patient on the basis of these two sets of criteria (Figure 1.1). It is now well established that diabetes may progress through several clinical stages during its natural history, quite independent of its etiology. The clinical staging reflects this and, indeed, individuals may move from one stage to another stage in both directions (Figure 1.1). Even if there is no information concerning the underlying etiology, persons with diabetes or those who are developing the disease can be categorized by stage according to clinical characteristics.

ITDMFig1.1

Current classification

The current classification allows for various degrees of hyperglycemia in individuals irrespective of the disease process.These are glycemic stages ranging from normoglycemia (normal glucose tolerance) to hyperglycemia where insulin is required for survival. All individuals with the disease can be categorized according to clinical stage [7]. The stage of glycemia may change over time depending on the extent of the underlying disease processes. As shown in Figure 1.1, the disease process may be present but may not have progressed far enough to cause hyperglycemia. The etiological classification is possible as the defect or process which may lead to diabetes may be identified at any stage in the development of diabetes, even at the stage of normoglycemia. As an example, the presence of islet cell antibodies (ICA) and/or antibodies to glutamic acid decarboxylase (anti-GAD) [8] in a normoglycemic individual indicates the autoimmune process, which underlies type 1 diabetes, is present, although the individual may or may not ultimately develop diabetes [7.9]. For type 2 diabetes, there are few useful highly specific indicators, though the presence of risk factors such as obesity indicates the likelihood of developing type 2 diabetes. Hopefully, future research will reveal some specific markers of the type 2 diabetes disease process.

The same disease process can cause various degrees of impaired glucose metabolism such as impaired fasting glycemia (IFG) and impaired glucose tolerance (IGT) without fulfilling the criteria for the diagnosis of diabetes [7]. Weight reduction, exercise and/or oral hypoglycemic therapy can achieve satisfactory glycemic control in some persons with type 2 diabetes. These persons, therefore, do not require insulin initially but may do so much later in their course as β-cell function deteriorates. Some persons require insulin for adequate glycemic control at an earlier stage in type 2 diabetes but could survive without it. By definition these persons have some residual insulin secretion. Patients with extensive β-cell destruction (minimal residual insulin secretion) do require insulin for survival and this is the hallmark of type 1 diabetes [7,9].

The classification by etiological type (Table 1.1) results from improved understanding of the causes of diabetes, although this is still far from complete, particularly for type 1 diabetes.

ITDMTable1.1

The terms “insulin-dependent diabetes mellitus,” “noninsulin-dependent diabetes mellitus” and their acronyms “IDDM” and “NIDDM” have been removed from classifications. These terms were very confusing and frequently resulted in misclassification, as patients were classified on the basis of their treatment, and indeed their age, rather than on pathogenesis. In the current classification, the terms “type 1” and “type 2” are retained (using Arabic rather than Roman numerals) [7].

Type 1 includes those cases attributable to an autoimmune process (although the basic precipitating cause of this process is still unknown), as well as those with β-cell destruction for which neither an etiology nor a pathogenesis is known (idiopathic). Those forms of β-cell destruction or failure to which specific causes can be assigned (e.g. cystic fibrosis, mitochondrial defects) are not included in this type of diabetes. These issues are discussed in greater detail later.

Type 2 includes the common major form of diabetes which results from defect(s) in insulin secretion and/or from insulin resistance, and often a combination of both. Malnutrition related diabetes (MRDM) is no longer part of the WHO classification [7]. Of its two subtypes, protein-deficient pancreatic diabetes (PDPD or PDDM) needs more studies for a better definition. The other former subtype of MRDM, fibrocalculous pancreatic diabetes (FCPD), is now classified as a disease of the exocrine pancreas labeled “fibrocalculous pancreatopathy,” which may lead to diabetes.

Impaired glucose tolerance (IGT) and impaired fasting glycemia (IFG) are classified as stages of impaired glucose regulation, since they can be observed in any hyperglycemic disorder.

Gestational diabetes is a state of glucose intolerance first recognized during pregnancy which usually resolves after delivery but is associated with later increased long-term risk of type 2 diabetes. It encompasses the groups formerly classified as gestational impaired glucose tolerance (GIGT) and gestational diabetes mellitus (GDM) [7].

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