Historically, type II diabetes mellitus (formerly known as non-insulin-dependent diabetes mellitus) has been considered a disease of adults and older individuals and not a pediatric condition. However, at the tum of the century it was recognized that some children who had diabetes presented with a mild and slowly progressive disease unlike type I diabetes mellitus.1 Type II diabetes mellitus is a polygenic condition in which insulin is not essential for survival, although it may be required for adequate metabolic control. It has a strong hereditary component and results from a combination of insulin resistance, increased hepatic glucose output, and progressive decline of glucose-stimulated insulin secretion. Unlike type I diabetes mellitus, where insulin secretion is almost nil, patients with type II diabetes mellitus have insulin secretory capacity, but insulin levels are inadequate to overcome the concomitant peripheral insulin resistance, causing hyperglycemia. This article discusses the recent emergence of type II diabetes mellitus as a pediatric condition.
The prevalence of type II diabetes mellitus varies among different populations and throughout the world.2 It is common among adults in the United States, affecting 6.6% of those 20 to 74 years of age and 17.1% of those 65 to 74 years of age.3 The prevalence is highest among Native Americans, with the Pima Indians of Arizona having the highest rate in the world (approximately 50% of those older than 35 years of age).4 African Americans and Mexican Americans have rates that exceed those for the Caucasian population.3
Among children, type II diabetes mellitus has been reported to account for 2% to 3% of all diabetes mellitus.5 More recently, several publications reported an increasing prevalence among children and especially adolescents with a greater representation among African Americans, Hispanics, and Native Americans.6"8 A recent study demonstrated a tenfold increase in type II diabetes mellitus between 1982 and 1994.5 Among patients 10 to 19 years of age, type II diabetes mellitus accounted for 33% of all newly diagnosed cases of diabetes in 1994. This related to the increasing prevalence of obesity.
Typically, rates of type I diabetes mellitus are lower in African-American children than in Caucasians. However, a recent analysis from Pennsylvania showed, for the first time, a higher incidence for African Americans (17.6 per 100,000) than for Caucasians (16.5 per 100,000). This was explained by a threefold higher incidence of diabetes mellitus among African Americans in the 15- to 19-year age group. The 1990 to 1994 incidence for African Americans was twofold and threefold higher than that reported in 1985 to 1989 and 1980 to 1984, respectively. Such findings may be explained by the potential inclusion of cases that were type II diabetes mellitus.9,10 Among African-American adolescents with diabetes mellitus, 42% had no evidence of autoantibodies compared with only 10% of Caucasian adolescents,10 suggesting a nonautoimmune (type ?) diabetes. The odds ratio for the development of type II diabetes mellitus in African-American children compared with Caucasian children in Cincinnati was 3.5 in boys and 6.1 in girls.5 At Arkansas Children's Hospital, 74% of youth with type II diabetes mellitus were African American.8 In California, more MexicanAmerican children present with type II diabetes mellitus than do Caucasian children.7 In all of these children, type II diabetes mellitus was related to obesity and appeared approximately at the time of puberty.
GENETICS ANO PATHOPHYSIOLOGY
Type II diabetes mellitus in adults, and likely in children, results from the interaction of genetic and environmental factors. The strongest evidence of its genetic basis comes from twin studies. Concordance rates for type ? diabetes mellitus in older identical twins range from approximately 50% to 90%." However, these studies provide no information on its mode of inheritance. Analysis of inheritance patterns of type II diabetes mellitus in Pima Indians suggests a single autosomal gene inherited codominantly that may reside on chromosome 4q.12 Mutations in the ß3 adrenergic receptor may contribute to the early onset of type ? diabetes mellitus in Pima Indians, although they may not be a major determinant.13 Mexican-American populations have a major susceptibility locus on chromosome 2.14
Genetic susceptibility appears to be a prerequisite for the disease. However, expression of type II diabetes mellitus seems largely determined by environmental factors, such as obesity, physical inactivity, and a diet that is high in fat and refined carbohydrates and low in fiber. These contribute to insulin resistance, a critical component in type II diabetes mellitus.1516 These factors appear to be additive, offering the possibility that intervention with lifestyle changes may reduce the incidence of type II diabetes mellitus.
Peripheral insulin resistance is the primary abnormality early in the course of type ? diabetes mellitus. This is initially offset by a compensatory increase in insulin secretion. With time, insulin secretion declines, with a marked defect in firstphase insulin response to glucose stimulation.1718 Chronic mild hyperglycemia gradually impairs ß-cell function and further worsens insulin resistance and hyperglycemia.18 The precise mechanism of this "glucose toxicity" is unknown, but seems to be temporary because both insulin secretion and sensitivity improve with control of hyperglycemia.
There are convincing epidemiologic data that African Americans are more hyperinsulinemic or insulin resistant than are Caucasians.19,20 In our separate studies, African- American children had higher insulin levels in response to acute elevations in plasma glucose compared with Caucasian peers.21"23 Moreover, insulin sensitivity was approximately 30% lower in AfricanAmerican adolescents,23 and among AfricanAmerican children, girls had lower insulin sensitivity than did boys.21 Such observations could explain the higher rates of type II diabetes mellitus in African-American adolescents, particularly females. Data in African-American versus Caucasian adults are in agreement with these pediatric data.24
As mentioned above, the majority of children who present with type ? diabetes mellitus are approximately 13 years of age and in mid-puberty. This is most likely due to the temporary evolution of insulin resistance during pubertal maturation, manifested by an approximately 30% reduction in insulin action compared with prepubertal children or adults.25,26
CLINICAL FINDDIGS: DISTINGUISHING TYPE I FROM TYPE II DIABETES MELLITUS
Children and adolescents with type II diabetes mellitus present with symptoms spanning a spectrum from severe insulin deficiency to mild hyperglycemia.5"8,27"32 The patient may have ketonuria, ketoacidosis, or both with signs and symptoms compatible with type I diabetes mellitus, such as polyuria, polydipsia, hyperventilation, weight loss, nausea, vomiting, and dehydration, and may require insulin therapy.5"8'28"32 Often the distinction between type I diabetes mellitus and type II diabetes mellitus is not possible until months or years later, when insulin requirements decline beyond those of the honeymoon period and a non-insulin-dependent course develops. During this non-insulin-dependent period, hyperglycemia, glycosuria, and elevated glycohemoglobin (hemoglobin A ) may or may not persist, and remitting recurrences of severe hyperglycemia and ketonuria may be present during acute illnesses. On the other hand, patients may be totally asymptomatic. In one series, 50% of children with type II diabetes mellitus were asymptomatic and were referred only because of glycosuria on routine urinalysis or hyperglycemia noted during blood testing for other reasons; 39% initially had polyuria, polydipsia, and weight loss, and only 11% had mild ketoacidosis.32 Unlike type I diabetes mellitus, more minority children are affected and there is an excess of female to male patients ranging from 1.6:1 to 3:1 in different studies.
Characteristics of Type I and Type II Diabetes Mellitus In Children and Adolescents
Obesity, acanthosis nigricans, and a strong family history of type ? diabetes mellitus can help raise suspicion about the possibilities of type II diabetes mellitus in older children and adolescents (Table). Obesity is present in the majority, with the body mass index exceeding the 85th percentile for age and sex in almost 95% of patients with type ? diabetes mellitus.5"8,30 The increasing rates of type ? diabetes mellitus in youth are most likely a reflection of increasing childhood obesity.30 Acanthosis nigricans, a cutaneous manifestation of insulin resistance or hyperinsulinism, is present in 60% to 86% of patients. It consists of hyperpigmentation with thickening of the skin into velvety, irregular folds in the intertriginous areas. It is found in 7% of school-aged children, and is most prevalent among AfricanAmerican and Hispanic children.33
A strong family history of type II diabetes mellitus is characteristic of children with type II diabetes mellitus. Seventy-two percent to 85% of patients have a positive family history, often with multiple affected members in more than one generation. However, in general the inheritance pattern is not autosomal dominant, distinguishing type II diabetes mellitus from maturity-onset diabetes of youth.34 We found that family history of type II diabetes mellitus was associated with approximately a 20% decrease in insulin sensitivity in African-American children who did not have diabetes.35 Additional risk factors were a history of maternal gestational diabetes with poor metabolic control and fetal hyperinsulinemia and nutritional deprivation in utero.36,37 The pathophysiologic mechanisms of these conditions remain to be elucidated.
Data remain scanty about the biochemical characteristics of youths who present with type II diabetes mellitus. However, the available information suggests that in comparison with type I diabetes mellitus, children with type II diabetes mellitus present with lesser degrees of hyperglycemia, have significantly higher levels of insulin and C-peptide, are less frequently ketonuric, and have milder degrees of acidosjs 5,6,8,28,30 Limited information indicates that children with type II diabetes mellitus have no serologic evidence of pancreatic autoimmunity.5,6,8 Additional studies are needed for a definitive conclusion, in part because latent autoimmune diabetes was recently described in adults with type II diabetes mellitus. These patients have islet cell autoantibodies and glutamic acid decarboxylase antibodies and manifest lower C-peptide and insulin responses to glucose compared with antibody-negative patients who have type II diabetes mellitus.38,39
Not much is known about the therapeutic management of youth-onset type II diabetes mellitus and any discussion about therapy will thus be anecdotal, based on personal experience and bias. Insulin will remain the approved and effective mode of therapy for children with type II diabetes mellitus, at least until such data become available regarding other therapeutic modalities.
When caring for youth with type II diabetes mellitus, the following help guide therapeutic approaches. The majority of youth with type II diabetes mellitus are obese. Therefore, it is reasonable to aim for lifestyle changes that incorporate dietary and activity interventions for weight reduction. Because type II diabetes mellitus is associated with a strong family history, such interventions should focus on the whole family. Emotional lability, rebellious behavior, and poor dietary adherence are characteristic of adolescents. A diabetes team approach that includes the physician, dietitian, nurse educator, and social worker or psychologist is essential to provide continuous education, follow-up, and feedback. Because a high percentage of patients with type ? diabetes mellitus have insulin resistance, testing the efficacy and safety of pharmacologic agents that increase insulin sensitivity, improve insulin secretion, or both is reasonable. Despite a wealth of data about these agents in adults with type II diabetes mellitus, there are no data from welldesigned clinical trials in children. Thus, one has to exercise caution in prescribing a therapy with unknown pharmacokinetics, efficacy, or safety in this age group.
Although ketoacidosis is corrected in the usual way, the approach to insulin therapy in type II diabetes mellitus is different from that used for type I diabetes mellitus in a non-emergency setting. Because insulin resistance is characteristic of type ? diabetes mellitus, insulin doses are often high. Intensive insulinization can achieve nearnormal glycémie control, but at the expense of inducing further hyperinsulinemia and weight gain. Soon after initiation of insulin therapy, insulin requirements often decline rapidly and near-normal glycémie control may become possible without insulin. Strict dietary management and weight loss facilitate this.
Type II diabetes mellitus is no longer exclusively a disease of adults. Health care professionals and agencies must gain a better understanding of (1) the epidemiology of type II diabetes mellitus in childhood; (2) the phenotypic, biochemical, metabolic, and autoimmune characteristics at diagnosis and during the course of the disease; (3) therapeutic modalities; (4) screening of high-risk populations; and (5) prevention strategies. This will be one of the challenges in pediatric diabetes as we approach the 21st century.
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Characteristics of Type I and Type II Diabetes Mellitus In Children and Adolescents