ABSTRACT
Diabetes mellitus (DM) is defined as a syndrome characterized by chronic hyperglycemia due to defects in insulin secretion, insulin action, or both which leads to disturbance in the protein, carbohydrate, and fat metabolism of the individual. The diagnosis of diabetes is made when on 2 or more occasions either the fasting plasma glucose is ≥126 mg/dL, postprandial plasma glucose 2 hours after 75 g oral glucose is ≥200 mg/dL, or in presence of symptoms of diabetes the random plasma glucose is ≥200/dL. Glycosylated hemoglobin ≥6.5% has recently been approved in adults for the diagnosis of diabetes mellitus. The WHO classifies diabetes into 4 major groups: type 1, which is mainly autoimmune in origin leading to absolute deficiency of insulin; type 2, due to insulin resistance commonly seen in adults; type 3 or other specific types, where diabetes occurs secondary to other diseases like pancreatic calculi, cushings, etc.; and type 4 or gestational diabetes. Type 1 DM contributes to 80% of diabetes occurring in children with the remaining contributed by type 2 DM, neonatal diabetes, maturity onset diabetes of the young, and other rare types of diabetes. The incidence of type 1 and type 2 DM is increasing in children. Type 1 DM is more common in Scandinavian countries and the incidence in India is reaching the same proportions as in the United States.
INTRODUCTION
Diabetes mellitus (DM) is defined as a syndrome characterized by chronic hyperglycemia due to defects in insulin secretion, insulin action, or both, which leads to disturbance in the protein, carbohydrate, and fat metabolism of the individual. Of these, type 1 DM is the end result of the destruction of pancreatic β-cells, triggered by some unknown environmental factors in a genetically predisposed individual. 2Type 2 DM affects many people from all types of ethnicity, social, and economic levels of the society. Diabetes is among the 5 leading causes of death in most countries.1 The prevalence of diabetes has reached epidemic proportions in India and a large number of patients belong to the younger age group. Better and early disease detection, changing lifestyle, and changes in the diagnostic criteria have led to this increase. Death and disability associated with diabetes poses a serious challenge to physicians and the health system at large.
HISTORY
Aretaeus of Cappadocia and Sushruta are the first to give descriptions of what we know today as type 1 and type 2 DM.2 It was Himsworth in 1936 who proposed that there were 2 clinical types of diabetes—the insulin sensitive and insulin insensitive.3 This was further confirmed when assays for insulin measurement were made available for use. The difference in age at onset led to the terms “juvenile-onset and maturity onset” diabetes.
The diagnostic criteria of insulin-dependent diabetes were quite obvious because of its presentation. The noninsulin-dependent variety did not have a very clear distinction between what was normal and what was a state of disease, and that created the need for a diagnostic criteria. The World Health Organization (WHO) in 1964 began discussions on a uniform classification system, but it took almost 16 years, and it was not until 1980 that an accepted classification was established.4 In 1985, the revised National Diabetes Data Group (NDDG)-WHO classification agreed upon the terms insulin-dependent diabetes mellitus (IDDM) and non-IDDM (NIDDM).5 The other types of diabetes, gestation diabetes mellitus and impaired glucose tolerance (IGT) based on the oral glucose tolerance test were retained from the 1980 classification system.
The understanding about the etiopathogenesis of diabetes has increased over the past 20 years. Changes that have happened include the identification of autoimmune markers and the recognition that diabetes has a dynamic phase.6 Thus, the classification of diabetes into IDDM an NIDDM would not be satisfactory. Autoimmune mechanisms causing diabetes were seen in the elderly, and diabetes of the young, which did not require insulin for treatment was seen in clinical practice. A patient diagnosed to have NIDDM may require insulin for survival years after the diagnosis. The development of immune markers has shed much more light on the type 2 diabetic patients who after a brief duration of treatment with oral hypoglycemic agents require insulin for survival and have positive immune markers, which we now know to belong to the class LADA (latent autoimmune diabetes of the adult).
EPIDEMIOLOGY OF TYPE 1 DIABETES MELLITUS
The prevalence of type 1 DM varies from place to place, population to population, and even within a given population. This variation may be based on the difference in environmental and genetic factors involved in the etiology of type 1 DM. The incidence of type 1 DM is age-dependent, increasing from near zero in early months of life to peak incidence in period of puberty. The incidence of type 1 DM is increasing all over the world by around 3%, and this is more so in low incidence populations.
Type 1 DM is predominantly a disease of white Caucasians and the worldwide incidence varies markedly. In Scandinavian countries, it is having the highest incidence of 35/100,000 population, whereas in Japan, it is lowest at 2/100,000 population. If we look at the Indian scenario, incidence is around 10.5/100,000 population according to the recent publication from Chennai. The incidence in United States is around 10–12/100,000 population, as per the latest reports.
There are reports of seasonal variation in the incidence of diabetes in Western world with higher frequency seen in cold winter season, compared to summer. There is no seasonal variation in the Indian subcontinent, but Indian diabetics show an association with vitamin D receptor gene. One of Scandinavian studies has shown that supplementing 2,000 units of vitamin D during the first few years of life reduced the incidence of type 1 DM.
A BRIEF HISTORY OF TODAY'S CLASSIFICATION SYSTEM
In 1979 the United States NDDG and in 1980 WHO dealt with the task of classification and criteria of diabetes.7,8 It is been endorsed by many bodies like the American Diabetes Association (ADA). The terms “juvenile-onset diabetes” and “maturity-onset diabetes” were replaced by IDDM and NIDDM, which has not been replaced by type 1 and type 2 DM, respectively. The categories impared glucose tolerance (IGT) and impaired fasting glucose were also created. The latest classification published in 1997 is discussed below.
The advantage of the latest ADA/WHO classification is that it combines both clinical stages of hyperglycemia and the etiological types (Figure 1). The actual staging reflects on the fact any etiological type can pass or progress through several clinical phases (both normoglycemic and hyperglycemic) during its natural history. Moreover, individuals may move in either direction from stage to stage. The type of diabetes, however, is now determined by the etiological process rather than the treatment modality.
CURRENT CRITERIA FOR DIAGNOSIS OF DIABETES MELLITUS
Diabetes is clinically diagnosed by the classical signs of polyuria, polydipsia, unexplained weight loss, and fatigue. The diagnostic thresholds are based on long-term diabetes complications. Microvascular changes in the kidney and retina have been used to define the diagnostic cut points. In 1997, the ADA confirmed the 2-hour plasma glucose criterion at 199.8 mg/dL based on the data from the Pima Indians, Egypt, and unpublished National Health and Nutrition Examination Survey III analyses.9
They also found that both fasting plasma glucose (FPG) and 2-hour plasma glucose were similarly associated with retinopathy indicating that both could be used equally well for the diagnosis of diabetes. Although the prevalence defined by these 2 measures may be similar, it has been found that the 2 tests clearly identify different individuals.10,11 Thus, the FPG cutoff was lowered in 1997 to enable the FPG to identify the same percentage of population identified by the 2-hour plasma glucose cutoff.9
DM is diagnosed when FPG is ≥126 mg/dL or 2-hour post 75 g plasma glucose value is ≥200 mg/dL or symptoms associated with hyperglycemia (polyuria, polydipsia, and unexplained weight loss) and a random plasma glucose is ≥200 mg/dL (Table 1).12 If fasting or 2-hour values are used, 2 abnormal readings are required to establish the diagnosis. Recently, glycosylated hemoglobin (HbA1C) level has also been accepted 5as a criterion for diagnosing diabetes. An HbA1C of ≥6.5% is taken as a criteria for making the diagnosis of diabetes.
CLASSIFICATION
The present day classification of DM was published in 1997, and is based on etiology, and it is divided into 4 types, type 1 DM, type 2 DM, other specific types, and gestational diabetes mellitus (GDM).9,12 It is easy to follow and the details are given in box 1.
Type 1 Diabetes Mellitus and the Present International Classification
Today, the classification of type 1 DM is made into 2 major types based on the etiology. This classification seems more logical, but a precise classification is yet to be reached given our fast-changing knowledge about the mechanisms of diabetes.
Immune-mediated Type 1 Diabetes Mellitus
This form of diabetes was previously known as insulin-dependent diabetes, type 1 DM, or juvenile-onset diabetes. This is the end-result of autoimmune destruction of the β-cells of the pancreas. Eighty-five to ninety percent of these patients have autoantibodies like islet cell antibodies (ICAs), autoantibodies to insulin, autoantibodies to glutamic acid decarboxylase (GAD65), and autoantibodies to the tyrosine phosphates [insulinoma-associated antigen 2 (IA-2 and IA-2b)]. The autoimmune type 1 DM has strong human leukocyte antigen associations, which may be either predisposing like DR3 and DR4 or protective like DR2. The autoimmune destruction of β-cells is the result of combination of genetic predisposition and environmental factors. Many of these patients initially present with ketoacidosis and all of them end with virtually no insulin secretion as manifested by low or undetectable plasma C-peptide. Even though, the immune mediated type 1 DM commonly occurs in children and adolescence, it can present in any age groups. There is an association of other autoimmune diseases like Graves’ disease, Hashimoto's thyroiditis, Addison's disease, pernicious anemia, and vitiligo with autoimmune type 1 DM.
Idiopathic Type 1 Diabetes Mellitus
This is the other type of type 1 DM where a definite etiology has not been established. These patients present with insulin deficient diabetes with or without ketoacidosis, but they will be negative for autoimmune markers like GAD65, IA-2, or ICAs. They will require insulin for metabolic control life long, and their natural history is almost similar to the other type 1 DM.
Type 2 Diabetes of Young
In clinical practice, we see more and more of our patients diagnosed to have diabetes at an increasingly younger age, which has been attributed to a variety of reasons. All over the world, type 2 DM is being diagnosed more and more in children and adolescents, and this is more so in certain races. Many of these children with diabetes are obese with clinical signs of insulin resistance like acanthosis nigricans and very strong family history of diabetes in both maternal and paternal side. Our understanding on the etiopathogenesis of diabetes is making us rethink and reconsider the diagnosis of diabetes in many patients. Details of type 2 DM and other types are discussed in other chapters. In a variety of studies the world over, it has been shown that a good number of young patients who have been tagged as type 1 and type 2 DM would move into the “other types of diabetes” category, which may have a bearing on the way we treat them as well.
CONCLUSION
DM in children is no longer a rarity and is seen in increasing frequency in present day clinical practice. Even though type 1 DM still contribute 80–85% of diabetes in children, other types like type 2 DM, neonatal diabetes, and maturity onset diabetes in the young are also increasingly being diagnosed. Treatment of each type of diabetes is different and will be considered in detail in subsequent chapters.
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- Dwivedi G, Dwivedi S. History of Medicine: Sushruta – the clinicial – teacher par excellence. Indian J Chest Dis Allied Sci. 2007;49:243–4.
- Himsworth H. Diabetes mellitus: its differentiation into insulin sensitive and insulin insensitive types. Diabet Med. 2011;28:1440–4.
- World Health Organization. World Health Organization expert committee on diabetes mellitus: first report. WHO, Geneva, 1965.
- World Health Organization. Diabetes mellitus: report of a WHO study group. WHO, Geneva, 1985.
- Abourizk N, Dunn J. Types of diabetes according to National Diabetes. Data Group Classification. Limited applicability and need to revisit. Diabetes Care. 1990;13:1120–3.
- Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. National Diabetes Data Group. Diabetes. 1979;28:1039–57.
- World Health Organization. WHO Expert Committee on Diabetes Mellitus. Second Report. World Health Org., Geneva, 1980. Technical Report No. 646.
- Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 1997;20:1183–97.
- McCance DR, Hanson RL, Charles MA, Jacobsson LT, Pettitt DJ, Bennett PH, et al. Comparison of tests for glycated haemoglobin and fasting and two hour plasma glucose concentrations as diagnostic methods for diabetes. BMJ. 1994;308:1323–8.
- Engelgau MM, Thompson TJ, Herman WH, Boyle JP, Aubert RE, Kenny SJ, et al. Comparison of fasting and 2-hour glucose and HbA1c levels for diagnosing diabetes. Diagnostic criteria and performance revisited. Diabetes Care. 1997;20:785–91.
- Standards of medical care in diabetes—2010. Diabetes Care. 2010;33:S11–S61.