- Email: [email protected]
Type 2 Diabetes in Children and Youth
Endocrinol Metab Clin N Am 34 (2005) 659–676
Type 2 Diabetes in Children and Youth Francine Ratner Kaufman, MDa,b,* a
Department of Pediatrics, Keck School of Medicine, University of Southern California at Los Angeles, Los Angeles, CA, USA b Division of Endocrinology and Metabolism, Children’s Hospital Los Angeles, Los Angeles, CA, USA
In 2000, then-Surgeon General David Satcher announced that the epidemic of obesity in the United States was increasingly affecting children and adolescents [1]. At the time of the Surgeon General’s announcement, approximately 16% of youth were categorized as being overweight, defined as a body mass index (BMI) greater than the 95th percentile for age and gender [2]. Concomitant with the rise in childhood overweight is a corresponding increase in the incidence of the metabolic syndrome [3] and type 2 diabetes in pediatric subjects [4–6]. Before the 1990s, it was rare for most pediatric centers to have patients with type 2 diabetes. By 1994, type 2 diabetes patients represented up to 16% of new cases of diabetes in children in urban areas [7], and by 1999, depending on geographic location, the range of percentage of new cases of type 2 was between 8% and 45% [8]. Type 2 diabetes, which occurs mainly in ethnic minorities in the United States [9], also has been described in children in a number of countries throughout the world [10]. A period of prediabetes, defined as either elevated fasting glucose levels or impaired glucose tolerance, occurs before the development of frank type 2 diabetes [11]. Type 2 diabetes in children and youth, as in adults, is caused by the combination of insulin resistance and relative b-cell secretory failure. Plasma insulin concentrations appear normal or elevated, but there is a loss of first-phase insulin secretion that cannot compensate for underlying insulin resistance [12]. There are a number of genetic and environmental risk factors for insulin resistance and limited b-cell reserve, including ethnicity, obesity, sedentary behavior, family history of type 2 diabetes, puberty, low birth weight, and female gender [13].
* Division of Endocrinology and Metabolism, Children’s Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027. E-mail address: [email protected] 0889-8529/05/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ecl.2005.04.010 endo.theclinics.com
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Type 2 diabetes in pediatric subjects has a variable presentation, although many children present with symptoms caused by elevated glucose [9]. There is an associated increase in glycosylated hemoglobin (HbA1c). Few pediatric subjects with type 2 diabetes can be treated with diet and exercise alone; therefore, pharmacologic therapy is most often required. Depending on initial glucose levels and the degree of symptoms caused by hyperglycemia, practitioners usually prescribe metformin for those subjects who are mildly affected, or subjects begin insulin therapy if they have more significant hyperglycemia [13]. Relatively few pediatric subjects use a secretagogue, a thiazolidinedione, or combination therapy. Unfortunately, while they are undergoing the present pharmacologic regimens, many patients appear unable to achieve glycemic targets over the long term. Specific treatment algorithms for pediatric patients with type 2 diabetes that are aimed at achieving glycemic targets have not been investigated in youth [8]. The ongoing Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) trial, sponsored by the National Institutes of Health, will investigate best treatments for type 2 diabetes in pediatric subjects and will provide evidence for improving the outcome of pediatric type 2 diabetes. Epidemiology of type 2 diabetes in pediatric subjects Between 1982 and 1994, a 10-fold increase in type 2 diabetes appeared in African-American patients in Cincinnati, OH [7]. By 1994, one third of new cases of diabetes in children and youth was attributed to type 2, with an odds ratio of 6.1 for the disease to develop in African-American girls and 3.5 in African-American boys, compared with whites. From 1994 to 1998, the proportion of new cases of pediatric diabetes in Florida attributed to type 2 increased from 9.4% to 20% [14]. In Mexican-American youth younger than 17 years of age with diabetes living in Ventura County, CA, 31% were found to have type 2 disease, as reported in 1998 [15]. In Arkansas, children as young as 8 years of age were reported to have type 2 diabetes [16]. In 1996, the Indian Health Service estimated diabetes prevalence for 15- to 19year-old children to be 0.45%, which was an increase of 54% from 1988. The prevalence of type 2 diabetes in American- Indian/Native American and First Nations Canadian youth is higher than that among other ethnic minorities [17–19]. In all groups, there was a skewed female:male gender ratio. For Native Americans the ratio was as high as 4 to 6:1, respectively, whereas for other groups, it was closer to 1.7:1 for females compared with males. The prevalence of type 2 diabetes increased in other countries of the world where there are predominantly high-risk ethnic and racial groups [20]. For example, in Thailand, among newly diagnosed children and adolescents, type 2 diabetes increased from 5% of all cases during 1986 to 1995 to 17.9% between 1996 and 1999 [21]. Japan saw an approximate 4-fold rise in the incidence of type 2 diabetes in 6- to 15-year-olds [22]. As a result, type 2 diabetes accounts for 80% of childhood diabetes in Japan.
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Insulin resistance The multiple factors that contribute to insulin resistance are shown in Box 1. Obesity may be the most important factor in the development of insulin resistance and type 2 diabetes [23–25]. Hyperinsulinism and decreased insulin sensitivity are seen in overweight adolescents. Approximately 50% of the variance seen in insulin sensitivity is accounted for by adiposity. As in adults, it is visceral fat, rather than total body fat, that correlates with basal and stimulated insulin levels and inversely correlates with insulin sensitivity [26–28]. In a cross-sectional study of 14 adolescents with impaired glucose tolerance (IGT) and matched controls, those with IGT had higher visceral and lower subcutaneous abdominal fat and decreased first-phase insulin secretion and glucose disposition index [29]. Intramyocellular fat content (as measured by nuclear magnetic resonance
Box 1. Factors that contribute to insulin resistance 1. Obesity/sedentary lifestyledThe marked increase in the incidence of type 2 diabetes has mirrored the increase in the rate of childhood and adolescent overweight. Along with a marked increase in the consumption of high calorie, high fat-containing foods, the increase in sedentary life-style among America’s children and teens has contributed to the epidemic of type 2 diabetes. 2. Race/ethnicitydAfrican-American and Hispanic youth have reduced insulin sensitivity compared with European-American children. 3. Positive type 2 diabetes family historydAt least 85% of children diagnosed have affected family members. 4. PubertydThe peak age of diabetes onset is during puberty, and puberty is associated with physiologic changes such as augmentation of growth hormone secretion, which causes insulin resistance. 5. Polycystic ovary syndrome (PCOS)dType 2 diabetes is more common in females (ratio of 1.7:1 female:male), and 15% of teenage subjects with PCOS have diabetes, and a one third have impaired glucose tolerance. 6. Intrauterine factorsdThere is a higher incidence of type 2 diabetes in those whose mothers had diabetes during pregnancy, in low birth weight infants, and in those with small head circumference. From Kaufman FR. Diabetes mellitus in childhood and adolescence. In: Rakel RE, Bope ET, editors. Conn’s current therapy. Philadelphia: Elsevier Science; 2003.
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spectroscopy) showed a strong positive correlation with insulin resistance and with 2-hour post-load plasma glucose, suggesting that intramyocellular fat may be important in the pathogenesis of insulin resistance and IGT. Obesity is not only a risk for insulin resistance and diabetes, it also is associated with an increased risk for cardiovascular disease caused by the elevation of lipid and blood pressure levels [30]. Puberty is a state of relative insulin resistance, and an increase in basal and stimulated insulin secretion occurs during the progression through normal puberty [31,32]. Insulin-mediated glucose disposal has been shown to be on average 30% lower in Tanner puberty stages 2 to 4 compared with the rate of disposal seen in Tanner stage 1 children during hyperinsulinemic euglycemic clamp studies. This change in insulin sensitivity is caused by the augmentation of the growth hormone–insulin-like growth factor axis, as evidenced by the fact that growth hormone supplementation in non-growth hormone-deficient adolescents resulted in lower insulin-stimulated glucose metabolism and hyperinsulinemia [33], which was not seen with supplementation of testosterone and dihydrotestosterone [34]. African American children are more insulin-resistant than white children [35–38]. African American teens are more obese and have higher insulin levels to oral glucose and higher insulin-to-glucose ratios compared with their white counterparts in the Bogalusa Heart Study [39–41]. Subsequently, African American subjects have been shown to have lower resting energy expenditure, higher fasting and first-phase insulin levels, and lower insulin sensitivity [42]. In a comparison of African American and white children with obesity and similar insulin sensitivity levels, African Americans had lower hepatic glucose output, lower total levels of cholesterol and lowdensity lipoprotein (LDL) cholesterol, lower triglyceride levels, and considerably lower visceral fat levels. Visceral adiposity was associated with lower insulin sensitivity in both groups. This was compensated for by higher insulin secretion in whites but not in African Americans [43]. These findings suggest a greater diabetogenic risk of obesity among African Americans but greater atherogenic risk among whites. Latino children have been reported to have lower insulin sensitivity. Studies suggest that increased total adiposity and visceral fat independently contribute to lower insulin sensitivity in Latino children [44]. Youth with type 2 diabetes have a strong family history of this disease. Between 45% and 80% of pediatric subjects have been reported to have at least one parent with diabetes; and 74% to 100% of subjects have reported having a first- or second-degree relative [45]. Even in healthy, prepubertal African American children, a family history of diabetes has been associated with an approximate 20% reduction in insulin sensitivity [46]. In Pima Indians, it has been shown that the cumulative incidence of type 2 diabetes was highest in the offspring if both parents had diabetes [47]. In addition, up to 28% of youth affected by type 2 have a positive family history of cardiovascular disease [48].
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There are gender differences in youth with type 2 diabetes. Girls are 1.7 times more likely than boys to be affected. Hypothetically, this difference is caused by elements of the polycystic ovary syndrome (PCOS) [49]. Studies have shown that insulin resistance, abnormal first- phase insulin release, and the lack of beta-cell compensation for the degree of insulin resistance are seen in girls with PCOS [50–52]. The same mechanism has been seen in adult women with PCOS. Fifteen percent of women with PCOS have diabetes, and one third of whom have impaired glucose olerance. The predisposition to type 2 diabetes may be programmed in utero [53– 55]. Maternal undernutrition may lead to a reduced endocrine pancreatic mass. This hypothesis is supported by the fact that adults with type 2 diabetes have lower birth weight and smaller head circumference [56]. Recent data from Taiwan confirmed this observation in children [57]. A study of 6- to 18-year-old children has shown a U-shaped relationship, with the highest risk for type 2 diabetes in children with a low (%2.5 kg) or a high (R4.0 kg) birth weight and lowest for those with a normal birth weight (3–3.5 kg). This U-shaped relationship was seen when adjustment for other factors, such as gestational diabetes, family history of diabetes, and socioeconomic status, were made [57]. A rapid weight gain in early childhood has been shown to be a risk factor for the development of obesity and glucose intolerance in adulthood [58,59]. In a longitudinal study of 8760 subjects born in Helsinki between 1934 and 1944, a rapid increase in BMI after age 2 increased the risk of type 2 diabetes in both high and low birth weight groups [60]. Maternal diabetes also is a risk for later development of insulin resistance and type 2 diabetes. Between 1977 and 1983, a study [61] was conducted to correlate amniotic fluid insulin levels measured between weeks 32 and 38 in pregnancies complicated by pregestational or gestational diabetes with the longitudinal assessment of insulin levels in the offspring. Oral glucose tolerance tests were followed in the offspring at 18-month intervals for up to 16 years, at which time 19.3% of the cohort had IGT. In this group with IGT, 12 of 36 subjects had elevated amniotic fluid insulin levels when measured between 32 and 38 weeks gestation compared with 1 of 27 subjects with normal amniotic fluid insulin levels. Therefore, the infants at particular risk were those whose mothers had poorly controlled diabetes. The specific environmental role of maternal hyperglycemia, as separate from maternal genetics, has been demonstrated in Pima Indians, in whom offspring born after the mother developed diabetes were more obese as children and more likely to have diabetes in their 20s than were their siblings born before their mothers developed diabetes [62]. No such differences were seen before and after diabetes was developed by fathers. The dysregulation of insulin secretory dynamics is required for the development of type 2 diabetes [63]. This dysregulation particularly affects first-phase insulin release. As a consequence of multiple factors, including lipotoxicity that is the consequence of obesity and visceral adiposity, and
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glucotoxicity resulting from less than optimal glycemic control and intrinsic beta-cell abnormalities that may be genetic, there is progressive decline in beta-cell function. It appears that apoptosis may play a role in the decline of the beta-cell mass and that marked improvement in glucose regulation may inhibit the apoptotic process. This makes it imperative that aggressive treatment protocols be developed that can reverse the negative effects of both glucotoxicity and lipotoxicity.
Metabolic syndrome and prediabetes Metabolic syndrome is a constellation of metabolic derangements that include obesity, insulin resistance, dyslipidemia, and hypertension and predict both type 2 diabetes mellitus and premature coronary artery disease. An analysis of cross-sectional data obtained from the Third National Health and Nutrition Examination Survey III, 1988 to 1994 [3], revealed that a large percentage of overweight children and adolescents were affected by metabolic syndrome. The study sample consisted of 2430 subjects aged 12 to 19 years. Metabolic syndrome was defined as a waist circumference greater than the 90th percentile for age and gender, blood pressure at or above the 90th percentile for age, gender, and height, fasting plasma glucose level greater than 110 mg/dL, high-density lipoprotein (HDL) cholesterol, and triglyceride levels greater than the 90th percentile for age. The overall prevalence of the metabolic syndrome in adolescents was 4.2%. It was more common in males (6.1%) than females (2.1%) and was more frequent in Mexican Americans (5.6%) and whites (4.8%) than in black subjects (2.0%). Almost half of the subjects (41%) had one or more risk factors, whereas 14% of the subjects had two or more. High triglyceride levels and low HDL cholesterol levels were most common, whereas high fasting plasma glucose levels were the least common. Further reports have shown that the metabolic syndrome is found in 30% of overweight youth with a family history of type 2 diabetes [64] and in 50% of subjects with severe obesity [65]. Prediabetes is defined as elevated fasting (R100 and %126 mg/dL) or 2-hour post-glucose load (R140 and %199 mg/dL) plasma glucose levels. Prediabetes is common in children and youth, as well as in adults [11]. After oral glucose tolerance testing, 25% of obese children 4 to 10 years of age and 21% of obese adolescents 11 to 18 years of age were found to have IGT. The best predictor of IGT was insulin resistance. In this limited study of 167 subjects, IGT was found in all ethnic groups, and overt type 2 diabetes was predicted by determining that there was an element of beta-cell failure as assessed by a reduced ratio of the 30-minute change in the insulin concentration compared with the 30-minute change in the plasma glucose level. IGT was reported in 28% of overweight Hispanic youth with a positive family history of type 2 diabetes [66].
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Screening for type 2 diabetes The diagnosis of diabetes in children and youth is made using the same American Diabetes Association criteria as those established for adults [45]. The diagnosis can be made when the subject is symptomatic and has a plasma glucose level greater than 200 mg/dL, by screening asymptomatic children and youth and finding a fasting plasma glucose level greater than 126 mg/dL, or by finding a 2-hour plasma glucose level greater than 200 mg/dL during an oral glucose tolerance test. In asymptomatic children, abnormal glucose levels must be confirmed on another day. A Consensus Panel convened by the American Diabetes Association in 2000 [5] recommended that testing for type 2 diabetes in at-risk youth be performed as outlined in Box 2. The recommendation to screen for type 2 diabetes was made, in the absence of sufficient data concerning the natural history of type 2 diabetes in pediatric subjects, because it is: common, serious, there is a prolonged latency period, screening is sensitive and specific, and treatment is available. A major consequence of the appearance of type 2 diabetes in the younger age group is that subjects with diabetes will
Box 2. Recommendations for screening for type 2 diabetes in children and youth Criteria Overweight (BMI ‚ 85th percentile for age and gender, weight for height ‚ 85th percentile, or weight ‚ 120th percentile of ideal for height) Plus Any two of the following risk factors: Family history of type 2 diabetes in first- or second-degree relatives Race and ethnicity (American Indian, African American, Hispanic, Asian/Pacific Islander) Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, PCOS) Age of initiation: age 10 years or at onset of puberty if puberty occurs at a younger age Frequency: every 2 years Test: fasting plasma glucose test is preferred Adapted from American Diabetes Association. Type 2 Diabetes in children and adolescents: consensus statement. Diabetes Care 2000;23(8):381–9; with permission.
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have a longer duration of the disease, which will increase the risk of the early development of both microvascular and macrovascular complications. The at-risk population that should be screened has been well defined. They are children and youth with obesity and a positive family history of type 2, those belonging to certain racial and ethnic groups such as American Indian/Native American, African American, Hispanic American, and Asian/Pacific Islander, and those having evidence of insulin resistance with hypertension, acanthosis nigricans, dyslipidemia, and polycystic ovarian disease. The Consensus Panel [5] also advocated for rigorous studies to be performed to establish the benefit of screening and to determine the contribution of the various factors involved in establishing risk.
Presentation of type 2 diabetes in youth At the time of diagnosis, it is important to obtain the necessary data to establish as firmly as possible the diagnosis of type 2 diabetes versus type 1 disease. A diagnosis can be made by historical, physical, and laboratory data as shown in Table 1 [4–6,9]. From the standpoint of the medical history, those patients who have type 2 have a more insidious progression of diabetes symptoms than those with type 1. Although the presence of ketosis and diabetic ketoacidosis (DKA) does not exclude type 2 diabetes as the appropriate diagnosis, they are usually less common and less severe. Ketonuria usually is present in type 1 patients at presentation, and 40% of them have DKA, whereas 33% of those with type 2 have ketonuria, and 5% to 10% of these patients have generally mild DKA. With regard to family
Table 1 How to distinguish type 1 and 2 diabetes Type 1
Type 2
With the increase in overweight subjects, up to a quarter may be overweight Short course 35%–40% of subjects have ketoacidosis
85% of subjects are overweight
5% of subjects have first- or second-degree relatives with type 1 diabetes Increase in other autoimmune disorders
C-peptide and insulin levels decrease, although they may be preserved during the remission phase Predominantly white Data from Refs. [5,6,8].
Indolent course 33% of subjects have ketonuria and 5%–25% have mild ketoacidosis 74%–100% with first- or second-degree relatives with type 2 diabetes Brought on by insulin resistance, hypertension, dyslipidemia, PCOS, acanthosis nigricans C-peptide and insulin levels increase, although they could be low at diagnosis with glucotoxicity and lipotoxicity Minority youth
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history, 5% of type 1 patients will have a first- or second-degree relative affected by type 1 diabetes. In contrast, virtually all patients with type 2 diabetes will have at least a second-degree relative who is affected, and from 45% to 80% of patients will have an affected parent. To determine whether relatives have type 1 or type 2, information concerning the age at onset, weight, and treatment of affected family members can be helpful. On physical examination, the presence of acanthosis nigricans will be found in 60% to 90% of subjects with type 2. In addition, many type 2 subjects will come to medical attention and be diagnosed as the result of investigating a variety of complaints such as obesity, sleep apnea, hyperlipidemia, hypertension, amenorrhea, and hirsutism associated with PCOS. Subjects with type 1 diabetes may have evidence of other autoimmune disorders. Laboratory evaluation should include assessment for the presence of autoantibodies against islet antigens and assessment of endogenous insulin reserve by serum insulin and C peptide measurement. Eighty-five percent of type 1 subjects will have the presence of one or more antibodies to isletderived antigens (positive anti-glutamic acid decarboxylase [GAD] antibodies, islet cell antibodies, and insulin autoantibodies). Although the presence of autoantibodies should be the hallmark for differentiating type 1 from type 2 diabetes, there is overlap [67]. In a study of 48 type 2 and 39 type 1 subjects, the diagnosis of type 2 was made on the basis of ethnicity, a firstdegree relative with type 2, a BMI greater than 24 kg/m2, and the presence of acanthosis nigricans [68]. DKA was present in 33% of type 2 subjects compared with 53% of type 1 subjects, and 81% of the type 2 subjects were islet cell antibody-positive, 30% were positive for anti-GAD, and 35% were positive for insulin autoantibodies. Insulin and C peptide levels may be deceptively low in type 2 patients at the time of presentation as the result of acute glucotoxicity, which impairs insulin secretion. However, this changes to the more typical pattern once glucotoxicity has resolved as the result of treatment [69]. Nonalcoholic fatty liver disease (NAFLD) in children is a growing problem and is frequently associated with obesity, insulin resistance, and type 2 diabetes. NAFLD is characterized by the presence of macrovesicular steatosis with parenchymal inflammation. In addition, youth with type 2 diabetes and obesity can have histologic findings that range from fatty changes in the liver alone to non-alcoholic steatohepatitis, cirrhosis, and finally to liver failure [70]. Treatment of type 2 diabetes in children and youth The overall treatment protocol in pediatric subjects includes diabetes education for the patient and family, lifestyle modification with emphasis on increasing exercise and following an appropriate nutrition plan, the setting of glycemic targets, and pharmacotherapy. The glycemic target should be to achieve a HbA1c of less than 7.0%; however, this target may be difficult to
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achieve in children and adolescents because of physiologic and psychologic reasons. Data on the dietary treatment of type 2 diabetes in children are scarce. A study of 20 children on a short-term ketogenic, very low calorie diet showed improvement in glycemic control, BMI, and the ability to discontinue diabetes medications [71]. Prospective, randomized studies to evaluate longterm outcomes and safety of this diet have not been performed. Less than 10% of pediatric subjects diagnosed with type 2 diabetes can achieve glycemic targets by following lifestyle interventions alone [13]. As a result, pharmacotherapy is required, and although there are many agents available to improve the metabolic abnormalities seen in subjects with type 2 diabetes, there are sparse data concerning their use in pediatrics [72–74]. A modification of the American Diabetes Association treatment scheme for pediatrics is given in Fig. 1. Metformin is approved in pediatrics. Metformin has been found to significantly improve glycemic control in youth with type 2 diabetes without serious adverse events [75]. However, gastrointestinal side effects are common in youth treated with metformin. Metformin is the oral agent of choice in pediatric type 2 diabetes. It can be used as the initial therapy for those without significant symptoms caused by hyperglycemia, or it can be added after glucose levels improve with insulin treatment. Other oral hypoglycemic agents, such as sulfonylureas, meglitinides, thiazolidinediones, and a-glucosidase inhibitors, have not been well studied in pediatric subjects. Unique issues concerning the use of these agents in pediatrics are described in Table 2. Insulin is used in youth with type 2 diabetes more often than it is used in adults. The reason for this is the likelihood that significant insulin deficiency
3. Combination Therapy DKA, BG
1. Diet Exercise
Metformin + Sulfonylurea Metformin + insulin Metformin + meglitinide Metformin + TZD
Glycemic goals not achieved Glycemic goals not achieved
2. Monotherapy Metformin Insulin Sulfonylurea
4. Insulin Therapy Intermediate + fast-acting bid Multiple injections ≥ 3 injections CSII
Fig. 1. American Diabetes Association treatment schema for type 2 diabetes, modified for Children and Youth. (Modified from American Diabetes Association. Clinical practice recommendations. Diabetes Care 1999;22(Suppl):S1–114; with permission.)
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Table 2 Advantages and disadvantages of pharmacologic therapy in pediatric subjects for type 2 diabetes Class
Advantages
Disadvantages
Insulin
Hypoglycemia Weight gain Need for injections
Sulfonylureas
Meglitinides
Biguanides
Metformina
a-Glucosidase inhibitors Thiazolidinediones
Overcomes glucotocity Will control all patients Flexibility in dosing Data in pediatric patients Rapid-acting Well-tolerated Broad range of dosing Improves insulin secretion Used with meals No lag period Flexibility of lifestyle Low risk of hypoglycemia Improves insulin resistance High initial response rate Less weight gain or loss Advantageous lipid profile Improves insulin resistance Decreases hirsutism, free androgen, LDLs, luteinizing hormone, and 17a-hydroxyprogersterone levels. Good safety profile No weight gain or loss Dose coupled with meals Corrects insulin resistance Once-daily dosing Improves lipids (pioglitazone)
Hypoglycemia Weight gain Hypoglycemia Weight gain Unknown long-term effects
GI side effects Risk of lactic acidosis Risk of impaired renal, hepatic, and cardiac function d
Needs high carbohydrate diet Flatulence and GI pain Cannot treat hypoglycemia Liver disease (rosiglitazone) Delayed action Weight gain
a For adolescent girls who have PCOS, evidence is emerging that metformin may be the agent of choice. Studies have shown the advantages indicated above. Modified from Kaufman FR. Type 2 diabetes in children and youth: A new epidemic. J Pediatr Endocrinol Metab 2002;15(1):737–44; with permission.
may be common among adolescents who are symptomatic at presentation. In addition, insulin is familiar to pediatricians and pediatric endocrinologists as the treatment of choice when there is uncertainty about whether a patient has type 1 or type 2 diabetes, and it has efficacy in ameliorating metabolic decompensation. The results of a survey of 130 clinical practices of members of the Lawson Wilkins Pediatric Endocrine Society reported in 2000 that 48% of subjects were treated with insulin and 44% with oral agents [76]. Those patients who received insulin were generally given two injections per day; of those on oral agents, 71% received metformin, 46% received sulfonylureas, 9% received thiazolidinediones, and 4% received meglitinide. Although at diagnosis, the majority of affected youth are initially placed on monotherapy with insulin or metformin, monotherapy is insufficient to control glycemia in most
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pediatric patients over the long-term. Failure to respond to monotherapy is similar to that described in adults in the UK Prospective Diabetes Study [77]. As the result of an apparent progressive loss of beta-cell function, which may be caused in part by poor glycemic control itself, patients are required to be placed on multiple pharmacologic agents years after diagnosis, at a time when microcirculatory complications and early macrovascular disease, dyslipidemia, and hypertension may develop. These complications and comorbidities also require treatment. The ADA has recently published consensus-based guidelines for the management of dyslipidemia in children with diabetes [78]. It was recommended that lipid levels should be measured every 2 years, blood glucose treated aggressively, and dietary counseling given to those with elevated lipid levels. Because of a lack of data on the use of pharmacotherapy for dyslipidemia in pediatrics and scant data on the progression of cardiovascular disease in youth, the level of LDL cholesterol that requires pharmacologic intervention was set high (160 mg/dL) by the consensus panel. However, for patients with additional cardiovascular risk factors (including blood pressure, family history, and smoking status), clinical discretion is indicated, and pharmacotherapy may be begun at LDL levels greater than 130 mg/dL or even lower in high-risk youth. Hypertension is a comorbidity of type 2 diabetes in youth and is a major risk factor for nephropathy and atherosclerosis. Blood pressure (BP) should be measured in all children with type 2 diabetes during diabetes health care visits. If hypertension, defined as a BP greater than the 95th percentile for age and gender, does not respond to lifestyle changes, the first line therapy should be administration of an angiotensin-converting enzyme inhibitor. Angiotensin II receptor antagonists are reserved as second line therapy because there are few primary data on their use in pediatric subjects. Extensive data on the long-term outcome of type 2 diabetes in youth is not available presently. However, there are data on outcomes in NativeAmerican youth. It appears that not only are American Indian/Native Americans and First Nation Canadians at highest risk to develop type 2 diabetes but also their outcome is poor. Dean and Flett [79] have reported that in young adults 18 to 33 years of age who were diagnosed before age 17, there was a 9% mortality rate, a 6.3% dialysis rate, and a 38% pregnancy loss caused by poor glycemic control.
The Treatment Options for type 2 Diabetes in Adolescents and Youth trial Although there are large numbers of clinical trials that assess the efficacy of treatment regimens in adults with type 2 diabetes, there are few efforts in children and youth. As a result, in 2002, the National Institutes of Diabetes, Digestive and Kidney Diseases funded multicenter primary diabetes prevention and diabetes treatment trials, together entitled the Studies to
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Treat Or Prevent Pediatric Type 2 Diabetes (STOPP-T2D). The TODAY trial, the treatment trial of STOPP-T2D, consists of investigators associated with twelve clinical centers (Baylor College of Medicine, Case Western Reserve University, Children’s Hospital Los Angeles, Children’s Hospital of Philadelphia, Children’s Hospital of Pittsburgh, Massachusetts General Hospital, Joslin Diabetes Center, State University of New York Upstate Medical University, University of Colorado Health Sciences Center, University of Oklahoma Health Sciences Center, University of Texas Health Sciences Center at San Antonio, Washington University in St Louis, and Yale University). The trial is planned to enroll 750 children and youth aged 10 to 17 years old who have been diagnosed with type 2 diabetes for less than 2 years. The trial will compare the efficacy of three treatments over 2 to 5 years. Study subjects will be randomized to one of three treatment assignments: metformin alone, metformin plus rosiglitazone, and metformin plus an intensive lifestyle program. The lifestyle program goals include weight loss and increased physical activity and will consist of weekly meetings with the youth and a designated adult for up to 24 weeks and then transition to maintenance meetings monthly for the duration of the trial. A lifestyle intervention pilot was performed at the 12 sites for the purposes of training and optimizing the intervention. Major eligibility criteria are diagnosis of diabetes by ADA criteria, with the absence of islet autoantibodies and fasting C peptide levels greater than 0.6 ng/mL, diabetes duration of less than 2 years, a BMI greater than the 85th percentile, age 10 to 17 years old, and the presence of a family member who will participate in the child’s treatment. Before randomization, subjects will enter a ‘‘run-in’’ phase for 2 to 6 months. During the run-in phase, patients will receive a standard diabetes education curriculum that is mastery based. They will be required to demonstrate adherence to certain diabetes management tasks such as taking medication, record keeping, glucose monitoring, and maintaining clinic appointments. To complete the run-in phase, participants will need to achieve an HbA1c level of less than 8% on a regimen of 1000 to 2000 mg/day of metformin alone. The primary outcomes of the TODAY trial are to determine how well and for how long each treatment approach controls blood glucose levels. The primary outcome is timed to treatment failure, defined as a HbA1c level greater than 8%, for 6 months. At treatment failure, subjects will be placed on an insulin rescue regimen with insulin glargine. Glargine will be titrated to control fasting blood glucose and improve HbA1c levels and, if this cannot be achieved, the subject’s insulin regimen will be adjusted at the discretion of the investigator. Secondary outcomes include measures of beta cell function and insulin resistance, body composition, nutrition, physical activity and aerobic fitness, cardiovascular risk factors, microvascular complications, quality of life, and psychologic outcomes. The influences of individual and family behaviors on treatment response and the relative cost
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effectiveness also will be evaluated. Critical design issues were developed to address the recruitment and retention of diverse study subjects in a complex treatment trial. During the summer of 2004, the first TODAY subjects entered the run-in phase of the study in the 12 centers, and as subjects completed run-in, they were randomized to the treatment arms. It is the hoped that referrals to the 12 centers will take place for subjects living in close proximity to one of the 12 centers. Summary A dramatic increase has occurred in the number of children and youth diagnosed with type 2 diabetes over the last decade. Doubtless, this epidemic follows the tremendous increase in childhood obesity around the world. Youth diagnosed with type 2 diabetes, in addition to being overweight, are members of ethnic minorities, have a positive family history of type 2 disease, most often involving a parent, and have acanthosis nigricans. Much still needs to be learned as to why this epidemic is occurring at the present time with regard to other environmental factors that might promote insulin resistance and beta-cell failure. We need to determine whether there are significant numbers of children with diabetes who are undiagnosed and how to design effective screening strategies. The TODAY trial will help to determine best treatment strategies to improve glycemia, reduce complications, and ameliorate insulin resistance and beta-cell failure. Because type 2 diabetes is emerging as a worldwide public health problem, improved care for affected youth must be coupled with a focus on prevention.
References [1] Satcher D. The Surgeon General’s call to action to prevent and decrease overweight and obesity. Rockville, MD: Public Health Service, Office of the Surgeon General, United States Department of Health and Human Services; 2001. Available at: http://www.surgeongeneral. gov/topics/obesity/calltoaction/CalltoAction.pdf. [2] Flegal KM, Carroll MD, Ogden CL, et al. Prevalence and trends in overweight among US children and adolescents, 1999–2000. JAMA 2002;288:1723–7. [3] Cook S, Weitzman M, Auinger P, et al. Prevalence of a metabolic syndrome phenotype in adolescents: findings from the third National Health and Nutrition Examination Survey, 1988–1994. Arch Pediatr Adolesc Med 2003;157:821–7. [4] Glaser NS, Jones KL. Non-insulin-dependent diabetes mellitus in Mexican-American children. West J Med 1998;168:11–6. [5] American Diabetes Association. Type 2 diabetes in children and adolescents: consensus statement. Diabetes Care 2000;23:381–9. [6] Rosenbloom AL, Joe JR, Young RS, et al. Emerging epidemic of type 2 diabetes in youth. Diabetes Care 1999;22:345–54. [7] Pinhas-Hamiel O, Dolan LM, Daniels SR, et al. Increased incidence of non-insulindependent diabetes mellitus among adolescents. J Pediatr 1996;128:608–15.
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[8] Silverstein JH, Rosenbloom AL. Type 2 diabetes in children. Curr Diab Rep 2001;1:19–27. [9] Fagot-Campagna A, Petit DJ, Engelgau MM. Type 2 diabetes among North American children and adolescents: an epidemiological review and a public health perspective. J Pediatr 2000;136:664–72. [10] Alberti G, Zimmet P, Shaw J, et al for the Consensus Workshop Group. Type 2 diabetes in the young: the evolving epidemic. Diabetes Care 2004;27:1798–811. [11] Sinha R, Fisch G, Teague B, et al. Prevalence of impaired glucose tolerance among children and adolescents with marked obesity. N Engl J Med 2002;346:802–10. [12] Porte D Jr. Banting lecture 1990: Beta-cells in type II diabetes mellitus. Diabetes 1991;40: 166–80. [13] Kaufman FR. Type 2 diabetes in children and youth: a new epidemic. J Pediatr Endocrinol Metab 2002;15:737–44. [14] Macaluso CJ, Bauer UE, Deeb LC, et al. Type 2 diabetes mellitus among Florida children and adolescents, 1994 through 1998. Public Health Rep 2002;117:373–9. [15] Neufeld ND, Raffel LF, Landon C, et al. Early presentation of type 2 diabetes in MexicanAmerican youth. Diabetes Care 1998;21:80–6. [16] Pihoker C, Scott CR, Lensing SY, et al. Non-insulin dependent diabetes mellitus in AfricanAmerican youths of Arkansas. Clin Pediatr (Phila) 1998;37:97–102. [17] Dean HJ, Young TK, Flett B, et al. Screening for type 2 diabetes in aboriginal children in Northern Canada. Lancet 1998;352:1523–4. [18] Kim C, McHugh C, Kwok Y, et al. Type 2 diabetes mellitus in Navajo adolescents. West J Med 1999;170:210–3. [19] Savage PJ, Bennett PH, Senter G, et al. High prevalence of diabetes in young Pima Indians: evidence of phenotypic variation and in a genetically isolated population. Diabetes 1979;28: 837–42. [20] Bloomgarden ZT. Type 2 diabetes in the young. Diabetes Care 2004;27:998–1010. [21] Likitmaskul S, Kiattisathavee P, Chaichanwatanakul K, et al. Increasing prevalence of type 2 diabetes mellitus in Thai children and adolescents associated with increasing prevalence of obesity. J Pediatr Endocrinol Metab 2002;87:1017–23. [22] Kitagawa T, Owada M, Urakami T, et al. Increased incidence of non-insulin dependent diabetes mellitus among Japanese school children correlates with an increased intake of animal protein and fat. Clin Pediatr (Phila) 1998;37:111–6. [23] Caprio S, Tamborlane WV. Metabolic impact of obesity in childhood. Endocrinol Metab Clin North Am 1999;28:731–47. [24] Caprio S. Insulin resistance in childhood obesity. J Pediatr Endocrinol Metab 2002;15: 487–92. [25] Caprio S, Bronson M, Sherwin RS, et al. Co-existence of severe insulin resistance and hyperinsulinemia in preadolescent obese children. Diabetologia 1996;39:1489–97. [26] Caprio S, Hyman DL, Limb C, et al. Central adiposity and its metabolic correlates in obese adolescent girls. Am J Physiol 1995;269:E118–26. [27] Arslanian S, Suprasongsin C. Insulin sensitivity, lipids, and body composition in childhood: is ‘‘syndrome X’’ present? J Clin Endocrinol Metab 1996;81:1058. [28] Robinson A, Wheeler L, Bianchi R, et al. Effect of insulin on glycerol in obese adolescents. Am J Physiol 1998;274:737. [29] Weiss R, Dufour S, Falk-Petersen K, et al. Increased intramyocellular lipid content in obese adolescents with impaired glucose tolerance. Diabetes 2002;51(Suppl 2):A68. [30] Morrison JA, Sprecher DL, Barton BA, et al. Overweight, fat patterning, and cardiovascular disease risk factors in black and white girls: the National Heart, Lung and Blood Institute Growth and Health Study. J Pediatr 1999;135:458–64. [31] Caprio S, Plewe G, Diamond MP, et al. Increase insulin secretion in puberty: a compensatory response to reductions in insulin sensitivity. J Pediatr 1989;114:963–7. [32] Arslanian SA, Kalhan SC. Correlations between fatty acid and glucose metabolism: potential explanation of insulin resistance of puberty. Diabetes 1994;43:908–14.
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[33] Arslanian SA, Danadian K, Suprasongsin C. GH treatment in adolescents with non-GH deficient short stature (NGHD-SS): physical, biochemical and metabolic changes [abstract]. Pediatr Res 1999;45:84A. [34] Saad RJ, Keenan BS, Danadian K, et al. Dihydrotestosterone treatment in adolescents with delayed puberty: does it explain insulin resistance of puberty? J Clin Endocrinol Metab 2000; 86:4881–6. [35] Arslanian S, Suprasongsin C. Differences in the in vivo insulin secretion and sensitivity in healthy black vs white adolescents. J Pediatr 1996;129:440–3. [36] Arslanian S. Metabolic differences between Caucasians and African-American children and the relationship to type 2 diabetes mellitus. J Pediatr Endocrinol Metab 2002;15:509–17. [37] Wong WW, Butte NF, Ellis KJ, et al. Pubertal African-American girls expend less energy at rest and during physical activity than Caucasian girls. J Clin Endocrinol Metab 1999;84: 906–11. [38] Danadian K, Balasekaran G, Lewy V, et al. Insulin sensitivity in African-American children with and without family history of type 2 diabetes. Diabetes Care 1999;22:1325–9. [39] Svec F, Nastasi K, Hilton C, et al. Black-white contrasts in insulin levels during pubertal development: the Bogalusa Heart Study. Diabetes 1992;41:313–7. [40] Jiang X, Srinivasan SR, Radhakrishnamurthy B, et al. Racial (black-white) differences in insulin secretion and clearance in adolescents: the Bogalusa Heart Study. Pediatrics 1996;97: 357–60. [41] Berenson GS, Srinivasan SR, Bao W, et al. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults: the Bogalusa Heart Study. N Engl J Med 1998;338:1650–6. [42] Arslanian S. Insulin secretion and sensitivity in healthy African-American versus Americanwhite children. Clin Pediatr (Phila) 1998;37:81–8. [43] Bacha F, Saad R, Gungor N, et al. Obesity, regional fat distribution and syndrome X in obese black versus white adolescents: race differential in diabetogenic and atherogenic risk factors. J Clin Endocrinol Metab 2003;88:2534–40. [44] Cruz ML, Bergman RN, Goran MI. Unique effect of visceral fat on insulin sensitivity in obese Hispanic children with a positive family history of type 2 diabetes. Diabetes Care 2002; 25:1631–6. [45] The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification diabetes mellitus. Diabetes Care 1999;22(Suppl 1):S5–19. [46] Danadian K, Balasekaran G, Lewy V, et al. Insulin sensitivity in African-American children with and without history of type 2 diabetes. Diabetes Care 1999;22:1325–9. [47] McCance D, Pettitt D, Hanson R, et al. Birth weight and non-insulin dependent diabetes: thrifty genotype, thrifty phenotype, or surviving small baby genotype? BMJ 1994;308: 942–5. [48] Glowinska B, Urban M, Koput A. Cardiovascular risk factors in children with obesity, hypertension and diabetes: lipoprotein (a) levels and body mass index correlate with family history of cardiovascular disease. Eur J Pediatr 2002;161:511–8. [49] Legro RE, Kunselman AR, Dodson WC, et al. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab 1999;84:165–9. [50] Arslanian SA, Lewy VD, Danadian K. Glucose intolerance in obese adolescents with polycystic ovary syndrome: roles of insulin resistance and B-cell dysfunction and risk of cardiovascular disease. J Clin Endocrinol Metab 2001;86:66–71. [51] Lewy V, Danadian K, Arslanian SA. Early metabolic abnormalities in adolescents with polycystic ovarian syndrome (PCOS). Pediatr Res 1999;45:93A. [52] Lewy V, Danadian K, Arslanian SA. Roles of insulin resistance and B-cell dysfunction in the pathogenesis of glucose intolerance in adolescents with polycystic ovary syndrome. Diabetes 1999;48:A292.
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[53] Cho NH, Silverman BL, Rizzo TA, et al. Correlations between the intrauterine metabolic environment and blood pressure in adolescent offspring of diabetic mothers. J Pediatr 2000; 136:587–92. [54] Phipps K, Barker DJP. Fetal growth and impaired glucose tolerance in men and women. Diabetologia 1993;36:225–8. [55] Lithell HO, McKeigue PM, Gerlund L, et al. Relation at birth to non-insulin-dependent diabetes and insulin concentration in men aged 50–60 years. BMJ 1996;312:406–10. [56] Phillips DI. Birth weight and the future development of diabetes: a review of the evidence. Diabetes Care 1998;21(Suppl 2):B150–5. [57] Wei JN, Sung FC, Li CY, et al. Low birth weight and high birth weight infants are both at an increased risk to have type 2 diabetes among school children in Taiwan. Diabetes Care 2003; 26:343–8. [58] Bhargava SK, Sachdev HS, Fall CH, et al. Relation of serial changes in childhood body-mass index to impaired glucose tolerance in young adulthood. N Engl J Med 2004;350:865–75. [59] Bavdekar A, Yajnik CS, Fall CH, et al. Insulin resistance syndrome in 8-year-old Indian children: small at birth, big at 8 years or both? Diabetes 1999;48:2422–9. [60] Eriksson JG, Forsen TJ, Osmond C, et al. Pathways of infant and childhood growth that lead to type 2 diabetes. Diabetes Care 2003;26(11):3006–10. [61] Silverman BL, Metzker BE, Cho NH, et al. Fetal hyperinsulinism and impaired glucose tolerance in adolescent offspring of diabetic mothers. Diabetes Care 1995;18:611–61. [62] Pettitt DJ, Nelson RG, Saad MF, et al. Diabetes and obesity in the offspring of Pima Indian women with diabetes during pregnancy. Diabetes Care 1993;16:310–4. [63] Haffner SM, Miettinen H, Gaskell SP, et al. Decreased insulin action and insulin secretion predict the development of impaired glucose tolerance. Diabetologia 1996;39:1201–7. [64] Cruz ML, Weigensberg MJ, Huang TT-K, et al. The metabolic syndrome in overweight Hispanic youth and the role of insulin sensitivity. J Clin Endocrinol Metab 2004;89: 108–13. [65] Weiss R, Dziura J, Burgert TS, et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med 2004;350:2362–74. [66] Goran MI, Bergman RN, Avila Q, et al. Impaired glucose tolerance and reduced beta-cell function in overweight Latino children with a positive family history for type 2 diabetes. J Clin Endocrinol Metab 2004;89:207–12. [67] Banerji MA, Chaiken RI, Huey H, et al. GAD antibody negative NIDDM in adult black subjects with diabetic ketoacidosis and increased frequency of human leukocyte antigen DR3 and DR4: flatbush diabetes. Diabetes 1994;43:741–5. [68] Hathout EH, Thomas W, El-Shahawy M, et al. Diabetic autoimmune markers in children and adolescents with type 2 diabetes. Pediatrics 2001;107:102, 1417. [69] Burghen G, Christensen M, Kritchevsky SB, et al. Characteristics of type 1 and type 2 newonset diabetes in children. Pediatr Res 2000;44:A741. [70] Rashid M, Roberts EA. Nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr 2000;30:48–53. [71] Ebbeling CB, Leidig MM, Sinclair KB, et al. A reduced-glycemic load diet in the treatment of adolescent obesity. Arch Pediatr Adolesc Med 2003;157(8):773–9. [72] DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 1999; 131:281–303. [73] Mahler RJ, Adler ML. Clinical Review 102: Type 2 diabetes mellitus: update on diagnosis, pathophysiology and treatment. J Clin Endocrinol Metab 1999;84:1165–70. [74] Riddle MC. Oral pharmacologic management of type 2 diabetes. Am Fam Physician 1999; 60:2613–20. [75] Jones KL, Arslanian S, Peterokova VA, et al. Effect of metformin in pediatric patients with type 2 diabetes. Diabetes Care 2002;25:89–94. [76] Silverstein JH, Rosenbloom AL. Treatment of type 2 diabetes mellitus in children and adolescents. J Pediatr Endocrinol Metab 2000;13(Suppl):1–7.
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[77] UK Prospective Diabetes Study Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–53. [78] American Diabetes Association. Management of dyslipidemia in children and adolescents with diabetes. Diabetes Care 2003;26:2194–7. [79] Dean H, Flett B. Natural history of type 2 diabetes diagnosed in childhood: Long term follow-up in young adults years. Diabetes 2002;51:A24.
Type 2 Diabetes in Children and Youth Francine Ratner Kaufman, MDa,b,* a
Department of Pediatrics, Keck School of Medicine, University of Southern California at Los Angeles, Los Angeles, CA, USA b Division of Endocrinology and Metabolism, Children’s Hospital Los Angeles, Los Angeles, CA, USA
In 2000, then-Surgeon General David Satcher announced that the epidemic of obesity in the United States was increasingly affecting children and adolescents [1]. At the time of the Surgeon General’s announcement, approximately 16% of youth were categorized as being overweight, defined as a body mass index (BMI) greater than the 95th percentile for age and gender [2]. Concomitant with the rise in childhood overweight is a corresponding increase in the incidence of the metabolic syndrome [3] and type 2 diabetes in pediatric subjects [4–6]. Before the 1990s, it was rare for most pediatric centers to have patients with type 2 diabetes. By 1994, type 2 diabetes patients represented up to 16% of new cases of diabetes in children in urban areas [7], and by 1999, depending on geographic location, the range of percentage of new cases of type 2 was between 8% and 45% [8]. Type 2 diabetes, which occurs mainly in ethnic minorities in the United States [9], also has been described in children in a number of countries throughout the world [10]. A period of prediabetes, defined as either elevated fasting glucose levels or impaired glucose tolerance, occurs before the development of frank type 2 diabetes [11]. Type 2 diabetes in children and youth, as in adults, is caused by the combination of insulin resistance and relative b-cell secretory failure. Plasma insulin concentrations appear normal or elevated, but there is a loss of first-phase insulin secretion that cannot compensate for underlying insulin resistance [12]. There are a number of genetic and environmental risk factors for insulin resistance and limited b-cell reserve, including ethnicity, obesity, sedentary behavior, family history of type 2 diabetes, puberty, low birth weight, and female gender [13].
* Division of Endocrinology and Metabolism, Children’s Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027. E-mail address: [email protected] 0889-8529/05/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ecl.2005.04.010 endo.theclinics.com
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Type 2 diabetes in pediatric subjects has a variable presentation, although many children present with symptoms caused by elevated glucose [9]. There is an associated increase in glycosylated hemoglobin (HbA1c). Few pediatric subjects with type 2 diabetes can be treated with diet and exercise alone; therefore, pharmacologic therapy is most often required. Depending on initial glucose levels and the degree of symptoms caused by hyperglycemia, practitioners usually prescribe metformin for those subjects who are mildly affected, or subjects begin insulin therapy if they have more significant hyperglycemia [13]. Relatively few pediatric subjects use a secretagogue, a thiazolidinedione, or combination therapy. Unfortunately, while they are undergoing the present pharmacologic regimens, many patients appear unable to achieve glycemic targets over the long term. Specific treatment algorithms for pediatric patients with type 2 diabetes that are aimed at achieving glycemic targets have not been investigated in youth [8]. The ongoing Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) trial, sponsored by the National Institutes of Health, will investigate best treatments for type 2 diabetes in pediatric subjects and will provide evidence for improving the outcome of pediatric type 2 diabetes. Epidemiology of type 2 diabetes in pediatric subjects Between 1982 and 1994, a 10-fold increase in type 2 diabetes appeared in African-American patients in Cincinnati, OH [7]. By 1994, one third of new cases of diabetes in children and youth was attributed to type 2, with an odds ratio of 6.1 for the disease to develop in African-American girls and 3.5 in African-American boys, compared with whites. From 1994 to 1998, the proportion of new cases of pediatric diabetes in Florida attributed to type 2 increased from 9.4% to 20% [14]. In Mexican-American youth younger than 17 years of age with diabetes living in Ventura County, CA, 31% were found to have type 2 disease, as reported in 1998 [15]. In Arkansas, children as young as 8 years of age were reported to have type 2 diabetes [16]. In 1996, the Indian Health Service estimated diabetes prevalence for 15- to 19year-old children to be 0.45%, which was an increase of 54% from 1988. The prevalence of type 2 diabetes in American- Indian/Native American and First Nations Canadian youth is higher than that among other ethnic minorities [17–19]. In all groups, there was a skewed female:male gender ratio. For Native Americans the ratio was as high as 4 to 6:1, respectively, whereas for other groups, it was closer to 1.7:1 for females compared with males. The prevalence of type 2 diabetes increased in other countries of the world where there are predominantly high-risk ethnic and racial groups [20]. For example, in Thailand, among newly diagnosed children and adolescents, type 2 diabetes increased from 5% of all cases during 1986 to 1995 to 17.9% between 1996 and 1999 [21]. Japan saw an approximate 4-fold rise in the incidence of type 2 diabetes in 6- to 15-year-olds [22]. As a result, type 2 diabetes accounts for 80% of childhood diabetes in Japan.
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Insulin resistance The multiple factors that contribute to insulin resistance are shown in Box 1. Obesity may be the most important factor in the development of insulin resistance and type 2 diabetes [23–25]. Hyperinsulinism and decreased insulin sensitivity are seen in overweight adolescents. Approximately 50% of the variance seen in insulin sensitivity is accounted for by adiposity. As in adults, it is visceral fat, rather than total body fat, that correlates with basal and stimulated insulin levels and inversely correlates with insulin sensitivity [26–28]. In a cross-sectional study of 14 adolescents with impaired glucose tolerance (IGT) and matched controls, those with IGT had higher visceral and lower subcutaneous abdominal fat and decreased first-phase insulin secretion and glucose disposition index [29]. Intramyocellular fat content (as measured by nuclear magnetic resonance
Box 1. Factors that contribute to insulin resistance 1. Obesity/sedentary lifestyledThe marked increase in the incidence of type 2 diabetes has mirrored the increase in the rate of childhood and adolescent overweight. Along with a marked increase in the consumption of high calorie, high fat-containing foods, the increase in sedentary life-style among America’s children and teens has contributed to the epidemic of type 2 diabetes. 2. Race/ethnicitydAfrican-American and Hispanic youth have reduced insulin sensitivity compared with European-American children. 3. Positive type 2 diabetes family historydAt least 85% of children diagnosed have affected family members. 4. PubertydThe peak age of diabetes onset is during puberty, and puberty is associated with physiologic changes such as augmentation of growth hormone secretion, which causes insulin resistance. 5. Polycystic ovary syndrome (PCOS)dType 2 diabetes is more common in females (ratio of 1.7:1 female:male), and 15% of teenage subjects with PCOS have diabetes, and a one third have impaired glucose tolerance. 6. Intrauterine factorsdThere is a higher incidence of type 2 diabetes in those whose mothers had diabetes during pregnancy, in low birth weight infants, and in those with small head circumference. From Kaufman FR. Diabetes mellitus in childhood and adolescence. In: Rakel RE, Bope ET, editors. Conn’s current therapy. Philadelphia: Elsevier Science; 2003.
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spectroscopy) showed a strong positive correlation with insulin resistance and with 2-hour post-load plasma glucose, suggesting that intramyocellular fat may be important in the pathogenesis of insulin resistance and IGT. Obesity is not only a risk for insulin resistance and diabetes, it also is associated with an increased risk for cardiovascular disease caused by the elevation of lipid and blood pressure levels [30]. Puberty is a state of relative insulin resistance, and an increase in basal and stimulated insulin secretion occurs during the progression through normal puberty [31,32]. Insulin-mediated glucose disposal has been shown to be on average 30% lower in Tanner puberty stages 2 to 4 compared with the rate of disposal seen in Tanner stage 1 children during hyperinsulinemic euglycemic clamp studies. This change in insulin sensitivity is caused by the augmentation of the growth hormone–insulin-like growth factor axis, as evidenced by the fact that growth hormone supplementation in non-growth hormone-deficient adolescents resulted in lower insulin-stimulated glucose metabolism and hyperinsulinemia [33], which was not seen with supplementation of testosterone and dihydrotestosterone [34]. African American children are more insulin-resistant than white children [35–38]. African American teens are more obese and have higher insulin levels to oral glucose and higher insulin-to-glucose ratios compared with their white counterparts in the Bogalusa Heart Study [39–41]. Subsequently, African American subjects have been shown to have lower resting energy expenditure, higher fasting and first-phase insulin levels, and lower insulin sensitivity [42]. In a comparison of African American and white children with obesity and similar insulin sensitivity levels, African Americans had lower hepatic glucose output, lower total levels of cholesterol and lowdensity lipoprotein (LDL) cholesterol, lower triglyceride levels, and considerably lower visceral fat levels. Visceral adiposity was associated with lower insulin sensitivity in both groups. This was compensated for by higher insulin secretion in whites but not in African Americans [43]. These findings suggest a greater diabetogenic risk of obesity among African Americans but greater atherogenic risk among whites. Latino children have been reported to have lower insulin sensitivity. Studies suggest that increased total adiposity and visceral fat independently contribute to lower insulin sensitivity in Latino children [44]. Youth with type 2 diabetes have a strong family history of this disease. Between 45% and 80% of pediatric subjects have been reported to have at least one parent with diabetes; and 74% to 100% of subjects have reported having a first- or second-degree relative [45]. Even in healthy, prepubertal African American children, a family history of diabetes has been associated with an approximate 20% reduction in insulin sensitivity [46]. In Pima Indians, it has been shown that the cumulative incidence of type 2 diabetes was highest in the offspring if both parents had diabetes [47]. In addition, up to 28% of youth affected by type 2 have a positive family history of cardiovascular disease [48].
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There are gender differences in youth with type 2 diabetes. Girls are 1.7 times more likely than boys to be affected. Hypothetically, this difference is caused by elements of the polycystic ovary syndrome (PCOS) [49]. Studies have shown that insulin resistance, abnormal first- phase insulin release, and the lack of beta-cell compensation for the degree of insulin resistance are seen in girls with PCOS [50–52]. The same mechanism has been seen in adult women with PCOS. Fifteen percent of women with PCOS have diabetes, and one third of whom have impaired glucose olerance. The predisposition to type 2 diabetes may be programmed in utero [53– 55]. Maternal undernutrition may lead to a reduced endocrine pancreatic mass. This hypothesis is supported by the fact that adults with type 2 diabetes have lower birth weight and smaller head circumference [56]. Recent data from Taiwan confirmed this observation in children [57]. A study of 6- to 18-year-old children has shown a U-shaped relationship, with the highest risk for type 2 diabetes in children with a low (%2.5 kg) or a high (R4.0 kg) birth weight and lowest for those with a normal birth weight (3–3.5 kg). This U-shaped relationship was seen when adjustment for other factors, such as gestational diabetes, family history of diabetes, and socioeconomic status, were made [57]. A rapid weight gain in early childhood has been shown to be a risk factor for the development of obesity and glucose intolerance in adulthood [58,59]. In a longitudinal study of 8760 subjects born in Helsinki between 1934 and 1944, a rapid increase in BMI after age 2 increased the risk of type 2 diabetes in both high and low birth weight groups [60]. Maternal diabetes also is a risk for later development of insulin resistance and type 2 diabetes. Between 1977 and 1983, a study [61] was conducted to correlate amniotic fluid insulin levels measured between weeks 32 and 38 in pregnancies complicated by pregestational or gestational diabetes with the longitudinal assessment of insulin levels in the offspring. Oral glucose tolerance tests were followed in the offspring at 18-month intervals for up to 16 years, at which time 19.3% of the cohort had IGT. In this group with IGT, 12 of 36 subjects had elevated amniotic fluid insulin levels when measured between 32 and 38 weeks gestation compared with 1 of 27 subjects with normal amniotic fluid insulin levels. Therefore, the infants at particular risk were those whose mothers had poorly controlled diabetes. The specific environmental role of maternal hyperglycemia, as separate from maternal genetics, has been demonstrated in Pima Indians, in whom offspring born after the mother developed diabetes were more obese as children and more likely to have diabetes in their 20s than were their siblings born before their mothers developed diabetes [62]. No such differences were seen before and after diabetes was developed by fathers. The dysregulation of insulin secretory dynamics is required for the development of type 2 diabetes [63]. This dysregulation particularly affects first-phase insulin release. As a consequence of multiple factors, including lipotoxicity that is the consequence of obesity and visceral adiposity, and
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glucotoxicity resulting from less than optimal glycemic control and intrinsic beta-cell abnormalities that may be genetic, there is progressive decline in beta-cell function. It appears that apoptosis may play a role in the decline of the beta-cell mass and that marked improvement in glucose regulation may inhibit the apoptotic process. This makes it imperative that aggressive treatment protocols be developed that can reverse the negative effects of both glucotoxicity and lipotoxicity.
Metabolic syndrome and prediabetes Metabolic syndrome is a constellation of metabolic derangements that include obesity, insulin resistance, dyslipidemia, and hypertension and predict both type 2 diabetes mellitus and premature coronary artery disease. An analysis of cross-sectional data obtained from the Third National Health and Nutrition Examination Survey III, 1988 to 1994 [3], revealed that a large percentage of overweight children and adolescents were affected by metabolic syndrome. The study sample consisted of 2430 subjects aged 12 to 19 years. Metabolic syndrome was defined as a waist circumference greater than the 90th percentile for age and gender, blood pressure at or above the 90th percentile for age, gender, and height, fasting plasma glucose level greater than 110 mg/dL, high-density lipoprotein (HDL) cholesterol, and triglyceride levels greater than the 90th percentile for age. The overall prevalence of the metabolic syndrome in adolescents was 4.2%. It was more common in males (6.1%) than females (2.1%) and was more frequent in Mexican Americans (5.6%) and whites (4.8%) than in black subjects (2.0%). Almost half of the subjects (41%) had one or more risk factors, whereas 14% of the subjects had two or more. High triglyceride levels and low HDL cholesterol levels were most common, whereas high fasting plasma glucose levels were the least common. Further reports have shown that the metabolic syndrome is found in 30% of overweight youth with a family history of type 2 diabetes [64] and in 50% of subjects with severe obesity [65]. Prediabetes is defined as elevated fasting (R100 and %126 mg/dL) or 2-hour post-glucose load (R140 and %199 mg/dL) plasma glucose levels. Prediabetes is common in children and youth, as well as in adults [11]. After oral glucose tolerance testing, 25% of obese children 4 to 10 years of age and 21% of obese adolescents 11 to 18 years of age were found to have IGT. The best predictor of IGT was insulin resistance. In this limited study of 167 subjects, IGT was found in all ethnic groups, and overt type 2 diabetes was predicted by determining that there was an element of beta-cell failure as assessed by a reduced ratio of the 30-minute change in the insulin concentration compared with the 30-minute change in the plasma glucose level. IGT was reported in 28% of overweight Hispanic youth with a positive family history of type 2 diabetes [66].
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Screening for type 2 diabetes The diagnosis of diabetes in children and youth is made using the same American Diabetes Association criteria as those established for adults [45]. The diagnosis can be made when the subject is symptomatic and has a plasma glucose level greater than 200 mg/dL, by screening asymptomatic children and youth and finding a fasting plasma glucose level greater than 126 mg/dL, or by finding a 2-hour plasma glucose level greater than 200 mg/dL during an oral glucose tolerance test. In asymptomatic children, abnormal glucose levels must be confirmed on another day. A Consensus Panel convened by the American Diabetes Association in 2000 [5] recommended that testing for type 2 diabetes in at-risk youth be performed as outlined in Box 2. The recommendation to screen for type 2 diabetes was made, in the absence of sufficient data concerning the natural history of type 2 diabetes in pediatric subjects, because it is: common, serious, there is a prolonged latency period, screening is sensitive and specific, and treatment is available. A major consequence of the appearance of type 2 diabetes in the younger age group is that subjects with diabetes will
Box 2. Recommendations for screening for type 2 diabetes in children and youth Criteria Overweight (BMI ‚ 85th percentile for age and gender, weight for height ‚ 85th percentile, or weight ‚ 120th percentile of ideal for height) Plus Any two of the following risk factors: Family history of type 2 diabetes in first- or second-degree relatives Race and ethnicity (American Indian, African American, Hispanic, Asian/Pacific Islander) Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, PCOS) Age of initiation: age 10 years or at onset of puberty if puberty occurs at a younger age Frequency: every 2 years Test: fasting plasma glucose test is preferred Adapted from American Diabetes Association. Type 2 Diabetes in children and adolescents: consensus statement. Diabetes Care 2000;23(8):381–9; with permission.
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have a longer duration of the disease, which will increase the risk of the early development of both microvascular and macrovascular complications. The at-risk population that should be screened has been well defined. They are children and youth with obesity and a positive family history of type 2, those belonging to certain racial and ethnic groups such as American Indian/Native American, African American, Hispanic American, and Asian/Pacific Islander, and those having evidence of insulin resistance with hypertension, acanthosis nigricans, dyslipidemia, and polycystic ovarian disease. The Consensus Panel [5] also advocated for rigorous studies to be performed to establish the benefit of screening and to determine the contribution of the various factors involved in establishing risk.
Presentation of type 2 diabetes in youth At the time of diagnosis, it is important to obtain the necessary data to establish as firmly as possible the diagnosis of type 2 diabetes versus type 1 disease. A diagnosis can be made by historical, physical, and laboratory data as shown in Table 1 [4–6,9]. From the standpoint of the medical history, those patients who have type 2 have a more insidious progression of diabetes symptoms than those with type 1. Although the presence of ketosis and diabetic ketoacidosis (DKA) does not exclude type 2 diabetes as the appropriate diagnosis, they are usually less common and less severe. Ketonuria usually is present in type 1 patients at presentation, and 40% of them have DKA, whereas 33% of those with type 2 have ketonuria, and 5% to 10% of these patients have generally mild DKA. With regard to family
Table 1 How to distinguish type 1 and 2 diabetes Type 1
Type 2
With the increase in overweight subjects, up to a quarter may be overweight Short course 35%–40% of subjects have ketoacidosis
85% of subjects are overweight
5% of subjects have first- or second-degree relatives with type 1 diabetes Increase in other autoimmune disorders
C-peptide and insulin levels decrease, although they may be preserved during the remission phase Predominantly white Data from Refs. [5,6,8].
Indolent course 33% of subjects have ketonuria and 5%–25% have mild ketoacidosis 74%–100% with first- or second-degree relatives with type 2 diabetes Brought on by insulin resistance, hypertension, dyslipidemia, PCOS, acanthosis nigricans C-peptide and insulin levels increase, although they could be low at diagnosis with glucotoxicity and lipotoxicity Minority youth
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history, 5% of type 1 patients will have a first- or second-degree relative affected by type 1 diabetes. In contrast, virtually all patients with type 2 diabetes will have at least a second-degree relative who is affected, and from 45% to 80% of patients will have an affected parent. To determine whether relatives have type 1 or type 2, information concerning the age at onset, weight, and treatment of affected family members can be helpful. On physical examination, the presence of acanthosis nigricans will be found in 60% to 90% of subjects with type 2. In addition, many type 2 subjects will come to medical attention and be diagnosed as the result of investigating a variety of complaints such as obesity, sleep apnea, hyperlipidemia, hypertension, amenorrhea, and hirsutism associated with PCOS. Subjects with type 1 diabetes may have evidence of other autoimmune disorders. Laboratory evaluation should include assessment for the presence of autoantibodies against islet antigens and assessment of endogenous insulin reserve by serum insulin and C peptide measurement. Eighty-five percent of type 1 subjects will have the presence of one or more antibodies to isletderived antigens (positive anti-glutamic acid decarboxylase [GAD] antibodies, islet cell antibodies, and insulin autoantibodies). Although the presence of autoantibodies should be the hallmark for differentiating type 1 from type 2 diabetes, there is overlap [67]. In a study of 48 type 2 and 39 type 1 subjects, the diagnosis of type 2 was made on the basis of ethnicity, a firstdegree relative with type 2, a BMI greater than 24 kg/m2, and the presence of acanthosis nigricans [68]. DKA was present in 33% of type 2 subjects compared with 53% of type 1 subjects, and 81% of the type 2 subjects were islet cell antibody-positive, 30% were positive for anti-GAD, and 35% were positive for insulin autoantibodies. Insulin and C peptide levels may be deceptively low in type 2 patients at the time of presentation as the result of acute glucotoxicity, which impairs insulin secretion. However, this changes to the more typical pattern once glucotoxicity has resolved as the result of treatment [69]. Nonalcoholic fatty liver disease (NAFLD) in children is a growing problem and is frequently associated with obesity, insulin resistance, and type 2 diabetes. NAFLD is characterized by the presence of macrovesicular steatosis with parenchymal inflammation. In addition, youth with type 2 diabetes and obesity can have histologic findings that range from fatty changes in the liver alone to non-alcoholic steatohepatitis, cirrhosis, and finally to liver failure [70]. Treatment of type 2 diabetes in children and youth The overall treatment protocol in pediatric subjects includes diabetes education for the patient and family, lifestyle modification with emphasis on increasing exercise and following an appropriate nutrition plan, the setting of glycemic targets, and pharmacotherapy. The glycemic target should be to achieve a HbA1c of less than 7.0%; however, this target may be difficult to
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achieve in children and adolescents because of physiologic and psychologic reasons. Data on the dietary treatment of type 2 diabetes in children are scarce. A study of 20 children on a short-term ketogenic, very low calorie diet showed improvement in glycemic control, BMI, and the ability to discontinue diabetes medications [71]. Prospective, randomized studies to evaluate longterm outcomes and safety of this diet have not been performed. Less than 10% of pediatric subjects diagnosed with type 2 diabetes can achieve glycemic targets by following lifestyle interventions alone [13]. As a result, pharmacotherapy is required, and although there are many agents available to improve the metabolic abnormalities seen in subjects with type 2 diabetes, there are sparse data concerning their use in pediatrics [72–74]. A modification of the American Diabetes Association treatment scheme for pediatrics is given in Fig. 1. Metformin is approved in pediatrics. Metformin has been found to significantly improve glycemic control in youth with type 2 diabetes without serious adverse events [75]. However, gastrointestinal side effects are common in youth treated with metformin. Metformin is the oral agent of choice in pediatric type 2 diabetes. It can be used as the initial therapy for those without significant symptoms caused by hyperglycemia, or it can be added after glucose levels improve with insulin treatment. Other oral hypoglycemic agents, such as sulfonylureas, meglitinides, thiazolidinediones, and a-glucosidase inhibitors, have not been well studied in pediatric subjects. Unique issues concerning the use of these agents in pediatrics are described in Table 2. Insulin is used in youth with type 2 diabetes more often than it is used in adults. The reason for this is the likelihood that significant insulin deficiency
3. Combination Therapy DKA, BG
1. Diet Exercise
Metformin + Sulfonylurea Metformin + insulin Metformin + meglitinide Metformin + TZD
Glycemic goals not achieved Glycemic goals not achieved
2. Monotherapy Metformin Insulin Sulfonylurea
4. Insulin Therapy Intermediate + fast-acting bid Multiple injections ≥ 3 injections CSII
Fig. 1. American Diabetes Association treatment schema for type 2 diabetes, modified for Children and Youth. (Modified from American Diabetes Association. Clinical practice recommendations. Diabetes Care 1999;22(Suppl):S1–114; with permission.)
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Table 2 Advantages and disadvantages of pharmacologic therapy in pediatric subjects for type 2 diabetes Class
Advantages
Disadvantages
Insulin
Hypoglycemia Weight gain Need for injections
Sulfonylureas
Meglitinides
Biguanides
Metformina
a-Glucosidase inhibitors Thiazolidinediones
Overcomes glucotocity Will control all patients Flexibility in dosing Data in pediatric patients Rapid-acting Well-tolerated Broad range of dosing Improves insulin secretion Used with meals No lag period Flexibility of lifestyle Low risk of hypoglycemia Improves insulin resistance High initial response rate Less weight gain or loss Advantageous lipid profile Improves insulin resistance Decreases hirsutism, free androgen, LDLs, luteinizing hormone, and 17a-hydroxyprogersterone levels. Good safety profile No weight gain or loss Dose coupled with meals Corrects insulin resistance Once-daily dosing Improves lipids (pioglitazone)
Hypoglycemia Weight gain Hypoglycemia Weight gain Unknown long-term effects
GI side effects Risk of lactic acidosis Risk of impaired renal, hepatic, and cardiac function d
Needs high carbohydrate diet Flatulence and GI pain Cannot treat hypoglycemia Liver disease (rosiglitazone) Delayed action Weight gain
a For adolescent girls who have PCOS, evidence is emerging that metformin may be the agent of choice. Studies have shown the advantages indicated above. Modified from Kaufman FR. Type 2 diabetes in children and youth: A new epidemic. J Pediatr Endocrinol Metab 2002;15(1):737–44; with permission.
may be common among adolescents who are symptomatic at presentation. In addition, insulin is familiar to pediatricians and pediatric endocrinologists as the treatment of choice when there is uncertainty about whether a patient has type 1 or type 2 diabetes, and it has efficacy in ameliorating metabolic decompensation. The results of a survey of 130 clinical practices of members of the Lawson Wilkins Pediatric Endocrine Society reported in 2000 that 48% of subjects were treated with insulin and 44% with oral agents [76]. Those patients who received insulin were generally given two injections per day; of those on oral agents, 71% received metformin, 46% received sulfonylureas, 9% received thiazolidinediones, and 4% received meglitinide. Although at diagnosis, the majority of affected youth are initially placed on monotherapy with insulin or metformin, monotherapy is insufficient to control glycemia in most
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pediatric patients over the long-term. Failure to respond to monotherapy is similar to that described in adults in the UK Prospective Diabetes Study [77]. As the result of an apparent progressive loss of beta-cell function, which may be caused in part by poor glycemic control itself, patients are required to be placed on multiple pharmacologic agents years after diagnosis, at a time when microcirculatory complications and early macrovascular disease, dyslipidemia, and hypertension may develop. These complications and comorbidities also require treatment. The ADA has recently published consensus-based guidelines for the management of dyslipidemia in children with diabetes [78]. It was recommended that lipid levels should be measured every 2 years, blood glucose treated aggressively, and dietary counseling given to those with elevated lipid levels. Because of a lack of data on the use of pharmacotherapy for dyslipidemia in pediatrics and scant data on the progression of cardiovascular disease in youth, the level of LDL cholesterol that requires pharmacologic intervention was set high (160 mg/dL) by the consensus panel. However, for patients with additional cardiovascular risk factors (including blood pressure, family history, and smoking status), clinical discretion is indicated, and pharmacotherapy may be begun at LDL levels greater than 130 mg/dL or even lower in high-risk youth. Hypertension is a comorbidity of type 2 diabetes in youth and is a major risk factor for nephropathy and atherosclerosis. Blood pressure (BP) should be measured in all children with type 2 diabetes during diabetes health care visits. If hypertension, defined as a BP greater than the 95th percentile for age and gender, does not respond to lifestyle changes, the first line therapy should be administration of an angiotensin-converting enzyme inhibitor. Angiotensin II receptor antagonists are reserved as second line therapy because there are few primary data on their use in pediatric subjects. Extensive data on the long-term outcome of type 2 diabetes in youth is not available presently. However, there are data on outcomes in NativeAmerican youth. It appears that not only are American Indian/Native Americans and First Nation Canadians at highest risk to develop type 2 diabetes but also their outcome is poor. Dean and Flett [79] have reported that in young adults 18 to 33 years of age who were diagnosed before age 17, there was a 9% mortality rate, a 6.3% dialysis rate, and a 38% pregnancy loss caused by poor glycemic control.
The Treatment Options for type 2 Diabetes in Adolescents and Youth trial Although there are large numbers of clinical trials that assess the efficacy of treatment regimens in adults with type 2 diabetes, there are few efforts in children and youth. As a result, in 2002, the National Institutes of Diabetes, Digestive and Kidney Diseases funded multicenter primary diabetes prevention and diabetes treatment trials, together entitled the Studies to
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Treat Or Prevent Pediatric Type 2 Diabetes (STOPP-T2D). The TODAY trial, the treatment trial of STOPP-T2D, consists of investigators associated with twelve clinical centers (Baylor College of Medicine, Case Western Reserve University, Children’s Hospital Los Angeles, Children’s Hospital of Philadelphia, Children’s Hospital of Pittsburgh, Massachusetts General Hospital, Joslin Diabetes Center, State University of New York Upstate Medical University, University of Colorado Health Sciences Center, University of Oklahoma Health Sciences Center, University of Texas Health Sciences Center at San Antonio, Washington University in St Louis, and Yale University). The trial is planned to enroll 750 children and youth aged 10 to 17 years old who have been diagnosed with type 2 diabetes for less than 2 years. The trial will compare the efficacy of three treatments over 2 to 5 years. Study subjects will be randomized to one of three treatment assignments: metformin alone, metformin plus rosiglitazone, and metformin plus an intensive lifestyle program. The lifestyle program goals include weight loss and increased physical activity and will consist of weekly meetings with the youth and a designated adult for up to 24 weeks and then transition to maintenance meetings monthly for the duration of the trial. A lifestyle intervention pilot was performed at the 12 sites for the purposes of training and optimizing the intervention. Major eligibility criteria are diagnosis of diabetes by ADA criteria, with the absence of islet autoantibodies and fasting C peptide levels greater than 0.6 ng/mL, diabetes duration of less than 2 years, a BMI greater than the 85th percentile, age 10 to 17 years old, and the presence of a family member who will participate in the child’s treatment. Before randomization, subjects will enter a ‘‘run-in’’ phase for 2 to 6 months. During the run-in phase, patients will receive a standard diabetes education curriculum that is mastery based. They will be required to demonstrate adherence to certain diabetes management tasks such as taking medication, record keeping, glucose monitoring, and maintaining clinic appointments. To complete the run-in phase, participants will need to achieve an HbA1c level of less than 8% on a regimen of 1000 to 2000 mg/day of metformin alone. The primary outcomes of the TODAY trial are to determine how well and for how long each treatment approach controls blood glucose levels. The primary outcome is timed to treatment failure, defined as a HbA1c level greater than 8%, for 6 months. At treatment failure, subjects will be placed on an insulin rescue regimen with insulin glargine. Glargine will be titrated to control fasting blood glucose and improve HbA1c levels and, if this cannot be achieved, the subject’s insulin regimen will be adjusted at the discretion of the investigator. Secondary outcomes include measures of beta cell function and insulin resistance, body composition, nutrition, physical activity and aerobic fitness, cardiovascular risk factors, microvascular complications, quality of life, and psychologic outcomes. The influences of individual and family behaviors on treatment response and the relative cost
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effectiveness also will be evaluated. Critical design issues were developed to address the recruitment and retention of diverse study subjects in a complex treatment trial. During the summer of 2004, the first TODAY subjects entered the run-in phase of the study in the 12 centers, and as subjects completed run-in, they were randomized to the treatment arms. It is the hoped that referrals to the 12 centers will take place for subjects living in close proximity to one of the 12 centers. Summary A dramatic increase has occurred in the number of children and youth diagnosed with type 2 diabetes over the last decade. Doubtless, this epidemic follows the tremendous increase in childhood obesity around the world. Youth diagnosed with type 2 diabetes, in addition to being overweight, are members of ethnic minorities, have a positive family history of type 2 disease, most often involving a parent, and have acanthosis nigricans. Much still needs to be learned as to why this epidemic is occurring at the present time with regard to other environmental factors that might promote insulin resistance and beta-cell failure. We need to determine whether there are significant numbers of children with diabetes who are undiagnosed and how to design effective screening strategies. The TODAY trial will help to determine best treatment strategies to improve glycemia, reduce complications, and ameliorate insulin resistance and beta-cell failure. Because type 2 diabetes is emerging as a worldwide public health problem, improved care for affected youth must be coupled with a focus on prevention.
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