Читать книгу Type 2 Diabetes in Children and Adolescents - Arlan L. Rosenbloom - Страница 8

Tables 2–6 outline the features of the types of diabetes that need to be considered in children and adolescents, based on what is known of the etiology, in keeping with the American Diabetes Association’s Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (1). Contemporary understanding of the pathogenesis of various forms of diabetes made previous classification based on treatment inappropriate.

TABLE 1. Criteria for the Diagnosis of Diabetes

Symptoms plus random plasma glucose concentration ≥200 mg/dl (11 mmol/l), or

Fasting plasma glucose ≥126 mg/dl (7 mmol/l), or

2-h plasma glucose ≥200 mg/dl (11 mmol/l) during an oral glucose tolerance test. The test should be performed using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water for individuals weighing >43 kg and 1.75 g/kg for individuals weighing ≤43 kg.

In the absence of marked hyperglycemia with decompensation, these criteria should be confirmed by repeat testing on a different day. The oral glucose tolerance test is not recommended for routine clinical use. Impaired glucose tolerance (IGT) is defined by a 2-h plasma glucose level between 140 and 200 mg/dl. Impaired fasting glucose is defined by a level between ≥110 and <126 mg/dl. From the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (1).

Table 2. Immune Mediated Type 1 Diabetes

β-Cell destruction, usually leading to absolute insulin deficiency

Occurs throughout childhood, with as great or greater incidence under 10 years of age as in 10–20 year olds

Much less frequent in Asians and native North Americans and somewhat less frequent in African-Americans than in those of European origin

Associated with HLA specificities

First-degree relatives of 5–10% of patients affected

Polygenic inheritance

Equal sex ratio

Autoantibodies to insulin (IAA), islet cell cytoplasm (ICA), glutamic acid dehydrogenase (GAD), or tyrosine phosphatase (insulinoma-associated) antibody (IA-2 and IA-2β) at diagnosis in 85–98%

Ketosis or ketoacidosis common at onset

Period of weight loss, polyuria, polydipsia, fatigue common; nonspecific symptoms often missed in infants and toddlers

Signs of insulin resistance, such as hypertension or acanthosis nigricans absent at diagnosis

Low to absent insulin secretion, as indicated by C-peptide concentration; however, following initial diagnosis and treatment, partial recovery can last for months to (very rarely) several years

Table 3. Idiopathic Type 1 Diabetes

May be difficult to distinguish from immune mediated type 1 diabetes

Includes what is referred to as atypical diabetes mellitus (ADM) or “Flatbush” diabetes, that has been variously considered as a form of type 1 diabetes, type 2 diabetes, or maturity onset diabetes of the young (MODY) (1–5)

Occurs throughout childhood, and rarely past age 40

Only described in African-American individuals

Not associated with HLA specificities

Strong family history in multiple generations with autosomal dominant pattern of inheritance

Not associated with obesity beyond that in the general African-American population

Abnormal sex ratio—M:F 1:3

No islet autoimmunity

Ketosis or ketoacidosis common at onset

Insulin usually not necessary for survival after treatment of acute metabolic deterioration, although diabetic control may be poor and ketoacidosis can recur without insulin treatment in some individuals

Insulin resistance not characteristic

Insulin secretion present but diminished, without long-term deterioration of islet cell function

Table 4. Maturity Onset Diabetes of the Young (MODY) (6)

MODY as a proportion of all diabetes widely variable among different populations, from 0.14% in Germany to 3% in England and 4.8% in Madras, India

Multigenerational transmission in an autosomal dominant pattern; often necessary to test asymptomatic individuals to demonstrate the presence of diabetes

Rarely affects racial/ethnic groups other than Caucasians

Onset subtle, usually before 25 years of age, with insulin usually not being required for treatment

Molecular defects in 6 genes, involving over 200 different mutations (7)

Table 5. Type 2 Diabetes (8,9)

Occurs predominantly during second decade of life, mean ∼13.5 years, but also in prepubertal children, including as young as 4 years

Much greater risk in African-American, native North American, Hispanic (especially Mexican)-American, Asian, and South Asian (Indian Peninsula) than in Caucasian individuals

Not associated with HLA specificities

75% or more have first- or second-degree relative affected

Polygenic inheritance

Variable sex ratio (M:F) from 1:4–6 in native North Americans to 1:1.7 in African-Americans, 1:1.3 in Mexican-Americans, and 1:1 in Libyan Arabs

Not usually associated with islet cell autoimmunity

Ketosis or ketoacidosis in one-third or more of newly diagnosed patients, accounting for most of the misclassification of type 2 diabetes patients as type 1 diabetes patients

Fatal complications of severe dehydration (hyperosmolar hyperglycemic coma, hypokalemia) possible at or before diagnosis

Often detected in the asymptomatic individual as a result of testing because of risk factors or during routine school or sports examinations

Insulin resistance, with other features of the insulin resistance syndrome (hyperlipidemia, hypertension, acanthosis nigricans, ovarian hyperandrogenism)

Highly variable insulin secretion, depending on disease status and duration, from delayed, but markedly elevated, to diminished; 50% reduction in insulin secretory capacity at the time of diagnosis in adults with symptoms, and insulin dependence by 6–7 years later

Obesity, with body mass index (BMI) above 85th–95th percentile for age and sex

Table 6. Autoantibody Positive Type 2 Diabetes

ICA and GADA in adults with typical type 2 diabetes, who are referred to as having either type 1.5 or, more commonly, latent autoimmune diabetes of adults (LADA) (10,11)

United Kingdom Prospective Diabetes Study (10) found that

LADA is age related: 21% of individuals 25–34 years old (n = 157) ICA positive, 34% GADA positive, and 20% positive for both antibodies, decreasing to 4%, 7%, and 2%, respectively among those 55–65 years old (n = 1769)

antibody positive individuals are significantly less overweight than antibody negative patients

glycated hemoglobin A1c (A1C) concentrations are significantly higher in antibody positive individuals

β-cell function is significantly less in antibody positive individuals, the most dramatic difference being in the younger patients, resulting in a more rapid development of insulin dependence, usually by 3 years duration

Swedish study of all individuals 15–34 years old with newly diagnosed diabetes over a two-year period (n = 764) who were tested for ICA, GADA, and IA/2A (11) found

76% classified type 1, 14% type 2, and the rest unclassified

47% of type 2 and 59% of unclassified patients positive for one or more antibodies

antibody positive type 2 or unclassifiable patients significantly lighter, with lower C-peptide concentrations, than antibody negative patients

Comparison of clinical parameters, haplotype and antibody patterns in 57 adults with type 1 diabetes, 54 with LADA, and 190 with type 2 diabetes indicates that LADA is a slowly progressive form of type 1 diabetes, rather than a variant of type 2 diabetes (12), with

no difference in BMI, waist:hip ratio, lipid profile, and BP between those with LADA and those with type 1 diabetes

lower BMI, waist:hip ratio, lipids, and BP in patients with LADA and type 1 diabetes than in those with type 2 diabetes

similar baseline C-peptide levels in patients with LADA and type 1 diabetes but a more rapid decline with type 1 diabetes

similar prevalence of HLA haplotypes associated with high risk for diabetes in LADA and type 1 diabetes

LADA more commonly associated with presence of a single islet-specific antibody compared to type 1 diabetes

Study of 48 children with type 2 diabetes (13) found

8% ICA512 (fragment of ICA) positive; 30% GADA positive, 35% IAA positive

no correlation of antibody positivity with degree of obesity

thyroid autoimmunity in subjects with islet cell autoimmunity

Study of 37 African-American children and adolescents with type 2 diabetes (14) found

10.8% positive for GADA, IA-2, or both

no difference in treatment requirements (oral agent vs. insulin) between positive and negative patients

The accelerator hypothesis has been proposed to explain the development of diabetes-related autoimmunity in typical type 2 diabetes as the result of hyperglycemia secondary to insulin resistance inducing β-cell apoptosis (glucotoxicity) with the development of β-cell autoimmunity (15). Because of the high frequency of evidence of islet cell autoimmunity in otherwise typical type 2 diabetes, particularly in young people, ICA and GADA testing may be worthwhile in all pediatric patients considered to have type 2 diabetes.

Antibodies will indicate an earlier need for insulin.

Antibodies will indicate the need to check for thyroid autoimmunity and to consider other associated autoimmune disorders.

GADA may be the more important predictor of insulin therapy over the short term (3 years) (11).

The characteristic features of the main forms of diabetes seen in children and adolescents are summarized in Table 7.