Pediatric Annals

Type 2 Diabetes in Children: Oxymoron or Medical Metamorphosis?

Kenneth C Copeland, MD; Laura J Chalmers, MD; Ryan D Brown, MD

Abstract

Before the 1990s, a diagnosis of "juvenile" diabetes meant type 1 diabetes, and the rare child or adolescent diagnosed with type 2 diabetes was considered an anomaly. During the past decade, pediatricians have witnessed a profound change in the epidemiology of diabetes, so that the "adult-onset" form of diabetes, previously relegated mostly to that associated with adiposity acquired in middle or older age, now is being diagnosed in children and adolescents at an alarming rate. This observation comes as no surprise, given the almost invariable association between obesity and type 2 diabetes and the new epidemic of obesity in childhood.

OBESITY IN CHILDHOOD AND ADOLESCENCE

Changing Epidemiology

The prevalence of obesity in the United States is increasing in all age groups. Between 1991 and 1998, the number of obese people in the US increased from 12% to 19%,! and the number of states in which 15% or more of the population was obese increased from 4 to 39 of 45 states surveyed.2 According to data from the National Health and Nutrition Examination Surveys (NHANES),3 the number of overweight (defined as a body mass index, BMI, greater than the 95th percentile) children and adolescents increased from approximately 5% in the 1970s to more than 15% by 1999. This trend is even more striking among ethnic minority children, with more than 23% of Mexican American and African American adolescents currently being overweight;4 this trend in ethnicity for obesity mirrors closely the recent trend in the occurrence of type 2 diabetes in these same ethnic groups.5

This increase in obesity prevalence is associated with several recent societal changes in eating habits. Today, high-calorie (especially in the form of high-fructose corn syrup6), high-fat,7 low-fiber foods are plentiful and cheap,8,9 and their ready availability is conducive to recent changes in the home, at work, and at school. During the past 4 decades, obesity has become big business, with extensive food marketing and promotion to children10 fueled by an invasion of cheap and potent sweeteners11 and tasty fats.12 The marketing practice of "value meals" and "super-sizing," combined with the idea that a child will overeat if excess food is provided, creates sinister synergy in the pathogenesis of childhood obesity.12 It thus follows that several well-known complications of obesity, including type 2 diabetes, are emerging as new public health problems for children and adolescents.

Known Contributing Factors

East foods. Only 38% of meals in the US today are home-cooked; thus the proliferation of fast food restaurants (170,000 in the US alone) should come as no surprise.13 Fast food has become a dietary staple for children both in the US and worldwide.14 Recently, Bowman et al.15 showed that, on a typical day, 30.3% of 6,212 US children reported eating fast food. This resulted in a higher consumption of total energy (187 kcal), 24 more grams of total carbohydrates, 9 more grams of total fat, and 228 more grams of sugar-sweetened beverages when compared with children who did not eat fast food.

From 1970 to the mid 1990s, the total energy intake from fast food increased from 2% to 10%,16 prompting a political and social debate about whether the incorporation of fast food into a diet can be considered healthy.17 Although it has been stated that the obesity epidemic may be related to unsafe neighborhoods (rendering it unsafe to go outside to play) and proximity to fast-food restaurants, Burdette et al.18 found no relationships between the distances from home to neighborhood playgrounds or to fast-food restaurants, nor to the amount of neighborhood crime in low-income overweight preschool children.

Soft drinks. Sodas, fruit-flavored drinks, and sport drinks are being consumed…

Before the 1990s, a diagnosis of "juvenile" diabetes meant type 1 diabetes, and the rare child or adolescent diagnosed with type 2 diabetes was considered an anomaly. During the past decade, pediatricians have witnessed a profound change in the epidemiology of diabetes, so that the "adult-onset" form of diabetes, previously relegated mostly to that associated with adiposity acquired in middle or older age, now is being diagnosed in children and adolescents at an alarming rate. This observation comes as no surprise, given the almost invariable association between obesity and type 2 diabetes and the new epidemic of obesity in childhood.

OBESITY IN CHILDHOOD AND ADOLESCENCE

Changing Epidemiology

The prevalence of obesity in the United States is increasing in all age groups. Between 1991 and 1998, the number of obese people in the US increased from 12% to 19%,! and the number of states in which 15% or more of the population was obese increased from 4 to 39 of 45 states surveyed.2 According to data from the National Health and Nutrition Examination Surveys (NHANES),3 the number of overweight (defined as a body mass index, BMI, greater than the 95th percentile) children and adolescents increased from approximately 5% in the 1970s to more than 15% by 1999. This trend is even more striking among ethnic minority children, with more than 23% of Mexican American and African American adolescents currently being overweight;4 this trend in ethnicity for obesity mirrors closely the recent trend in the occurrence of type 2 diabetes in these same ethnic groups.5

This increase in obesity prevalence is associated with several recent societal changes in eating habits. Today, high-calorie (especially in the form of high-fructose corn syrup6), high-fat,7 low-fiber foods are plentiful and cheap,8,9 and their ready availability is conducive to recent changes in the home, at work, and at school. During the past 4 decades, obesity has become big business, with extensive food marketing and promotion to children10 fueled by an invasion of cheap and potent sweeteners11 and tasty fats.12 The marketing practice of "value meals" and "super-sizing," combined with the idea that a child will overeat if excess food is provided, creates sinister synergy in the pathogenesis of childhood obesity.12 It thus follows that several well-known complications of obesity, including type 2 diabetes, are emerging as new public health problems for children and adolescents.

Known Contributing Factors

East foods. Only 38% of meals in the US today are home-cooked; thus the proliferation of fast food restaurants (170,000 in the US alone) should come as no surprise.13 Fast food has become a dietary staple for children both in the US and worldwide.14 Recently, Bowman et al.15 showed that, on a typical day, 30.3% of 6,212 US children reported eating fast food. This resulted in a higher consumption of total energy (187 kcal), 24 more grams of total carbohydrates, 9 more grams of total fat, and 228 more grams of sugar-sweetened beverages when compared with children who did not eat fast food.

From 1970 to the mid 1990s, the total energy intake from fast food increased from 2% to 10%,16 prompting a political and social debate about whether the incorporation of fast food into a diet can be considered healthy.17 Although it has been stated that the obesity epidemic may be related to unsafe neighborhoods (rendering it unsafe to go outside to play) and proximity to fast-food restaurants, Burdette et al.18 found no relationships between the distances from home to neighborhood playgrounds or to fast-food restaurants, nor to the amount of neighborhood crime in low-income overweight preschool children.

Soft drinks. Sodas, fruit-flavored drinks, and sport drinks are being consumed at an increasing frequency in the home, when dining out, and even in recent years at school. Soft drinks are reported to be available in 60% of private and public middle and high schools.19 Between 1994 and 1995, daily consumption had risen to an average of 19 ounces per day among adolescent boys.20 This increase may reflect the increased marketing of super-sized drinks with unlimited refills.21 With the increase in sweetened drink consumption, the amount of solid food consumed does not decline, thus leading to a higher daily caloric intake consumed.22

School lunches, snacking, and routine eating habits. Today, school lunch for many children10 consists almost exclusively of pizza, frenen fries, and sodas or sports drinks served a la carte. These patterns are difficult or impossible to alter.23 French fries constitute 30% of the vegetables consumed by teenagers, and only 20% of children get the recommended five or more servings of fruits and vegetables per day.24 In recent years, more than 25% of calorie intake in children has come from high-density snacks.25

Television, computers, and video games. On average, children between ages 2 and 18 spend 5 hours and 29 minutes a day using different types of media.26 Both longitudinal27 and crosssectional3,28 studies have shown an association between television viewing and childhood obesity. The average child watches more than 3 hours of television per day, and the risk of obesity has been demonstrated to increase when 4 hours or more are watched per day.29

In one study, when television viewing was contingent on pedaling a stationary cycle (an ergometer "TV cycle"), there was a substantial decrease in both television viewing and total body fat.30 This suggests that making television viewing contingent on performed physical activity might lead to both increased physical activity and less obesity.31

The appeal of television to children is substantial, possibly in part because approximately 50% of children's television programming is sponsored by food commercials,32 amounting to an expenditure of more than 30 billion dollars per year for commercial advertising.13 However, the relationship between the television viewing of children and advertising raises an interesting "chicken versus egg" question - that is, does more television watching by children lead to more advertising, or does more child-specific advertising lead to more television watching by children? Neither causation nor the direction of causation has been demonstrated.

Physical education in schools. Between 1991 and 1995, the daily enrollment in high school physical education classes dropped from 42% to 25%,33 despite recommendations from the Centers for Disease Control and Prevention and the American College of Sports Medicine calling for 30 minutes per day of moderate to vigorous physical activity.34

Treatment

Diets. Numerous diets for weight management have been promoted and tested in adults, with far fewer tested in children. Such diets include portion control using the Food Guide Pyramid, which was restructured to a horizontal pyramid in 2005, now including exercise as one of the key components to a healthy body.35 Other suggested diets include the Traffic Light or Stoplight Diet36 and low-carbohydrate diets.37 Although short-term results often are positive and encouraging, few dietary regimens have been shown to be effective in long-term weight reduction. Few reports of the effects of low-carbohydrate diets have been reported in children, perhaps due to fear of complications, even though ketogenic diets have been used in children for several decades with few complications or side effects.38

It should be noted that, contrary to traditional practice, restriction of dairy foods may not be necessary or beneficial in reducing obesity or its attendant risk of insulin resistance, at least in obese adults. In fact, Pereira et al.39 reported that the odds of developing metabolic syndrome are actually reduced with increased dairy intake.

Although a number of these dietary manipulations are encouraging, more data in children, with longer observation periods, are needed before conclusive recommendations for children and adolescents can be made.

Behavioral interventions. Although dietary intervention and a plan for increasing energy expenditure are essential components to a successful weight control program, neither in isolation or even both together appears to be adequate for long-term success. Possibly the most effective long-term intervention reported in overweight children is that proposed by Epstein, using family-based behavioral modification.36,40 With such an approach, parents are taught to use stimulus control, positive reinforcement, incentives (including praise), and environmental restructuring, and are expected to participate in the intervention themselves.40 In such programs, the degree of success for the child correlates closely with parental weight reduction.41 It has been suggested that these behavioral techniques may be more effective in overweight children if taught before adulthood, as long-term results in weight maintenance are less promising in adults.42

Figure. Clinical recommendations for detecting type 2 diabetes, from the Oklahoma State Medical Association (reproduced with permission).

Figure. Clinical recommendations for detecting type 2 diabetes, from the Oklahoma State Medical Association (reproduced with permission).

Comorbidities of Obesity

Recent observations suggest a clustering of metabolic derangements (ie, dyslipidemia, insulin resistance, hypertension) in obese children and adults, that has been termed metabolic syndrome43 or syndrome X.44 Metabolic syndrome in overweight adolescents has been defined as the presence of three or more of the following gender- and age-specific risk components:45

* BMI above the 97th percentile.

* Systolic or diastolic blood pressure above the 95th percentile.

* Impaired glucose tolerance (2-hour blood glucose greater than 140 mg/dL after a standard oral glucose load).

* Triglyceride levels above the 95th percentile.

* High-density lipoprotein (HDL) cholesterol below the 5th percentile.

Specific cut points for children and adolescents recently have been proposed, although no definitions have been accepted universally.43

The Third National Health and Nutrition Examination Survey (NHANES III) demonstrated that roughly 22% of the general population46 and 32% to 50% of overweight adolescents45,47 met the criteria for metabolic syndrome, with an increased prevalence in males.47 Although the precise mechanisms involved in the development and pathogenesis of the metabolic syndrome are incompletely understood, elevated circulating free fatty acids appear to contribute to insulin resistance, affecting pancreatic beta cell function;48 this may contribute to the deposition of fat into muscle.49 Although not all obese patients progress to insulin resistance, glucose intolerance, and diabetes,50 it appears that a large percentage of obese adolescents do.51 Nevertheless, at least among adolescent girls, there appears to be a much greater prevalence of insulin resistance and glucose intolerance than overt diabetes.52

Obesity per se is associated with increased cardiovascular risk: 65% of obese children ages 5 to 10 have one cardiovascular risk factor and 25% have two or more, in addition to obesity.53 An atherogenic profile consisting of high cholesterol, low-density lipoprotein (LDL), and triglycerides along with low HDL is found routinely in overweight children and adolescents.54 Inflammatory proteins, including C-reactive protein, are increased, and adiponectin levels are decreased as BMI increases in children and adolescents.45 Elevated insulin levels in youth may contribute to hypertension.55 Coronary atherosclerotic lesions are more likely to be present in overweight youth,56 and being overweight during adolescence doubles the risk of cardiovascular disease later in life.57

Other serious medical conditions have been associated with obesity in children and adolescence,58 including slipped capital femoral epiphysis,59 Blount's disease,60 nonalcoholic steatohepatitis (NASH), pseudotumor cerebri, polycystic ovarian syndrome, cholelithiasis, and severe degenerative joint disease. Obese children are more likely to exhibit low self-esteem and severe depression.61 Finally, life-threatening obstructive sleep apnea is far more likely to be seen in obese children compared with normal weight children.62

TYPE 2 DIABETES IN CHILDREN AND ADOLESCENTS

Changing Epidemiology

In 2002, the total number of people in the US estimated to have diabetes was more than 18 million, or 6.3% of the total population, with about 13 million already diagnosed and another 5 million undiagnosed. Approximately 210,000 of those diagnosed with diabetes, approximately 0.26% of the population for that age group, were younger than 20.63

Traditionally, most children and adolescents with diabetes have type 1, but the proportions are changing dramatically. Before the 1990s, a diagnosis of type 2 diabetes was rare in childhood (according to most reports, less than 4% of all cases). By the year 2000, up to 46% of all newly diagnosed cases of childhood diabetes were type 2 diabetes.33 This problem is not unique to the US, however, with the estimated worldwide prevalence of diabetes increasing from about 30 million in 1985 to 177 million in 2000 and predicted to be at least 300 million by 2025, according to the World Health Organization.64 Type 2 diabetes accounts for about 90% to 95% of the total number of diagnosed cases of diabetes.63

These data do not include gestational diabetes, which is known to complicate approximately 4% of all pregnancies in the US.63 From a public health standpoint, this is of great potential significance, as 5% to 10% of women diagnosed with gestational diabetes will develop type 2 diabetes at some point after delivery.63 Furthermore, an infant of a woman with gestational diabetes is at higher risk for developing hyperinsulinemia and diabetes, with 1.2% having impaired glucose tolerance by age 5, 5.4% by age 5 to 9, and 19.3% by age 10 to 16.65

Paradoxically, in contrast to the large babies classically associated with being offspring of diabetic mothers, a small birth weight, especially if associated with rapid early growth in infancy, is associated with insulin resistance66 or diabetes later in life, possibly due to reduced endocrine pancreatic mass.67

Risk Factors

The four major risk factors for a child to develop type 2 diabetes are family history (including being an infant of a mother with gestational diabetes), ethnicity, obesity, and biologic markers of insulin resistance, including acanthosis nigricans and polycystic ovarian syndrome. Because of these well-known risk factors, it is possible to devise a logical approach to screening for type 2 diabetes. Such guidelines for children and adolescents were proposed by the American Diabetes Association in a consensus statement in 2000.68 These recommendations have been modified slightly and incorporated into an algorithm for screening and diagnosis at our institution (Figure, see page 599).

In addition, gender and puberty appear to be risk factors; females are at slightly higher risk for acquiring type 2 diabetes compared with males (1.7:1),69 and children are most likely to develop type 2 diabetes during adolescence.68 Puberty in both normal and diabetic children is associated with the development of relative insulin resistance, likely attributable mostly to the pubertal increase in growth hormone.68

One might speculate as to why females are more likely to develop type 2 diabetes than males. One reason may be that girls are less likely than boys to participate regularly in vigorous physical activity. In 2001, 57% of high school girls participated regularly in vigorous physical activity, compared with 72.6% of boys.70 Also, girls may be diagnosed earlier than boys, because girls go to the physician's office more regularly for routine visits.71

Family history. Among children who have been diagnosed with type 2 diabetes, 40% to 80% have at least one parent with type 2 diabetes.68 This relationship is consistent with the concordance rate in exogenous obesity, in which there is a 66% chance that a child will be obese if both parents are obese, compared with a 9% chance of a child being obese if both parents are thin.72 In addition, if one identical twin develops type 2 diabetes in adulthood, the other twin has at least a 50% to 90% risk of developing the disease.73

Ethnicity. Several ethnic minority groups, including Native Americans, Hispanics, African Americans, and Asian/Pacific Islanders, are known to be at higher risks than others for developing type 2 diabetes. Among these ethnic groups, perhaps the most studied is the Pima Indian tribe of Arizona. Within the Pima tribe, between 1992 and 1996, there was a prevalence of type 2 diabetes of about 5% in 15- to 19-year-old adolescents, about twice that found in 10- to 14-year-old Pima children over the same time period.68 Similar rates of type 2 diabetes have been observed in young Native Americans of other tribes, in both genders.68

Although no well-controlled study comparing ethnicity risk has been published, extremely high prevalence rates of type 2 diabetes also have been observed in Hispanics and African Americans.68 It is likely that the high risk of type 2 diabetes in Hispanics derives in large part, at least among Mexican Hispanics, from their Native American heritage.74

Obesity. The hallmark of type 2 diabetes is obesity. Approximately 85% of all patients diagnosed with type 2 diabetes are considered clinically overweight or obese,68 and among children with type 2 diabetes, the percentage is even greater. Conventional working definitions for obesity are defined clinically, using normative standards for BMI - weight in kilograms divided by height in meters2. Gender-and age-specific BMI charts are available on the CDC Web site (http:// www.CDC.gov/growthcharts).

Markers of insulin resistance. Acanthosis nigricans is characterized by hyperpigmented and thickened skin, most prominent in intertriginous areas including the neck, axillae, lower abdominal folds, antecubital area, and groin. Mild cases appear hyperpigmented but flat, whereas deep rugation, widening of the pigmented area, and associated skin tags or papillae develop in severe cases. It is most evident in ethnic minority and dark-skinned people and is seen in as many as 90% of children and adolescents with type 2 diabetes.68

Polycystic ovarian syndrome is another condition indicative of insulin resistance, especially in cases associated with obesity. It usually presents with signs of hyperandrogenism, including acne, hirsutism, menstrual irregularities, or infertility. For a complete discussion of this condition, see the article by Mansfield and Reischman on page 733.

Diagnosis

Few would question that an ethnic minority teenager who is profoundly obese, with severe acanthosis nigricans, a positive family history of type 2 diabetes, and a markedly elevated fasting insulin has metabolic pathology similar or identical to full-blown type 2 diabetes,75 and that aggressive treatment with diet, exercise, and lifestyle changes should be initiated early, regardless of the blood glucose. Nevertheless, a diagnosis of diabetes cannot be made unless certain glucose thresholds are met,68 a factor critically important whenever pharmacologic intervention is contemplated.

As noted in the Figure, a diagnosis of diabetes is made whenever any one of three conditions exists:

* Symptoms of diabetes plus casual plasma glucose concentration ≥ 200 mg/dL (11.1 mmol/L);

* Fasting plasma glucose ≥ 126 mg/dL (7.0 mmol/L); or

* 2-hour plasma glucose ≥ 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test (WHO criteria: 75 g glucose).

Note that neither finger-stick blood glucose nor hemoglobin AlC is included as a viable approach to the diagnosis of diabetes. While an elevated hemoglobin AlC test is likely to indicate diabetes, a normal value does not exclude the diagnosis. Although all physicians should know how to properly screen and diagnose diabetes, in a recent survey,76 only 67.7% of pediatricians knew the guidelines for screening patients for type 2 diabetes (overweight children 10 or older with any two risk factors). Respondents did, however, recognize family history (92.9%), obesity (91.5%), race or ethnicity (85%), and signs of insulin resistance (85.7%) as risk factors, while 61.2% incorrectly identified hyperhpidemia as a risk factor.

Distinction Between Type 1 and Type 2 Diabetes

Absolute or almost complete insulin-deficiency characterizes classic type 1 diabetes, whereas insulin-resistance is an almost incontrovertible feature of type 2 diabetes. Unfortunately, all cases are not perfectly clear-cut, especially in children, where many as one-third of those with one type have at least some features common to the other type.77

Children with type 2 diabetes are far more likely to be obese, to have acanthosis nigricans, and to be islet cell, glutamic acid decarboxylase, and insulin antibody negative, and less likely to present in ketoacidosis (5% to 25% present in diabetic ketoacidosis, as opposed to 30% to 40% with Type 1 diabetes)68 or to require insulin treatment. However, there is substantial overlap. Various tests have been devised to distinguish types 1 and 2 in children, including antibody status and determination of residual insulin secretion (insulin levels, if untreated, or C-peptide or proinsulin levels), yet no single test has yet been shown to disalminate very well.68

One recent study78 examined the value of measuring adiponectin and leptin concentrations in patients with type 1 versus type 2. In this study, a determination of the adiponectin/leptin ratio had a sensitivity of 80% to 100% and a specificity of 65% to 91% in differentiating type 1 from type 2 (mean ratio values 6.3 versus 0.3, respectively). Whether these tests will be found useful in larger clinical settings remains to be seen.

Type 2 Diabetes Prevention Trials

Several diabetes prevention trials have been completed and published in recent years, although most have involved adults exclusively. The first such trial, performed in Malmö, Sweden, between 1985 and 199 1,79 examined the effects of lifestyle intervention in a nonrandomized, controlled study design. After 6 years, there was a significant reduction in the cumulative incidence of diabetes in the lifestyle versus usual-care group (28.6% reduction versus 10.6% reduction, respectively) among patients entering the trial with impaired glucose tolerance. Similar positive results of lifestyle intervention have been observed in other trials in China,80 Finland,81 and in the United States.82

The Diabetes Prevention Program trial in the United States is the largest study published to date.82 Inclusion criteria included age of at least 25, BMI ≥ 24 kg/ m2, diagnosis of IGT, and fasting plasma glucose between 95 and 125 mg/dL. Four groups were designed into which patients were randomized: intensive lifestyle, metformin therapy with standard lifestyle advice, troglitazone therapy with standard lifestyle advice (discontinued early due to drug safety concerns), and a control group who received standard lifestyle advice and placebo. DPP results included a 58% lower incidence of diabetes in the lifestyle group and a 31% lower incidence of diabetes in the metformin group, compared with placebo.

More recently, an international, multicenter, randomized controlled trial examined the effect of acarbose in preventing of diabetes in adults.83 These data revealed a 25% lower cumulative incidence of diabetes after 3.3 years in the acarbose group compared with placebo.

Two short-term prevention trials have examined the effects of metformin for prevention of type 2 diabetes in children, but neither was large or long enough to demonstrate actual prevention of diabetes. Freemark and Bursey84 reported data from a study of 29 obese, hyperinsulinemic adolescents with BMIs above 30 kg/m2, fasting plasma glucose concentrations below 110 mg/dL, hemoglobin A1C ≤ 6%, and at least one first- or second-degree relative with type 2 diabetes. This double-blind, placebo-controlled study randomized participants into a metformin (500 mg twice per day) or placebo group. At the end of 6 months, insulin levels in the metformin group had declined relative to those in the placebo group (31.3 ±3.4 to 19.2 ±1.5 µU/rnL, versus 28.0 ±3.2 to 26.4 ±7.7 µU/mL, respectively; P < .02). Glucose levels declined in the metformin group but increased in the placebo group (84.9 ±4.5 to 75.1 ±1.6 mg/dL versus 77.2 ±2.2 to 82.3 ±2.7 mg/dL, respectively; P < .02) over the same period. There were no statistical differences in insulin sensitivity, hemoglobin AlC, serum lipids, or serum lactate in the two groups.

Kay et al.85 studied 24 nondiabetic but hyperinsulinemic obese (BMI above 30 kg/m2) children in a double-blind placebo-controlled trial using metformin at 850 mg twice per day. Participants in both groups were placed on a low-calorie diet (1,500 kcal/d for females and 1,800 kcal/d for males). After 8 weeks, the metformin group had greater weight loss (6.5% ±0.08% versus 3.8% ±0.4%, respectively; P < .01) than the placebo group. In addition, participants in the metformin group had higher insulin sensitivity and lower plasma leptin, cholesterol, triglycerides, and free fatty acid levels than those in the placebo group.

In a randomized double-blind placebo-controlled trial, Jones et al.86 enrolled 86 adolescents ages 10 to 16 and followed them for up to 16 weeks. Patients in the metformin arm had a decrease in hemoglobin A1C by about 1.0% and fasting plasma glucose level by 44 mg/dL, compared with no change in hemoglobin A1C and an increase of 22 mg/dL in the fasting plasma in the control group. They recommended a maximum daily dose in children ages 10 to 16 of 2,000 mg per day (1,000 mg twice per day).

Because the current epidemic of type 2 diabetes in children and adolescents is recent, virtually no data pertaining to its optimal treatment in this age group have been published. Previous clinical treatment trials of type 2 diabetes have focused almost exclusively on adults. Currently, the National Institutes of Health is supporting one such treatment trial in children and adolescents. The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TOD2AY) trial examines the effects of three treatments for safety and efficacy. In this multicenter, double-blind study, the effects of metformin plus placebo, metformin plus rosiglitazone, and metformin plus lifestyle change are examined in obese children and adolescents ages 10 to 17 diagnosed with type 2 diabetes for less than 2 years. Patients with autoimmunity or absolute insulin deficiency are excluded. Participation of an adult family member or guardian is essential for enrollment.

The design is treatment to failure, defined as a hemoglobin AlC ≥ 8% during a 6-month period or an inability to wean off temporary insulin therapy due to metabolic decomposition. Enrollment was initiated in April 2004 and will continue for 3 years, with patients followed for a minimum of 2 years. Study medications and supplies, education materials, and physician visits are provided to participants free of charge. A total of 750 patients are expected to be enrolled to have adequate power to observe a treatment effect. More information on the TOD2AY study may be found on the TOD2AY study Web site at http://www. todaystudy.org.

Treatment

Treatment recommendations for children with type 2 diabetes are scarce, in large part because the appearance of type 2 diabetes in children is a new development.68 Most of the educational materials pertaining to childhood diabetes refer specifically to type 1 diabetes, and those pertaining to type 2 diabetes are targeted at adults and are largely inappropriate for children. Most of the pharmacologic agents available for use in type 2 diabetes have been studied only in adults and are not approved for use in children by the Food and Drug Administration. Thus, today there is widespread use of type 2 diabetes medications among physicians treating children, but neither safety nor efficacy of these medications has ever been documented.

Lifestyle, diet, and exercise. Treatment of type 2 diabetes in children begins with up-to-date and age-appropriate education covering dietary expectations, an exercise or physical activity plan, and appropriate use of medications.87 Usually, this initial education plan requires substantial modification in habits and lifestyle, and establishing rapport between the medical team and the entire family is crucial for both short-term and long-term success. Sensitivity to family resources and cultural appropriateness of recommendations must be considered by all members of the healthcare team. Recommendations for lifestyle changes, including both dietary and physical activity, should be directed to the entire family and all caregivers whenever possible, rather than to the child in isolation.

In general, lifestyle changes require modification in both eating and physical activity habits. However, recommending a change in lifestyle and actually accomplishing such a change may be two vastly different things.88 Although a referral to a dietician is an essential first line of therapy in the patient with nonacute type 2 diabetes, such a referral is rarely, if ever, sufficient to ensure a positive longterm treatment response.

Modest weight loss of 5% to 10% of body weight and modest physical activity of 30 minutes daily are reasonable recommended goals for adults and for most profoundly overweight children and adolescents with diabetes,89 although cessation of excessive weight gain with continued normal linear growth is a reasonable goal for younger children and adolescents who are only slightly overweight. It is well known that physical activity effectively increases insulin sensitivity in children.90 Less well appreciated is the fact that physical activity in children and adolescents can be increased merely as a byproduct of limiting television or computer use to 2 hours daily and removing televisions from children's rooms.31

Medications. Prescribed diet and exercise rarely are adequate for achieving glycemic or weight goals. In adults, successful management of diabetes with diet and exercise occurs less than 10% of the time,68 although similar data in children have not been reported. Thus, most patients require treatment with medications to achieve treatment goals. Although many patients with newly diagnosed type 2 diabetes require initial treatment with insulin, particularly if they are ketotic or in ketoacidosis, some respond well to oral medications for variable lengths of time.87 One dilemma of the prescribing physician, however, as noted previously, is that few of the oral medications used and approved for type 2 diabetes treatment have ever been studied for safety or efficacy or are approved for use in children by the FDA.

Other than insulin, metformin is the only diabetic medication approved by the FDA for use in children. Marketed in the US since 1995, metformin has been in use worldwide for more than 40 years. Pharmacologically, metformin is a biguanide that acts in at least three ways to improve glycemic control. It reduces hepatic glucose production, increases sensitivity to insulin, and reduces intestinal glucose absorption.

If glycemic goals are not met after 3 to 6 months of combined lifestyle modification, including diet and exercise, and metformin, and after addressing any barriers to compliance, a second oral medication may be added. Controversy exists regarding which oral diabetic agent should be chosen as adjunct medication, as none are FDA-approved for use in children. However, several might be considered. Sulfonylureas are among the most widely used oral agents in adults. Second-generation sulfonylureas (including glipizide, glyburide, and glimepiride) are preferred over the first-generation sulfonylureas (including chlorpropamide, tolazamide, tolbutamide, and acetohexamide) because of generally fewer side effects.

The mechanism of action for the sulfonylureas is stimulation of pancreatic beta cells to release insulin, reduction of glucose output from the liver, and increase in insulin sensitivity at peripheral target sites. However, use of the sulfonylurea agents in children and adolescents is problematic due to the risk of hypoglycemia.

Other second-line antidiabetic agents include the meghtinides (including mitiglinide, repaglinide, and nateglinide), which work by increasing insulin secretion, and alpha-glucosidase inhibitors (including acarbose and mightol), which work by reducing carbohydrate absorption in the small intestine. The last class of oral diabetic medications, and perhaps that holding the most promise, are the thiazohdinediones (including rosiglitazone and pioglitazone). These agents function primarily by decreasing hepatic glucose production and increasing insulin sensitivity in the liver, muscle, and fat tissue, although additional biologic actions are under investigation.91

SUMMARY

The full public health effects of the new epidemic of obesity and diabetes in children and adolescents may not be known for many years but are certain to be substantial. Diagnosed diabetes, which is present in only 4.2% of the US population, along with its consequences, already represents approximately 19% of the total personal healthcare expenditures in this country. Between 1997 and 2002, the estimated direct medical cost of diabetes increased from $44 billion to $92 billion, a staggering increase of $8 billion a year.92 In 2002, diabetes annual costs per capita rose by more than 30% to $13,243 per person, compared with the average annual health care costs for persons without diabetes of $2,560.92

An estimate from the CDC indicates that approximately one-third of children born in 2000 will develop diabetes at some time in their life, and nearly onehalf of all Hispanic children born in 2000 will develop diabetes.93 As type 2 diabetes is being diagnosed at an earlier age, more young people can expect to live many more years with diabetes and its complications, adding even further to this already enormous health burden.

An appropriate starting place is recognition of the magnitude of the problem by physicians, politicians, public health policy makers, and other healthcare workers. An aggressive approach to management of diabetes must begin well before the appearance of cardiovascular, eye, renal, and other complications of diabetes appear, and even before obesity leads to diabetes.51 Currently, physicians and other healthcare workers are poorly reimbursed for management of obesity, for diabetes education,94 and for ongoing telephone contact with diabetic patients and families,95 essential for optimal diabetes management. National policies and priorities must be readjusted to emphasize prevention, rather than crisis management, if we are to avoid a catastrophic public health crisis within the next several decades.

REFERENCES

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