Clinical and Health Affairs
The Increase of Type 2 Diabetes Mellitus in Children
By Brandon M. Nathan, M.D.
Abstract
Communities around the world have seen a dramatic rise in the incidence of childhood obesity and pediatric type 2 diabetes mellitus (T2DM). Although significant advancement has been made in our understanding of the pathogenesis and risk factors for T2DM in children during the past 15 years, we have yet to find the safest and most effective ways to prevent and treat this disease. This review highlights our understanding of T2DM in children and outlines treatment strategies.
Before 1980, Type 2 diabetes mellitus (T2DM) was rarely reported in children, accounting for less than 2% of all cases of pediatric diabetes.1 However, by 2000, 8% to 45% of all new cases of diabetes in children in the United States were categorized as type 2.2 More recent data collected between 2002 and 2003 show the percentage of T2DM among all new pediatric diabetes cases in 10- to 19-year-olds in this country was 14.9% for Caucasians, 46.1% for Hispanics, 57.8% for African Americans, 69.7% for Asian/Pacific Islanders, and 86.2% for American Indians.3 Similar trends have been noted elsewhere in the world. In Japan, for instance, up to 80% of all new cases of pediatric diabetes are T2DM.4 Given the rising rates, it is believed that T2DM will be the predominant form of diabetes among children from a variety of ethnic backgrounds by 2015.5
Factors Contributing to T2DM
T2DM is a complex disease with both genetic and environmental factors contributing to its pathogenesis. Ultimately, T2DM results from a state of insulin resistance combined with impaired insulin secretion from pancreatic beta cells. Development of this state is influenced by ethnic and family history, multiple contributory genes, and environmental factors including high-risk behaviors associated with obesity.
♦ Obesity
The major risk factor for T2DM in children is obesity. The increase in the rate of type 2 diabetes has paralleled the rise in pediatric obesity in the United States during the past 20 years.6 A combination of high-calorie diets and reduced physical activity are at the core of this epidemic. Obesity leads to insulin resistance through impaired insulin signaling, interference with glucose transport, decreased insulin clearance related to elevated intraportal free fatty acids, and increased systemic adipocyte cytokines.7 Resistance to the effects of insulin results in increased hepatic glucose output, poor glucose uptake by muscle and fat, and impaired glucose disposal. Hyperglycemia eventually occurs in those individuals who are unable to secrete sufficient compensatory insulin to overcome their insulin-resistant state. This combination of insulin resistance and a defect in insulin secretion is intrinsic to the pathogenesis of T2DM in children.
The location of fat tissue (visceral as opposed to subcutaneous or total) may be just as, if not more, important to the pathogenesis of T2DM in children as body mass index (BMI). Visceral fat, which is stored in the abdomen and around the internal organs, is indirectly associated with insulin sensitivity in obese adolescents.8 Alterations in several recently identified adipose tissue-derived hormones and cytokines (adipokines), including adiponectin, visfatin, IL-6, and TNF-alpha, may contribute directly to insulin resistance that is inherent to T2DM as well as the cardiovascular risks associated with obesity in children and adults.9
Both children born small or large for their gestational age are more likely to be obese, develop insulin resistance, and be at risk for T2DM and components of the metabolic syndrome.10-12 The thrifty phenotype hypothesis is one explanation for this phenomenon. It theorizes that infants born small for their gestational age or with intrauterine growth restriction respond to inadequate nutrition in utero by diverting nutrients away from skeletal muscle and core organs in order to preserve brain growth and aid in survival. The consequence of this prenatal metabolic reprogramming is insulin resistance and obesity later in life. The rate and timing of catch-up growth among these infants may also contribute to future risk.13 At the other extreme, infants born to mothers with gestational diabetes are often larger because of increased glucose supply resulting in increased fetal insulin secretion and weight gain. The metabolic effect of tissue and pancreas adaptation to excess glucose in utero is manifested later in childhood as insulin resistance.
♦ Ethnic and Family Background
A child’s ethnic background and family history also influence his or her risk for developing T2DM. Children of Native-American, Mexican-American, African-American, and Asian-American heritage are at greatest risk for developing the disease. Researchers have found insulin sensitivity is significantly lower in Hispanic children when compared with a control group of non-Hispanic white children.14 African-American children have higher glucose responses on oral glucose tolerance tests compared with Caucasian children after adjusting for puberty, age, and BMI. They also have a baseline increase in basal and stimulated insulin responses during clamp studies when compared with Caucasian children.15
Family history and gender also appear to be risk factors for children with T2DM. Between 74% and 100% of children diagnosed with T2DM will have a primary or secondary family member with the disease, and girls are 1.7 times more likely than boys to develop T2DM.1 In a study of mostly Caucasian individuals, the lifetime risk for developing diabetes increased 3.5-fold for children who had 1 parent with the disease and 6.1-fold for those with both parents who have T2DM.16 Even prior to being diagnosed, African-American children with a family history of diabetes have lower insulin-stimulated glucose disposal than those who do not have diabetes in the family.17
♦ Genetics
T2DM likely involves multiple genes conferring risk, in addition to environmental influences. Although few proposed candidate genes have been replicated in independent studies, one candidate region that has been replicated in Mexican Americans is the NIDDM1 region on chromosome 2. This may account for 30% of risk in the Mexican-American population.18 Within this region, CAPN10, the gene encoding calpain, has been proposed as a high-risk gene in Mexican Americans but has not been as strongly associated with the development of diabetes in individuals of other ethnic backgrounds.19
♦ Autoantibody Effect
Type 2 diabetes was previously believed to be exclusively nonautoimmune-mediated; but several studies have demonstrated varying degrees of autoantibody positivity in adolescents with T2DM. Studies have shown at least 1 diabetes autoantibody (ie, autoantibodies versus islet cell antigen, insulin, glutamic acid decarboxylase) may be present in up to 36% of adolescents with T2DM.20,21 Thus far, there is no consistent data on the significance of these autoantibodies in the T2DM cohort with respect to insulin requirements, co-morbidities, or outcomes. These individuals may represent a subgroup of patients who have a slowly progressive form of diabetes that incorporates features of both type 1 and type 2, known as latent autoimmune diabetes of adulthood (LADA).
Clinical Presentation and Diagnostic Criteria
Most children in the United States are diagnosed with type 2 diabetes in early to late adolescence, which correlates with the inherent increase in insulin resistance accompanying puberty. A BMI in the range that places a child at risk for being overweight (greater than the 85th percentile for age) is part of the primary screening criteria (Table 1). The clinical presentation for T2DM can vary from the child being completely asymptomatic to being acutely ill. Many children with T2DM will have a very insidious presentation without the classic symptoms of polyuria, polydipsia, and weight loss.
Approximately 90% of adolescents with T2DM will have acanthosis nigricans, a dark, velvety thickening of the skin along the neckline and intertriginous spaces. Girls may present with symptoms of a vaginal yeast infection. Unlike adults, between 5% and 33% of children with T2DM present with diabetic ketoacidosis, which can cloud the initial diagnostic picture.22 This may, however, be more prevalent in children of African-American and Latino heritage, reflecting an underlying genetic predisposition toward a more rapid depletion of beta cells in these populations.23,24 As with adults, hyperglycemic hyperosmolar coma, marked by altered mental status or coma and severe hyperglycemia in the absence of significant acidosis or ketonemia, also can be a presenting symptom of T2DM in children and may be fatal.
The recommended laboratory diagnostic criteria are listed in Table 2. The preferred screening is a fasting plasma glucose test. This test rarely misses children with asymptomatic or “silent” T2DM. However, it may miss individuals with impaired glucose tolerance and early beta-cell dysfunction. It is estimated that between 17% and 33% of children in high-risk populations have impaired glucose tolerance.25 Therefore, although more extensive screening is unlikely to detect significantly more cases of T2DM, it may identify those children who are at higher risk for progression of the disease and for whom more intensive lifestyle interventions or metformin therapy could be considered. For that reason, many physicians are performing a fasting insulin level, Hgb A1c, or oral glucose tolerance test to more thoroughly assess high-risk children.
Complications of T2DM in the Pediatric Population
Complications and co-morbidities associated with T2DM are listed in Table 3. Perhaps most notable and consistent is microalbuminuria. Microalbuminuria is frequently encountered at presentation, and the rate of progression to nephropathy may be quite rapid in adolescents.26 An astounding 40% of adolescents with T2DM were found to have microalbuminuria within 3 years of their diagnosis.27 Rates of hypertension and microalbuminuria in children with T2DM exceed those found in children with type 1 diabetes mellitus.28 In Pima Indians, end-stage renal disease occurs at a much earlier age and more rapidly in individuals diagnosed with T2DM in adolescence than in those diagnosed in adulthood.29
The risk for developing accelerated atherosclerosis is greater in individuals who develop T2DM during childhood than those who develop it as adults.30 Markers of arterial stiffness, a surrogate for cardiovascular events, are higher in children with T2DM compared with an otherwise healthy obese control group.31 Rates of dyslipidemia (elevated total cholesterol, LDL, and triglycerides) are markedly higher in children with T2DM compared with children who have T1DM and obese controls.32 Among adolescents with poorly controlled T2DM, 65% had elevated total cholesterol, 43% elevated LDL, and 40% elevated triglycerides. Other risk factors such as hypertension were present in 10% to 32% of adolescents who present with T2DM.26 This clustering of metabolic derangements including abdominal obesity, dyslipidemia, insulin resistance or impairment in glucose regulation, and hypertension is known as the metabolic syndrome. Metabolic syndrome is associated with early cardiovascular disease and mortality in adults. Presence of metabolic syndrome in childhood confers an increased risk for significant cardiovascular disease in early adulthood.33
Other disorders associated with insulin resistance that may occur in the T2DM population include polycystic ovary syndrome (PCOS) and nonalcoholic fatty liver disease (NAFLD). PCOS refers to a variable constellation of hyperandrogenism, anovulatory menstrual cycles or oligomenorrhea, hirsutism, and polycystic ovaries. The etiology of PCOS is complex and likely multifactorial, although insulin resistance is believed to play a major role. NAFLD is common among obese adolescents and, in particular, adolescents with T2DM. Rates have been reported to be as high as 48% in one study.34 NAFLD is a likely consequence of an increase in free fatty acid release by abundant visceral adipocytes into the portal circulation that results in higher triglyceride levels and subsequent excessive intrahepatic lipid storage.35 NAFLD is an important co-morbidity to diagnose, as diabetes, along with obesity and advanced age, is a strong predictor for progression to fibrosis and end-stage liver disease.
Treating T2DM
Treatment of T2DM in the pediatric population remains challenging because of the difficulties of successfully employing lifestyle changes and a relatively small FDA-approved pharmaceutical armamentarium.
♦ Lifestyle Alterations
The most successful interventions combine dietary changes, exercise, and behavior modification. Dietary goals should include stopping excessive weight gain, preserving normal linear growth, and maintaining fasting glucose levels below 126 mg/dL with Hgb A1c values less than 7%. Efforts should focus on eliminating high-calorie beverages such as juices, sodas, and energy drinks, and eating smaller portions. Parents should consult with a nutritionist familiar with pediatric weight management who can outline goals in order to maintain weight or promote a small monthly weight loss.
In addition to dietary changes, efforts should be made to decrease sedentary behaviors and increase physical activity both in school and at home. The American Academy of Pediatrics recommends children limit time spent watching television, playing video games, and working on the computer to less than 2 hours per day. Children also should be encouraged to find a sport or activity that they enjoy and are likely to continue. Perhaps most important to the success of lifestyle changes is parental and family involvement. Programs designed to help the family eat properly and exercise can help obese children lower their BMI, total cholesterol, triglycerides, and blood pressuree.36 School programs that focus on lifestyle choices and aerobic activity also can help obese children.37
The National Diabetes Education Program provides tip sheets that health care providers can use when counseling adolescents with type 2 diabetes (http://ndep.nih.gov/diabetes/youth/youth.htm).
♦ Drug Therapy
The only pharmaceutical agents approved for treating T2DM in the pediatric population are metformin and insulin. Metformin is a biguanide that enhances insulin-stimulated glucose uptake in the muscle and adipose tissue and decreases hepatic glucose output. In a double-blind, placebo-controlled trial, metformin significantly lowered fasting glucose and A1c levels in adolescents with T2DM over 4 months.38 Metformin also may have a modest secondary benefit of moderating weight gain and even inducing mild weight loss in the pediatric population.39 It also may be an excellent choice for adolescent females with PCOS, as use of metformin has been associated with improvement in ovulatory cycles and insulin resistance.40
Recently, metformin was shown to reduce subcutaneous fat stores, improve fasting glucose and insulin levels, and improve insulin sensitivity among overweight adolescents who show evidence of insulin resistance but do not meet the criteria for T2DM.41 In earlier studies, metformin improved fasting insulin levels, fasting glucose levels, and BMI compared with placebo in a group of obese adolescents at risk for T2DM.42 Although no follow-up data is available on progression to disease, these studies provide preliminary data that metformin may be a useful adjunct to lifestyle modification in preventing T2DM.
For those children whose T2DM is not well-controlled or who are in the early stages of the disease, insulin therapy is crucial to glycemic management. Use of subcutaneous insulin is important to overcoming insulin resistance and achieving glycemic control early in the course of management for many patients. In addition, a greater number of overweight children are being diagnosed with T1DM. Distinguishing between T1DM and T2DM during the initial diagnosis can be difficult. Typically, basal-bolus regimens of insulin can be initiated by combining long-acting insulin such as insulin glargine or detemir with short-acting insulin such as insulin aspart or lispro at meal time. Giving premixed insulin (70/30 or 75/25) twice a day can also be attempted in cases where there is poor adherence to the basal-bolus regimen. Eventually weaning the patient to a long-acting basal insulin or off insulin altogether may be possible once the patient gets his or her glucose under control, begins metformin therapy, and follows lifestyle recommendations.
Other classes of pharmaceutical agents are available for use in the adult population including sulfonylureas, thiazolidinediones, glucosidase inhibitors, and incretins. None of these drugs have been approved for use in the pediatric population, and only a few small trials have been conducted using these agents. In a randomized trial comparing the sulfonylurea, glimepiride, with metformin in adolescents with T2DM, glimepiride showed comparable reduction in A1c values over 24 weeks of treatment.43 Participants also showed no differences in frequency of hypoglycemia, a common side effect of sulfonylurea therapy. However, glimepiride was associated with a significant increase in BMI compared with placebo. The TODAY (Treatment Options for type 2 Diabetes in Adolescents and Youth) study is investigating the benefits of metformin combined with intensive lifestyle modification, rosiglitazone (a thiazolidinedione), or placebo in a double-blind, placebo-controlled multicenter trial, but results are not yet available.44 For pediatric patients whose condition remains poorly controlled on a combination of metformin, insulin, and lifestyle interventions, addition of another class of oral agents should be considered.45 Long-term safety and efficacy data are not available for most of these drugs, and each carries its own side effect profile, with which providers must be familiar before prescribing.
Conclusion
The number of cases of T2DM in children remains relatively small compared with the number of cases of T1DM. However, as the rate of obesity continues to increase, T2DM may soon become the predominant form of diabetes in children. This has major ramifications for the future care of these children as young adults. Developing strategies to prevent and eliminate obesity is imperative to our public health. In addition, efforts need to focus on clinical trials aimed at finding safe and effective pharmacotherapy that can be used as an adjunct to lifestyle intervention.
The NIH-sponsored STOPP-T2D (Studies to Treat or Prevent Pediatric Type 2 Diabetes) is one effort to prevent T2DM among children who are at risk for developing the disease and to identify and treat those who have it. Thus far, 1,700 high-risk adolescents have been studied in order to help identify those who require additional screening.46 From a therapeutic standpoint, the TODAY study will provide valuable information about the potential role for rosiglitazone in pediatric diabetes management. Other studies assessing the efficacy and safety of other classes of oral agents are needed to better define their role in controlling pediatric T2DM.
Continued research into genetic markers also may help better identify pediatric patients who are at risk for T2DM or customize future therapies. Such work is necessary in order to avert a health crisis in this generation and future generations of youths. MM
Brandon Nathan is an assistant professor in the division of pediatric endocrinology at the University of Minnesota.
The author would like to acknowledge Brad Miller, M.D., Ph.D., for his insightful commentary and direction in preparing this manuscript.
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