Vol. 67, No. 1, 2007
Issue release date: February 2007
Free Access
Horm Res 2007;67:22–34
Mini Review
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Prevention and Treatment of Type 2 Diabetes in Youth

Libman I.M. · Arslanian S.A.
Divisions of Weight Management & Wellness and Pediatric Endocrinology, Metabolism and Diabetes Mellitus, Children’s Hospital of Pittsburgh, Pittsburgh, Pa., USA
email Corresponding Author


 goto top of outline Key Words

  • Type 1 diabetes
  • Juvenile-onset type 2 diabetes, prevention
  • Juvenile-onset type 2 diabetes, treatment
  • Type 2 diabetes, pathophysiology
  • Type 2 diabetes, risk factors
  • Type 2 diabetes, diagnosis and screening

 goto top of outline Abstract

Parallel to the increase in obesity worldwide, there has been a rise in the prevalence of type 2 diabetes mellitus (T2DM) in children and adolescents. The etiology of T2DM in youth, similar to adults, is multifactorial including genetic and environmental factors, among them obesity, sedentary lifestyle, family history of the disease, high-risk ethnicity and insulin resistance phenotype playing major roles. Treatment of T2DM should not have a glucocentric approach; it should rather target improving glycemia, dyslipidemia, hypertension, weight management and the prevention of short- and long-term complications. Prevention strategies, especially in high-risk groups, should focus on environmental change involving participation of families, schools, the food and entertainment industries and governmental agencies. Presently, limited pharmacotherapeutic options need to be expanded both for childhood T2DM and obesity. The coming decades will prove very challenging for healthcare providers battling socioeconomic waves conducive to obesity and T2DM. Evidence-based research and clinical experience in pediatrics, possibly modeled after adult trials, need to be developed if this public health threat is to be contained.

Copyright © 2007 S. Karger AG, Basel

goto top of outline Introduction

Not long ago, type 2 diabetes mellitus (T2DM) was regarded as a disease of adulthood, with type 1 diabetes (T1DM) accounting for almost all cases seen in children and adolescents [1]. While it is true that T2DM is still more prevalent in adults, there is increasing evidence that onset in youth is frequently observed [2]. This relatively new phenomenon, strongly associated with the escalating prevalence of obesity, brings a serious new aspect to the diabetes epidemic, especially in certain ethnic groups (African-Americans, Native Americans and Hispanics) [3,4,5,6,7]. However, the problem of youth T2DM is not unique to North America because it has also been reported in children from Africa [8], Asia [9,10,11,12], Australia [13], and Europe [14,15,16,17]. For a comprehensive evaluation of prevention and treatment strategies of youth T2DM, this chapter will briefly review the pathophysiology, risk factors, diagnosis and screening of the disease.


goto top of outline Pathophysiology

The etiology of T2DM in youth, similar to adults, is multifactorial including genetic and environmental factors. It results from the combination of insulin resistance and impaired β-cell function. Insulin resistance is strongly associated with obesity, mainly visceral adiposity, and is believed to be an early abnormality in the development of T2DM preceding the impairment in insulin secretion [18, 19]. Early in the pathogenesis of glucose intolerance, insulin-producing β-cells are able to compensate for the insulin resistance by increasing insulin secretion. This compensatory hyperinsulinemia maintains glucose homeostasis in the face of insulin resistance. The failure of the pancreatic β-cell, resulting in insufficient insulin secretion, underlies the transition from insulin resistance to impaired glucose tolerance (IGT) and clinical diabetes [18, 20]. Limited cross-sectional studies in children show that T2DM and IGT are characterized by impaired insulin secretion in the backdrop of insulin resistance [21,22,23,24,25,26]. Our group was the first to demonstrate that in adolescents with T2DM, insulin sensitivity is around 50% lower, and first phase insulin is ∼75% lower compared with obesity-matched non-diabetic adolescents [24]. This degree of impairment in insulin secretion appears to be more severe than that observed in adults, especially considering the relatively short duration of diabetes in youth. There are no systematic longitudinal observations regarding the natural history of progression to T2DM in high-risk youth. In adults, the United Kingdom Prospective Diabetes Study (UKPDS) found that β-cell function was 50% of normal at the time of clinical diagnosis of T2DM [27]. In 5,396 adults from the Botnia Study, an absolute decompensation of β-cell function characterized the transition from IGT to T2DM [20]. Limited longitudinal case observations by our group are consistent with the adult findings [28, 29]. In a high-risk youth the transition from normal glucose tolerance to IGT or pre-diabetes was associated with rapid weight gain and decline in the insulinogenic index, and progression to T2DM was associated with further weight gain, decrease in insulin sensitivity and a dramatic decline in insulin secretion [28]. In an established T2DM youth followed over 6 years, the decline in β-cell function was approximately 15%/year with no substantial change in insulin sensitivity [29]. This is a more than twofold faster decline in β-cell function compared with adult UKPDS data (7%/year) [27]. Additional studies are needed to determine if this accelerated loss of β-cell function is generalizable to all youths with T2DM.


goto top of outline Risk Factors

Risk factors for youth T2DM include family history of the disease, high-risk ethnicity, obesity, sedentary lifestyle and insulin resistance phenotype.

goto top of outline Family History of T2DM

Although few susceptibility genes have been identified so far, a very recent finding points towards a gene locus that dramatically increases the risk of T2DM in Icelanders, Danes and a US cohort, specifically a variant of transcription factor 7-like 2 (TCF7L2) gene [30]. The genetic component of T2DM is evidenced by the strong heritability of the disease [31]. A strong family history of T2DM is present in most pediatric patients regardless of ethnic background [32]. Our studies demonstrate that family history of T2DM is associated with approximately 25% lower insulin sensitivity in prepubertal healthy African-American children compared with their peers without a family history of T2DM [33]. White children who do not have diabetes, but have a positive family history of the disease, have lower insulin sensitivity with an inadequate compensation in insulin secretion compared with youngsters without a family history of diabetes [34].

goto top of outline Ethnicity

The highest incidence of T2DM in youth in the USA is evident in African-Americans, Native Americans, especially Pima Indians, and Hispanics [3,4,5,6]. Studies have shown that Black children and Hispanic youth are hyperinsulinemic and insulin-resistant compared with their white peers [35, 36]. These racial differences could be attributable to genetic differences [37] or to environmental/cultural differences [35]. Our studies have shown that for the same obese BMI, Black adolescents have around 30% lower visceral fat compared with their white obese peers but they are at higher diabetes risk because of inadequate compensation of insulin secretion for the degree of insulin resistance [38]. Moreover, differences in adiponectin levels, lower in Blacks, may be a biological marker which predisposes them to a greater risk of insulin resistance [39, 40]. In the presence of such racial differences in risk of T2DM, it remains to be determined if the natural history and the tempo of progression to T2DM differ between different racial groups.

goto top of outline Obesity and Sedentary Lifestyle

Obesity, an outcome of positive energy balance and the result of higher caloric intake and sedentary lifestyle, may be the most important environmental factor in the development of insulin resistance and T2DM [41]. Insulin resistance and hyperinsulinemia are metabolic features of overweight youth [42, 43]. As in adults [44], within a given ethnic group, it is visceral fat, rather than total body fat, that correlates with basal and stimulated insulin levels and inversely with insulin sensitivity [39, 42,45,46,47]. With increasing rates of obesity in children [48] and enlarging abdominal girth [49], prevention and treatment of T2DM should target prevention and management of obesity.

goto top of outline Insulin Resistance Phenotype

Puberty [50], polycystic ovary syndrome [51, 52], acanthosis nigricans [53] and exposure to gestational diabetes [54, 55] or intrauterine growth retardation [56, 57] have insulin resistance as a metabolic feature and are associated with an increased risk of T2DM [58].


goto top of outline Diagnosis

The criteria for the diagnosis of diabetes in children, based on standard values of fasting blood glucose, random blood glucose and the oral glucose tolerance test (OGTT), are the same as in adults [59] (table 1). However, while the American Diabetes Association (ADA) defines impaired fasting glucose (IFG) as a fasting plasma glucose ≥100 mg/dl (≥5.6 mmol/l) but <126 mg/dl (<7.0 mmol/l), the International Diabetes Federation (IDF) [60] and the World Health Organization (WHO) [61] define the lower end of IFG as a fasting plasma glucose level ≥110 mg/dl (≥6.1 mmol/l). Moreover, there are some differences in terminology, with pre-diabetes used in Europe in favor of IGT by the USA. In adults, recent data from men in the Israeli Defense Forces 26–45 years of age, revealed a progressively increased risk of T2DM with fasting plasma glucose levels of 87 mg/dl (4.83 mmol/l) or more, as compared with those whose levels were in the bottom quintile <81 mg/dl (4.5 mmol/l) (p for trend <0.001). Higher fasting plasma glucose levels within the normoglycemic range, the authors concluded, constituted an independent risk factor for T2DM among young men, and such levels could help, along with body mass index (BMI) and triglyceride levels, to identify apparently healthy men at increased risk for diabetes [62]. In our research experience, the reproducibility of the fasting glucose in children is quite varied. Among 150 youth with normal glucose tolerance, ages 8–18 years old admitted twice within a 1- to 3-week period to the General Clinical Research Center at Children’s Hospital of Pittsburgh, the correlation between the fasting plasma glucose performed during the two admissions is only 0.598. The variation was higher in the upper normal ranges of glucose [unpubl. data]. Moreover, data are lacking regarding the longitudinal outcome of different fasting cut-offs in children. Therefore, additional studies are needed to compare diagnostic categories in the pediatric population according to the ADA versus the WHO diagnostic criteria before arriving at valid conclusions. Once the diagnosis of diabetes is established, it is important to distinguish between T1DM and T2DM to optimize therapy. Given the heterogeneity of clinical presentation of T2DM in children, classification into type 1 or type 2 may not be made reliably on the basis of clinical presentation. Clinical signs helpful in distinguishing T2DM from T1DM are obesity, signs of insulin resistance and elevated C-peptide levels [58]. However, with the prevalence of obesity increasing not only in the general population but also in children with T1DM [63], it is becoming increasingly difficult to distinguish between the two types of diabetes. Markers of the cellular-mediated immune destruction of the β-cell such as islet cell antibodies, glutamic acid decarboxylase antibodies, tyrosine phosphatase-like protein autoantibodies, and insulin antibodies, can be useful, as they are usually identifiable in those individuals with or at risk of autoimmune T1DM. Currently, absence of diabetes autoimmune markers is a prerequisite for the diagnosis of T2DM in children and adolescents [32]. Some contradictory data exist in the literature, however. Studies from the First Nation Youth of Manitoba [64], the USA [65,66,67] and Germany [68] have shown the presence of pancreatic autoantibodies in children with clinically diagnosed T2DM. Preliminary unpublished data from our group suggest that the metabolic profile of insulin resistance and secretion is very different between those with vs. without pancreatic autoantibodies [69]. The clinical translation of the presence of β-cell autoantibodies in youth with clinically diagnosed T2DM is uncertain. Longer prospective studies are needed for definite answers.

Table 1. Criteria for the diagnosis of impaired glucose tolerance and diabetes


goto top of outline Screening

In a clinical setting and in order to make a timely diagnosis of T2DM in children, the ADA recommends screening of high-risk children. The major criteria for screening are obesity with two additional risk factors (table 2). Screening should start at 10 years of age or at onset of puberty, if it occurs at an earlier age, and should be performed every 2 years. The ADA recommends fasting plasma glucose as a screening tool because of its greater convenience. This is in disagreement to the WHO recommendation of an OGTT. Adult data show that approximately 30% of all persons with undiagnosed diabetes have a non-diabetic fasting glucose [70]. A study in obese children with IGT showed that the prevalence of IFG (based on the former threshold of 111–125 mg/dl) was low (<0.08%) [71]. Another study, evaluating 710 Italian obese children, showed that 30 had IGT (4.2%) and 3 had IFG (0.4%), 2 of whom also had IGT [72]. Adult data suggest that screening with only a fasting glucose will miss around 30% of abnormal 2-hour glucose levels during an OGTT [73]. In a study of 102 high-risk obese children, using the ADA screening criteria would have missed 68% of IGT and 66% of T2DM diagnosed with an OGTT [74]. Unpublished preliminary data from our group shows that only 27% of children who had IGT, also had IFG (based on the current ADA threshold of 100–125 mg/dl), suggesting that an OGTT may be needed to identify those at high risk of developing diabetes. In our experience, we favor performing an OGTT if there is a high risk of developing diabetes. We would also check an HbA1c, not as a screening tool, but to monitor treatment if somebody is diagnosed with T2DM.

Table 2. Screening guidelines for T2DM in children and adolescents


goto top of outline Treatment

Ideally, the care of children with T2DM should be shared among a pediatric endocrinologist, diabetes nurse educator, nutritionist, physical-activity leader and behavioral specialist. It should be family-centered and, as obesity is at the core of this problem, include lifestyle modification with increase in physical activity, decrease in sedentary behavior and changes in nutritional habits. It is true that the effectiveness of lifestyle modification may be limited, but so are its risks [41, 58].

Treatment regimens should be individualized and glycemic goals clearly stated. Ideally, therapy should try to eliminate symptoms of hyperglycemia, promote achievement of a healthy body weight and growth and reach and maintain near-normoglycemia (fasting blood glucose <126 mg/dl). Glycosylated hemoglobin (HbA1c) should be checked every 3 months. Based on the ADA recommendations, the goal should be ≤7% [32]. The American College of Endocrinology [75] and the European Diabetes Policy Group of the International Diabetes Federation (European Region) [76] recommend a more stringent goal of ≤6.5%, for adults, based on evidence showing that there is no minimum increased level of HbA1c at which complications of diabetes and mortality do not occur [77]. Figure 1 provides a proposed algorithm for the management of children with T2DM based on our present knowledge and approved medications. The ultimate goal is to decrease the acute and chronic complications associated with diabetes mellitus and to reduce the risk of premature death. Atherosclerotic disease is the major cause of mortality and morbidity in adults with T2DM [78]. The origin of atherosclerosis is early in childhood with progression toward clinically significant lesions in adulthood [79, 80]. Carotid artery intima media thickness and aortic pulse wave velocity, a measure of arterial stiffness, are non-invasive measures of subclinical atherosclerosis that have been used as surrogate measures of cardiovascular events in adult studies [81, 82]. Our group has recently demonstrated significantly higher aortic pulse wave velocity measurements in adolescents with T2DM compared with obese and normal weight controls, with no differences in intima media thickness among the three groups [83]. The elevated aortic pulse wave velocity in the children with T2DM was comparable to values reported in 41- to 59-year-old obese adults [84] and in approximately 40-year-old men in the Baltimore Longitudinal Study of Aging [82]. Such an observation is consistent with a process of premature aging of the cardiovascular system in youth with T2DM and supports the need to achieve tight metabolic control in these children. In adults with T2DM, the UKPDS [85] and the Kumamoto Study [86] demonstrated that intensive treatment improved metabolic control and decreased the risk of complications. In the UKPDS, for each 1% reduction in mean HbA1c, there was an overall reduction of around 21% in risk of diabetes-related endpoints (i.e., 21% for deaths, 14% for myocardial infarction, and 37% for microvascular complications) [87]. Follow-up of a cohort of men in Norfolk participating in the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk) showed that HbA1c concentration was a significant predictor of death from cardiovascular disease and all-cause mortality. An increase of 1% in HbA1c was associated with a 28% increase in risk of death independent of age, blood pressure, serum cholesterol, BMI, and cigarette smoking habit [88]. Even though such information is not available in pediatrics, common sense would dictate that treatment of youth with T2DM should be comprehensive and not glucocentric (fig. 2). It should include screening and treatment of co-morbidities, particularly hypertension and dyslipidemia which are common conditions in this population.

Fig. 1. Proposed algorithm for the management of youth with T2DM. * 1,000 mg with dinner for 1–2 weeks, and if well tolerated without gastrointestinal discomfort increase the dose to 1,000 mg twice a day [adapted from 41].

Fig. 2. Comprehensive care of T2DM in youth.

goto top of outline Pharmacologic Options

Pharmacologic management of youth with T2DM depends on the severity of presentation. Patients with mild hyperglycemia (126–200 mg/dl) and HbA1c <8.5% or an incidental diagnosis of T2DM can be treated initially with metformin, the only drug, except for insulin, approved in Europe and in the USA by the Food and Drug Administration for pediatric patients with T2DM. However, this must be combined with therapeutic lifestyle intervention with the objective of weight loss and maintenance. The antihyperglycemic action of metformin is due to the inhibition of endogenous (liver) glucose production, mainly gluconeogenesis, and improved insulin-stimulated glucose uptake in peripheral tissues [89]. In addition, it can cause modest weight loss in overweight T2DM patients, improve lipid profile, increase fibrinolysis [90, 91] and decrease transaminases in patients with non-alcoholic steatohepatitis [92].

Metformin gained approval for its use in pediatrics based on a randomized, double-blind, placebo-controlled trial that evaluated the efficacy and safety of the medication, at doses up to 1,000 mg twice daily in 82 children aged 10–16 years. The participants were treated up to 16 weeks. Metformin significantly improved glycemic control and HbA1c values with no cases of lactic acidosis and minimal side effects [93]. At the present, metformin is prescribed in non-ketotic patients starting at a low dose and escalating it over a 1- to 3-week period to the final therapeutic dose of 1,000 mg twice a day. We typically start patients on 1,000 mg with dinner for 1–2 weeks, and if well tolerated, without gastrointestinal discomfort, we increase the dose to 1,000 mg twice a day. On occasion we may start at a 500 mg/day dose based on the individual patient’s need and increase slowly. A modest amount of weight loss is a desirable effect (the mechanism not clearly understood). This medication should not be given to a child who has renal impairment or hepatic or cardiopulmonary insufficiency, or is undergoing evaluation with radiographic contrast materials, because it may precipitate lactic acidosis. Patients and families should be instructed about the hazards of alcohol consumption while on metformin because of this risk. It should also not be prescribed to children with T2DM with ketosis. However, it can be started once the child recovers from ketosis after treatment by rehydration and insulin. The most frequently encountered side effect is mild gastrointestinal discomfort which rarely necessitates drug discontinuation.

There are no other oral hypoglycemic agents that have been approved for use in the pediatric population, though rosiglitazone, a potent insulin sensitizer, was evaluated in juvenile-onset T2DM. The study included 195 obese T2DM children (age range 8–17 years), in a 24-week double-blind, randomized, metformin-controlled, parallel-group design. Participants were randomized to rosiglitazone, maximum dose of 4 mg twice a day, or metformin, maximum dose 1,000 mg twice a day. Median reductions in HbA1c from baseline (rosiglitazone group: –0.25%, p = 0.027; metformin group: –0.55%, p <0.0001) and from screening (rosiglitazone group: –0.5%, p = 0.011; metformin group: –0.5%, p = 0.0037) to week 24 were statistically significant in both groups. Differences between groups were not statistically significant. The rosiglitazone group gained ∼3 kg at 24 weeks, with the occurrence of peripheral edema in 1 child [94].

Sulfonylureas (e.g. glimepiride, glyburide, glipizide), which increase both basal and meal-stimulated insulin secretion, have been used in the treatment of T2DM in adults for more than half a century. A recent single-blind, 26-week study compared metformin and glimepiride in 263 obese youth with T2DM. Glimepiride was started at 1 mg once a day and increased to 8 mg once a day, with metformin escalated to a maximum of 1,000 mg twice a day. There was no significant difference in HbA1c reduction between the two groups (glimepiride: change from baseline –0.85 ± 0.30%, metformin: –0.70 ± 0.30%). However, there was a difference in weight gain (kg) (glimepiride: change from baseline +2.2 ± 0.6 and metformin: +0.7 ± 0.64) [95]. Recent therapeutic advances in adults with T2DM including GLP-1 analogs (exenetide) or amylin analogs (pramlintide) may prove to be beneficial in youth. GLP-1 is secreted upon the ingestion of food and has numerous functions including promoting satiety and reducing appetite, enhancing glucose-dependent insulin secretion and decreasing postprandial glucagon secretion and helping to regulate gastric emptying [96,97,98,99]. In adults, amylin analogs have been shown to reduce food intake and weight. They also reduce glucose levels by suppressing postprandial glucagons secretion and delaying gastric emptying [100,] [101]. These agents have not been tested in children to date.

When a child presents with severe hyperglycemia (>200 mg/dl, HbA1c >8.5% and/or ketosis), he/she should be treated initially with insulin to rapidly achieve metabolic control. Once the youth recovers from ketosis after hydration and treatment with insulin, and once the diagnosis of T2DM is made unequivocally (absent pancreatic autoantibodies), metformin with lifestyle intervention should be started and insulin may be weaned gradually if normoglycemia is maintained [58]. Accelerated deterioration in β-cell function may occur in some youth with T2DM needing the early introduction of insulin to achieve metabolic control [29].

Because evidence in adult patients suggests that the early introduction of insulin therapy facilitates glucose control in the long term, possibly reversing to some extent the damage induced by hyperglycemia on β cells and insulin-sensitive tissues, such an approach has been proposed by some in youth T2DM [102, 103]. New insulin analogs, such as glargine and detemir, may allow for more options in the treatment of patients with T2DM. Insulin glargine, a long-acting analog has a prolonged duration of action (∼24 h) with a relatively smooth blood concentration profile without a pronounced peak, making it useful as a once-a-day basal insulin. Clinical trials in adults with T2DM have shown that bedtime insulin glargine is effective in promoting optimal glycemic control [104]. Similar studies in children with T2DM are needed.

goto top of outline Management of Complications

Acute Complications

Diabetic ketoacidosis and hyperosmolar non-ketotic coma can be life-threatening complications in youth with T2DM [32, 105, 106]. Diabetic ketoacidosis may not be present at diagnosis of T2DM but could present years later during acute intercurrent illness. Although hyperosmolar non-ketotic coma is much less frequent, its case fatality in youth is reported to be 14.3% [105]. Either of these acute complications requires tertiary care referral to specialized pediatric diabetes centers for inpatient management by a medical team with experience in the appropriate fluid hydration, insulin therapy, correction of electrolytes, neurologic/mental status evaluation and airway management [32, 106].


Fasting lipid levels should be measured after establishing good metabolic control upon diagnosis and then annually. The management of dyslipidemia starts with dietary changes and increased physical activity. Target levels and treatment recommendations have been established by the ADA consensus for the treatment of diabetes in youth (fig. 2). Goals include an LDL cholesterol <100 mg/dl, HDL cholesterol >35 mg/dl and triglyceride levels <150 mg/dl. Treatment should include diet, maximizing glycemic control and weight reduction [107]. If lipid levels remain elevated after 6 months of lifestyle modification, medical therapy should be started. HMG-CoA inhibitors (statins) are the most commonly used lipid-lowering agents in pediatric patients and are currently indicated in boys >10 years and in postmenarchal girls with familial hypercholesterolemia.

goto top of outline Hypertension

Blood pressure should be measured in all children with T2DM at every clinic visit. Pre-hypertension is defined as either systolic or diastolic blood pressure between the 90th and 95th percentile for age, sex and height, and above the 95th percentile is considered hypertension (fig. 2). Every T2DM child’s medical record should include the standardized blood pressure tables for an accurate evaluation of the patient’s blood pressure percentile similar to BMI charts [108]. If and when hypertension is documented, treatment should be initiated including lifestyle modifications, with weight loss, dietary changes and increased physical activity. If it does not respond to these interventions, the first line of pharmacological treatment is angiotensin-converting enzyme inhibitors. If normotension is not achieved, combination therapy may be considered by adding angiotensin receptor blockers, calcium channel blockers, cardioselective β-blockers and/or low-dose diuretics [108]. To date, there are no pharmacotherapeutic outcome studies of hypertension or dyslipidemia in youth with T2DM.


goto top of outline Prevention

It is known that T2DM is a progressive disease that often begins years prior to clinical diagnosis, with an increase in insulin resistance, a period of compensatory hyperinsulinemia, and then a decline in pancreatic function with decrease in insulin secretion [23, 24, 40]. A proposed scheme of the natural history of T2DM progression in youth with several unknowns, represented as question marks, is depicted in figure 3. The natural course of T2DM provides the opportunity to intervene at different steps and prevent the development of T2DM. However, there are still many unanswered questions related to this progression in youth, i.e.: What is the induction time for obesity-related diabetes in youth? What is the population prevalence of T2DM and IGT? What is the magnitude of diabetes risk for every kilogram of weight gain and/or BMI increase in youth? And, as important, what are the methods that will prove to be feasible and effective to prevent this condition? These questions can only be answered with careful, systematic research in pediatrics, taking advantage of the accrued knowledge in adults.

Fig. 3. Progression to T2DM in youth. IS = insulin sensitivity; IR-NGT = insulin resistance – normal glucose tolerance; IR-IGT = insulin resistance – impaired glucose tolerance [see 23, 24, 40].

goto top of outline What Have We Learned from Adult Prevention Trials?

There is now convincing evidence from controlled clinical trials that, in adults, lifestyle modification can prevent or delay the development of T2DM in high-risk individuals. Two studies from the 1990s, the Malmo Feasibility Study [109] and the Da Qing Impaired Glucose Tolerance and Diabetes Study [110], reported that lifestyle changes in subjects with IGT led to a significant decrease in the incidence of diabetes. Two more recent randomized, controlled clinical trials have demonstrated the benefits of lifestyle intervention on the prevention or delay in the progression from IGT to T2DM. The Diabetes Prevention Program (DPP) demonstrated that among adults with IGT, over a 3-year period, a low-fat diet in combination with 150 min/week of exercise and around 5–7% body weight loss reduced the risk of converting to diabetes by 58% compared with no lifestyle intervention. Metformin also reduced the risk but not as dramatically as lifestyle changes (38%) [111]. A 58% reduction in progression from IGT to T2DM was also demonstrated in the Finnish Diabetes Prevention Study, comparing individuals with IGT who received aggressive lifestyle intervention with those who did not [112]. Other studies have focused on the use of different medications to prevent or delay the development of T2DM, among those the STOP-NIDDM randomized trial, which evaluated the effect of acarbose in subjects with IGT, showing that this medication was associated with a 32% decreased conversion to T2DM and an increased reversion of IGT to normal glucose tolerance [113], the TRIPOD Study which randomized Hispanic women with prior gestational diabetes mellitus to troglitazone versus placebo and found a reduction of 56% in diabetes risk in the group on the medication [114], and the XENDOS study which randomized subjects with a BMI >29 to lifestyle change plus either orlistat or placebo and found a 37% risk reduction in the incidence of diabetes in the former group [115]. Bariatric surgery-induced weight loss in adults with clinically severe obesity has also been found to prevent the progression from IGT to diabetes mellitus by >30-fold [116].

Regarding duration of the effects, information is quite limited. In the DPP, follow-up analysis showed that in patients who took metformin and were reassessed with a repeat OGTT 1–2 weeks after discontinuation of the medication, a sizable minority had developed diabetes, so the diabetes-preventing effect of metformin was reduced from 31 to 25% [117].

goto top of outline What Do We Know about Pediatric Prevention Trials?

Very limited studies in pediatrics have assessed the outcome of lifestyle intervention or pharmacotherapy on obesity and metabolic parameters but none in youth with IGT to evaluate progression to T2DM. One main reason for this is the fact that despite the escalating rates of childhood obesity, IGT and T2DM remain relatively uncommon compared with the rates in adults.

Family-based behavioral treatment has been associated with short- and long-term effects on weight control in obese children aged 6–12 years in a prospective randomized controlled study [118,] [119]. Obese children and their parents were randomized to three groups that were provided similar diet, exercise, and behavior management training but differed in the reinforcement for weight loss and behavior change. The child and parent group reinforced parent and child behavior change and weight loss, the child group reinforced child behavior change and weight loss, and the non-specific control group reinforced families for attendance. Children in the child and parent group showed significantly greater decreases in percent overweight after 5 and 10 years (–11.2 and –7.5%, respectively) than children in the non-specific control group (+7.9 and +14.3%, respectively). Children in the child group showed increases in percent overweight after 5 and 10 years (+2.7 and +4.5%, respectively) that were midway between those for the child and parent and non-specific groups and not significantly different from either [119].

In a limited study of obese adolescents, a program of behavioral lifestyle intervention combined with sibutramin vs. placebo in a double-blind, placebo-controlled fashion demonstrated that, at month 6, participants in the behavioral therapy group with sibutramine lost around 7.8 ± 6.3 kg (SD), and had an 8.5 ± 6.8% reduction in BMI, which was significantly more than the 3.2 ± 6.1 kg weight loss, and the 4.0 + 5.4% reduction in BMI in the behavioral therapy and placebo group. However, after unblinding and from months 7 to 12, adolescents initially treated with sibutramine gained weight despite continued use of the drug, whereas those who switched from placebo to sibutramine lost weight. The authors concluded that the addition of sibutramine to a comprehensive behavioral program induced significantly more weight loss than did behavioral therapy alone. However, they also cautioned that, until more extensive safety and efficacy data are available, medications for weight loss should be used only on an experimental basis in children [120]. Metformin use has been popularized for the treatment of pediatric obesity by practitioners despite no such labeling by the drug maker and despite the lack of convincing long-term, well-controlled, large-scale studies in pediatrics. Metformin treatment in morbidly obese adolescents, together with low calorie diet for only 8 weeks, when compared to placebo, resulted in greater weight loss (6.5 ± 0.8 vs. 3.8 ± 0.4%), greater decrease in body fat, and greater attenuation of insulin area under the curve during an OGTT [121]. However, one has to interpret the results cautiously since the very low calorie diet may have played a crucial role in the observed outcomes. In another double-blind, placebo-controlled study of metformin in only 29 obese adolescents (ages 12–19 years) with family history of T2DM, the metformin group had a modest decline of –1.3% from baseline in BMI compared with +2.3% in the control group after 6 months of treatment. There was a significant decline in fasting blood glucose and insulin levels; however, there were no significant improvements in insulin sensitivity, nor HbA1c or lipid levels [122]. It is clear that more studies are needed to clarify the potential benefits of behavioral lifestyle intervention and pharmacotherapy in obese children at high risk for T2DM. Until such studies become available, healthcare providers should practice primum non nocere.

In general, weight loss and/or prevention of weight gain are considered the best approach to prevent T2DM and decrease the prevalence of risk factors among children who are at risk for the disease. This should be achieved by lifestyle modification including dietary change, increased physical activity and reduced sedentary behavior. Unfortunately, evidence for the long-term effectiveness of obesity treatment and prevention programs among children is scarce. The most promising approaches involve schools and families. Examples of programs include the Kahnawake Diabetes Prevention Project in Canada [123], the Ho-Chunk Youth Fitness Program in Native Americans in the USA [124], the Pathways Intervention [125], the Zuni Diabetes Prevention Program [126], also in Native Americans and the Bienestar school-based diabetes mellitus prevention program focusing on Mexican-American children [127], among others. These interventions have showed mixed results, with some of them improving knowledge of healthy lifestyles but most of them failing to have an impact on the prevention of obesity, glucose, insulin levels and other risk factors [128].

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) has sponsored a collaborative agreement entitled Studies to Treat or Prevent Pediatric Type 2 Diabetes (STOPP-T2D) to conduct a clinical treatment trial, Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY), and a school-based primary prevention trial of T2DM in children and youth, HEALTHY Trial. The primary objective of the TODAY trial is to compare the efficacy of three treatment arms on time to treatment failure based on glycemic control. Treatment failure is defined as: (1) HbA1c >8% over a 6-month period and (2) inability to wean from temporary insulin therapy due to metabolic decompensation.

The three treatment regimens are: (1) metformin alone; (2) metformin plus rosiglitazone, and (3) metformin plus an intensive lifestyle intervention [129]. The outcome of these studies will be instrumental in advancing the knowledge in pediatric T2DM.


goto top of outline The Future

With the unabated increasing prevalence of obesity, T2DM in youth is emerging as a serious new public health problem. Not only pediatricians’ armamentarium in managing these children is very limited, but the future is unclear with respect to the chronic complications of the disease. Is it possible that we will witness these youngsters with T2DM succumb to CVD morbidity and mortality at the peak of their productive life? In the absence of evidence-based research and in the lack of information it is only prudent to err on the safe side while learning from the experiences of our adult colleagues. Vigilance in managing glycemia, dyslipidemia, hypertension, smoking and weight control may prove essential in this patient population. Undoubtedly, focus should be directed towards strategies for disease prevention and treatment optimization. Prevention of obesity and its co-morbid conditions, T2DM being one of several, will require major environmental change. This necessitates the collaboration among all sectors of society, parents, schools, educators, healthcare providers, food and entertainment industries, economists, policy-makers, and governmental agencies. Safe and effective pharmacotherapeutic or surgical approaches may also be helpful in the treatment of obesity and T2DM. There is no question that the next decade will be a challenging one for all of us involved in the care of these young patients.

 goto top of outline References
  1. Libman I, Arslanian S: Type 2 diabetes mellitus: no longer just adults. Pediatr Ann 1999;28:589–593.
  2. Fagot-Campagna A, Pettitt D, Engelgau MM, Burrows NR, Geiss LS, Valdez R, Beckles GL, Saaddine J, Gregg EW, Williamson DF, Narayan KM: Type 2 diabetes among North American children and adolescents: an epidemiologic review and a public health perspective. J Pediatr 2000;136:664–672.
  3. Dabelea D, Hanson RL, Bennett PH, Roumain J, Knowler WC, Pettitt DJ: Increasing prevalence of type 2 diabetes in American-Indian children. Diabetologia 1998;41:904–910.
  4. Neufeld N, Raffel L, Landon C, Chen Y, Valdheim C: Early presentation of type 2 diabetes in Mexican-American youth. Diabetes Care 1998;21:80–86.
  5. Pihoker C, Scott C, Lensing SY, Cradock MM, Smith J: Non-insulin-dependent diabetes mellitus in African-American youths of Arkansas. Clin Pediatr (Phila) 1998;37:97–102.
  6. Pinhas-Hamiel O, Dolan LM, Daniels SR, Standiford D, Khoury P, Zeitler P: Increased incidence of non-insulin-dependent diabetes mellitus among adolescents. J Pediatr 1996;128:608–615.
  7. Dean H: NIDDM-Y in First Nation children in Canada. Clin Pediatr 1998;37:89–96.
  8. Kadiki O, Reddy M, Marzouk A: Incidence of insulin-dependent diabetes and non-insulin-dependent diabetes (0–34 years at onset) in Benghazi, Libya. Diabetes Res Clin Pract 1996;32:165–173.
  9. Huen KF Low LC, Wong GW, Tse WW, Yu AC, Lam YY, Cheung PC, Wong LM, Yeung WK, But BW, Cheung PT, Kwan EY, Karlberg JP, Lee C: Epidemiology of diabetes mellitus in children in Hong Kong: the Hong Kong childhood diabetes register. J Pediatr Endocrinol Metab 2000;13:297–302.
  10. Wei JN, Sung FC, Lin CC, Lin RS, Chiang CC, Chuang LM: National surveillance for type 2 diabetes mellitus in Taiwanese children. JAMA 2003;290:1345–1350.
  11. Kitagawa T, Owada M, Urakami T, Yamauchi K: Increased incidence of non-insulin-dependent diabetes mellitus among Japanese school children correlates with an increased intake of animal protein and fat. Clin Pediatr 1998;37:111–115.
  12. Likitmaskul S, Kiattisathavee P, Chaichan-Watanakul K, Punnakanta L, Angsusiangha K, Tuchinda C: Increasing prevalence of type 2 diabetes mellitus in Thai children and adolescents associated with increasing prevalence of obesity. J Pediatr Endocrinol Metab 2003;16:71–77.
  13. Braun B, Zimmermann MB, Kretchmer N, Spargo RM, Smith RM, Gracey M: Risk factors for diabetes and cardiovascular disease in young Australian aborigines: a 5-year follow-up study. Diabetes Care 1996;19:472–479.
  14. Ehtisham S, Hattersley AT, Dunger DB, Barrett TG; British Society for Paediatric Endocrinology and Diabetes Clinical Trials Group: first UK survey of paediatric type 2 diabetes and MODY. Arch Dis Child 2004;89:526–529.
  15. Schober E, Holl RW, Grabert M, Thon A, Rami B, Kapellen T, Seewi O, Reinehr T: Diabetes mellitus type 2 in childhood and adolescence in Germany and parts of Austria. Eur J Pediatr 2005;164:705–707.
  16. Ortega-Rodriguez E, Levy-Marchal C, Tubiana N, Czernichow P, Polak M: Emergence of type 2 diabetes in an hospital based cohort of children with diabetes mellitus. Diabetes Metab 2001;27:574–578.
  17. Rami B, Schober E, Nachbauer E, Waldhor T, Austrian Diabetes Incidence Study Group: Type 2 diabetes mellitus is rare but not absent in children under 15 years of age in Austria. Eur J Pediatr 2003;162:850–852.
  18. Weyer C, Bogardus C, Mott DM, Pratley RE: The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest 1999;104:787–794.
  19. Arslanian SA: Insulin resistance and insulin secretion in childhood and adolescence: their role in type 2 diabetes; in Silink M, Kida K, Rosenbloom AL (eds): Type 2 Diabetes in Childhood and Adolescence: A Global Perspective. London, Dunitz, 2003, pp 93–116.
  20. Tripathy D, Carlsson M, Almgren P, Isomaa B, Taskinen MR, Tuomi T, Groop LC: Insulin secretion and insulin sensitivity in relation to glucose tolerance: lessons from the Botnia Study. Diabetes 2000;49:475–480.

    External Resources

  21. Kobayashi K, Amemiva S, Higashida K, Ishihara T, Sawanobori E, Kobayashi K, Mochizuki M, Kikuchi N, Tokuyama K, Nakazawa S: Pathogenic factors of glucose intolerance in obese Japanese adolescents with type 2 diabetes. Metabolism 2000;49:186–191.
  22. Umpaichitra V, Bastian W, Taha D, Banerji MA, Ruskin TW, Castells S: C-peptide and glucagon profiles in minority children with type 2 diabetes mellitus. J Clin Endocrinol Metab 2001;86:1605–1609.
  23. Arslanian SA, Lewy VD, Danadian K: Glucose intolerance in obese adolescents with polycystic ovary syndrome: roles of insulin resistance and β-cell dysfunction and risk of cardiovascular disease. J Clin Endocrinol Metab 2001;86:66–71.
  24. Gungor N, Bacha F, Saad R, Janosky J, Arslanian S: Youth type 2 diabetes: insulin resistance, β-cell failure, or both? Diabetes Care 2005;28:638–644.
  25. Weiss R, Caprio S, Trombetta M, Taksali SE, Tamborlane WV, Bonadonna R: Beta-cell function across the spectrum of glucose tolerance in obese youth. Diabetes 2005;54:1735–1743.
  26. Elder D, Prigeon R, Wadwa R, Dolan L, D’Alessio D: Beta-cell function, insulin sensitivity, and glucose tolerance in obese diabetic and nondiabetic adolescents and young adults. J Clin Endocrinol Metab 2006;91:185–191.
  27. Matthews DR, Cull CA, Stratton IM, et al: UKPDS26: sulfonylurea failure in non-insulin-dependent diabetic patients over 6 years. Diabet Med 1998;15:297–303.
  28. Saad R, Gungor N, Arslanian S: Progression from normal glucose tolerance to type 2 diabetes in a young girl: longitudinal changes in insulin sensitivity and secretion assessed by the clamp technique and surrogate estimates. Pediatr Diabetes 2005;6:95–99.
  29. Gungor N, Arslanian S: Progressive β-cell failure in type 2 diabetes mellitus in youth. J Pediatr 2004;144:656–659.
  30. Grant SFA, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, et al: Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet DOI: 10.1038/ng1732.
  31. Hansen L, Pedersen O: Genetics of type 2 diabetes mellitus: status and perspectives. Diabetes Obes Metab 2005;7:122–135.
  32. American Diabetes Association. Type 2 diabetes in children and adolescents. Diabetes Care 2000;23:381–389.
  33. Danadian K, Balasekaren G, Lewy V, Mesa MP, Robertson R, Arslanian SA: Insulin sensitivity in African-American children with and without family history of type 2 diabetes. Diabetes Care 1999;22:1325–1329.
  34. Arslanian S, Bacha F, Saad R, Gungor N: Family history of type 2 diabetes is associated with decreased insulin sensitivity and impaired balance between insulin sensitivity and insulin secretion in white youth. Diabetes Care 2005;28:115–119.
  35. Arslanian S, Saad R, Lewy V, Danadian K, Janosky J: Hyperinsulinemia in African-American children: decrease insulin clearance and increased insulin secretion and its relationship to insulin sensitivity. Diabetes 2002;51:3014–3019.
  36. Goran MI, Bergman RN, Cruz ML, Watanabe R: Insulin resistance and associated compensatory responses in African-American and Hispanic children. Diabetes Care 2002;25:2184–2190.
  37. Gower BA, Nagy TR, Goran MI: Visceral fat, insulin sensitivity, and lipids in prepubertal children. Diabetes 1999;48:1515–1521.
  38. Bacha F, Saad R, Gungor N, Arslanian SA: Does adiponectin explain the lower insulin sensitivity and hyperinsulinemia of African-American children? Pediatr Diabetes 2005;6:100–102.
  39. Lee S, Bacha F, Gungor N, Arslanian SA: Racial differences in adiponectin in youth: relationship to visceral fat and insulin sensitivity. Diabetes Care 2006;29:51–56.
  40. Bacha F, Saad R, Gungor N, Arslanian SA: Adiponectin in youth: relationship to visceral adiposity, insulin sensitivity, and β-cell function. Diabetes Care 2004;27:547–552.
  41. Hannon TS, Rao G, Arslanian SA: Childhood obesity and type 2 diabetes mellitus. Pediatrics 2005;116:473–480.
  42. Caprio S, Bronson M, Sherwin RS: Co-existence of severe insulin resistance and hyperinsulinemia in preadolescent obese children. Diabetologia 1996;39:1489–1497.
  43. Arslanian S, Suprasongsin C: Insulin sensitivity, lipids and body composition in childhood: is ‘syndrome X’ present? J Clin Endocrinol Metab 1996;81:1058.
  44. Wajchenberg BL: Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 2000;21:697–738.
  45. Owens S, Gutin B, Barbeau P, Litaker M, Allison J, Humphries M, Okuyama T, Le NA: Visceral adipose tissue and markers of the insulin resistance syndrome in obese black and white teenagers. Obes Res 2000;8:287–293.
  46. Goran MI, Gower BA: Relation between visceral fat and disease risk in children and adolescents. Am J Clin Nutr 1999;70:149S–156S.
  47. Bacha F, Saad R, Gungor N, Janosky J, Arslanian SA: Obesity, regional fat distribution, and syndrome X in obese black versus white adolescents: race differential in diabetogenic and atherogenic risk factor. J Clin Endocrinol Metab 2003;88:2534–2340.
  48. Strauss RS, Pollack HA: Epidemic increase in childhood overweight, 1986–1998. JAMA 2001;286:2845–2848.
  49. McCarthy HD, Ellis SM, Cole TJ: Central overweight and obesity in British youth aged 11–16 years: cross-sectional surveys of waist circumference. BMJ 2003;326:624.
  50. Amiel SA, Caprio S, Sherwin RS, Plewe G, Haymond MW, Tamborlane WV: Insulin resistance of puberty: a defect restricted to peripheral glucose metabolism. J Clin Endocrinol Metab 1991;72:277–282.
  51. Dunaif A: Insulin action in the polycystic ovary syndrome. Endocrinol Metab Clin North Am 1999;28:341–359.
  52. Lewy VD, Danadian K, Witchel SF, Arslanian SA: Early metabolic abnormalities in adolescent girls with polycystic ovary syndrome. J Pediatr 2001;138:38–44.
  53. Brickman WJ, Howard JC, Metzger BE: Abnormal glucose tolerance in children with acanthosis nigricans: a chart review. Diabetes 2002;51:A429.
  54. Pettitt DJ, Baird HR, Aleck KA, Bennett PH, Knowler WC: Excessive obesity in offspring of Pima Indian women with diabetes during pregnancy. N Engl J Med 1983;308:242–245.
  55. Silverman BL, Rizzo TA, Cho NH, Metzger BE: Long-term effects of the intrauterine environment: the Northwestern University Diabetes in Pregnancy Center. Diabetes Care 1998;21:B142–B149.
  56. Barker DJP, Hales CN, Fall CHD, Osmond C, Phipps K, Clark PM: Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia 1993;36:62–67.
  57. Hales CN, Barker DJ: The thrifty phenotype hypothesis. Br Med Bull 2001;60:5–20.
  58. Gungor N, Hannon T, Libman I, Bacha F, Arslanian S: Type 2 diabetes mellitus in youth: the complete picture to date. Pediatr Clin North Am 2005;52:1579–1609.
  59. American Diabetes Association: Diagnosis and classification of diabetes mellitus. Diabetes Care 2006;28:S43–S48.

    External Resources

  60. Alberti G, Zimmett P, Shaw J, Bloomgarden Z, Kaufman F, Silink M, Consensus Workshop Group: Type 2 diabetes in the young: the evolving epidemic. The International Diabetes Federation Consensus Workshop. Diabetes Care 2004;27:1798–1811.
  61. WHO Consultation: Definition, diagnosis and classification of diabetes mellitus and its complications. I. Diagnosis and classification of diabetes mellitus. 99:2. Geneva, WHO, 1999.
  62. Tirosh A, Shai I, Tekes-Manova D, Israeli E, Pereg D, Shochat T, Kochba I, Rudich A, for the Israeli Diabetes Research Group: Normal fasting plasma glucose levels and type 2 diabetes in young men. N Engl J Med 2005;353:1454–1462.
  63. Libman IM, Pietropaolo M, Arslanian SA, LaPorte RE, Becker DJ: Changing prevalence of overweight children and adolescents at onset of insulin-treated diabetes. Diabetes Care 2003;26:2871–2875.
  64. Dean HE, Mandy RLL, Miffed M: Non-insulin-dependent diabetes mellitus in Indian children in Manitoba. Can Med Assoc J 1992;147:52–57.
  65. Hathout EH, Thomas W, El-Shahawny M, Nahab F, Mace JW: Diabetic autoimmune markers in children and adolescents with type 2 diabetes. Pediatrics 2001;107:e102.

    External Resources

  66. Umpaichitra V, Banerji MA, Castells S: Autoantibodies in children with type 2 diabetes mellitus. J Pediatr Endocrinol Metab 2002;15:525–530.
  67. Brooks-Worrell BM, Greenbaum CJ, Palmer JP, Pihoker C: Autoimmunity to islet proteins in children diagnosed with new-onset diabetes. J Clin Endocrinol Metab 2004;89:2222–2227.
  68. Reinehr T, Schober E, Wiegand S, Thon A, Holl R and on behalf of the DPV-Wiss Study Group: β-Cell autoantibodies in children with type 2 diabetes mellitus: subgroup of misclassification? Arch Dis Child 2006;91:73–477.

    External Resources

  69. Arslanian S, Bacha F, Gungor N: Youth type 2 diabetes: What are the implications of positive islet-cell autoantibodies? American Diabetes Association 66th Annual Scientific Sessions, 2006, abstr. 57-LB.
  70. Shaw J, Zimmett P, McCarthy D, de Courten M: Type 2 diabetes worldwide according to the new classification and criteria. Diabetes Care 2000;23:B5–B10.

    External Resources

  71. Sinha R, Fisch G, Teague B, Tamborlane WV, Banvas B, Allen K, Savoye M, Rieger V, Taksali S, Barbetta G, Sherwin RS, Caprio S: Prevalence of impaired glucose tolerance among children and adolescents with marked obesity. N Engl J Med 2002;346:802–810.
  72. Invitti C, Guzzaloni G, Gilardini L, Morabito F, Viberti G: Prevalence and concomitants of glucose intolerance in European obese children and adolescents.Diabetes Care 2003;26:118–124.
  73. Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) Study Group, on behalf of the European Diabetes Epidemiology Group: Consequences of the new diagnostic criteria for diabetes in older men and women. Diabetes Care 1999;22:1667–1671.
  74. Wiegand S, Maikowski U, Blankenstein O, Biebermann H, Tarnow P, Gruters A: Type 2 diabetes and impaired glucose tolerance in European children and adolescents with obesity – a problem that is no longer restricted to minority groups. Eur J Endocrinol 2004;151:199–206.
  75. American College of Endocrinology: Implementation conference for ACE outpatient diabetes mellitus consensus conference recommendations: Position statement February 2, 2005;http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf
  76. Alberti G: A desktop guide to Type 2 diabetes mellitus. European Diabetes Policy Group 1998–1999 International Diabetes Federation European Region. Diabetic Medicine 1999;16:716–730.
  77. The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–986.
  78. Meigs JB: Epidemiology of cardiovascular complications in type 2 diabetes mellitus. Acta Diabetol 2003;40:S358–S361.

    External Resources

  79. Zieske AW, Malcom GT, Strong JP: Natural history and risk factors of atherosclerosis in children and youth: the PDAY Study. Pediatr Pathol Mol Med 2002;21:213–237.
  80. Berenson GS: Childhood risk factors predict adult risk associated with subclinical cardiovascular disease: the Bogalusa Heart Study. Am J Cardiol 2002;90:3L–7L.
  81. Salonen R, Salonen JT: Progression of carotid atherosclerosis and its determinants: a population-based ultrasonography study. Atherosclerosis 1990;81:33–40.
  82. Vaitkevicius PV, Fleg JL, Engel JH, O’Connor FC, Wright JG, Lakatta LE, Yin FC, Lakatta EG: Effects of age and aerobic capacity on arterial stiffness in healthy adults. Circulation 1993;88:1456–1462.
  83. Gungor N, Thompson T, Sutton-Tyrrell K, Janosky J, Arslanian S: Early signs of cardiovascular disease in youth with obesity and type 2 diabetes. Diabetes Care 2005;28:1219–1221.
  84. Wildman RP, Mackey RH, Bostom A, Thompson T, Sutton-Tyrrell K: Measures of obesity are associated with vascular stiffness in young and older adults. Hypertension 2003;42:468–473.
  85. UK Prospective Diabetes Study (UKPDS) Group: Intensive blood glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. BMJ 1998;317:703–713.
  86. Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M: Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with noninsulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995;28:103–107.
  87. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR: Association of glycemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405–412.
  88. Khaw KT, Wareham N, Luben R, Bingham S, Oakes S, Welch A, Day N: Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European Prospective Investigation of Cancer and Nutrition (EPIC-Norfolk). BMJ 2001;322:15–18.
  89. DeFronzo RA, Gottman A, Metformin Investigator Group: Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 1995;333:541–549.
  90. Bailey CJ, Turner RC: Metformin. N Engl J Med 1996;334:574–579.
  91. De Fronzo R, Goodman AM, The Multicenter Metformin Study Group: Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 1995;333:541–549.
  92. Caballero A, Arora S, Saouaf R, Lim SC, Smakowski P, Park JY, King GL, LoGerfo FW, Horton ES, Veves A: Micro- and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes. Diabetes 1999;48:1856–1862.
  93. Jones K, Arslanian S, Peterokova VA, Park JS, Tomlinson MJ: Effect of metformin in pediatric patients with type 2 diabetes: a randomized controlled trial. Diabetes Care 2002;25:89–94.
  94. Dabiri G, Jones K, Krebs J, Sun Y, Mudd P, Weston W, Cobitz A, Freed M, Porter LE: Benefits of rosiglitazone in children with T2DM (abstract). Diabetes 2005;A457.
  95. Gottschalk M, Danne T, Cara J, Vlajinic A, Issa M: Glimepiride vs. metformin as monotherapy in pediatric subjects with T2DM: a single-blind comparison study (abstract). Pediatr Diabetes 2005;6:SP18.
  96. Flint A, Raben A, Astrup A, Holst JJ: Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest 1998;101:515–520.
  97. Larsson H, Holst JJ, Ahren B: Glucagon-like peptide-1 reduces hepatic glucose production indirectly through insulin and glucagon in humans. Acta Physiol Scand 1997;160:413–422.
  98. Nauck MA, Wollschlager D, Werner J, Holst JJ, Orskov C, Creutzfeldt W, Willms B: Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [7–36 amide]) in patients with NIDDM. Diabetologia 1996;39:1546–1553.
  99. Drucker DJ: Glucagon-like peptides. Diabetes 1998;47:159–169.
  100. Chapman I, Parker B, Doran S, Feinle-Bisset C, Wishart J, Strobel S, Wang Y, Burns C, Lush C, Weyer C, Horowitz M: Effect of pramlintide on satiety and food intake in obese subjects and subjects with type 2 diabetes. Diabetologia 2005;48:838–848.
  101. Hollander P, Maggs DG, Ruggles JA, Fineman M, Shen L, Kolterman OG, Weyer C: Effect of pramlintide on weight in overweight and obese insulin-treated type 2 diabetes patients. Obes Res 2004;12:661–668.
  102. Sellers EA, Dean H: Short-term insulin therapy in adolescents with type 2 diabetes mellitus. J Pediatr Endocrinol Metab 2004;17:1561–1564.
  103. Glaser B: Early intensive insulin treatment for induction of long-term glycaemic control in type 2 diabetes. Diabetes Obes Metab 1999;1:67–74.
  104. Yki-Jarvinen H, Dressler A, Ziemen M, HOE 901/3002 Study Group: Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. Diabetes Care 2000;23:1130–1136.
  105. Fourtner SH, Weinzimer SA, Levitt Katz LE: Hyperglycemic hyperosmolar non-ketotic syndrome in children with type 2 diabetes. Pediatr Diabetes 2005;6:129–135.
  106. Morales AE, Rosenbloom AL: Death caused by hyperglycemic hyperosmolar state at the onset of type 2 diabetes. J Pediatr 2004;144:270–279.
  107. American Diabetes Association: Management of dyslipidemia in children and adolescents with diabetes. Diabetes Care 2003;26:2194–2197.
  108. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents: The 4th Report on the Diagnosis, Evaluation and Treatment of High Blood Pressure in Children and Adolescents. Pediatrics 2004;114:555–576.
  109. Eriksson KF, Lindgarde: Prevention of type 2 (non-insulin-dependent) diabetes mellitus by diet and physical exercise. The 6-year Malmo Feasibility Study. Diabetologia 1991;34:891–898
  110. Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, Hu ZX, Lin J, Xiao JZ, Cao HB, Liu PA, Jiang XG, Jiang YY, Wang JP, Zheng H, Zhang H, Bennett PH, Howard B: Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997;20:537–544.
  111. Diabetes Prevention Program Research Group: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Eng J Med 2002;346:393–403.
  112. Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Hanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salmien V, Uusitupa M, Finnish Diabetes Prevention Study Group: Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Eng J Med 2001;344:1343–1350.
  113. Chiasson JL, Josee RG, Gomis R, Hanefed M, Karasik A, Laakso M, STOP-NIDDM Trial Research Group: Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomized trial. Lancet 2002;359:2072–2077.
  114. Buchanan TA, Xiang AH, Peters RK, Kios SL, Marroquin A, Goico J, Ochoa C, Tan S, Berkowitz K, Hodis HN, Azen SP: Preservation of pancreatic β-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes 2002;51:2796–803.
  115. Torgerson JS, Hauptman J, Boldrin MN, Sjostrom L, XENical in the prevention of Diabetes in Obese Subjects (XENDOS) Study: A randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 2004;27:155–161.
  116. Long SD, O’Brien K, MacDonald KG JR, Leggett-Frazier N, Swanson MS, Pories WJ, Caro JF: Weight loss in severely obese subjects prevents the progression of impaired glucose tolerance to type II diabetes. A longitudinal interventional study. Diabetes Care 1994;17:372–375.
  117. Diabetes Prevention Research Group: Effects of withdrawal from metformin on the development of diabetes in the diabetes prevention program. Diabetes Care 2003;26:977–980.
  118. Epstein LH, Myers MD, Raynor HA, Saelens BE: Treatment of pediatric obesity. Pediatrics 1998;101:554–570.
  119. Epstein, LH, Valoski, A, Wing, RR, McCurley J: Ten-year follow-up of behavioral family-based treatment for obese children JAMA 1990;264:2519–2523.
  120. Berkowitz RI, Wadden TA, Tershakovec AM, Cronquist JL: Behavior therapy and sibutramine for the treatment of adolescent obesity: a randomized controlled trial. JAMA 2003;289:1805–1812.
  121. Kay JP, Alemzadeh R, Langley G, D’Angelo L, Smith P, Holshouser S: Beneficial effects of metformin in normoglycemic morbidly obese adolescents. Metabolism 2001;50:1457–1461.
  122. Freemark M, Bursey D: The effects of metformin on body mass index and glucose tolerance in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes. Pediatrics 2001;107:E55.
  123. Paradis G, Levesque L, Macaulay AC, Cargo M, McComber A, Kirby R, Receveur O, Kishchuk N, Potvin L: Impact of a diabetes prevention program on body size, physical activity and diet among Kanien’keha:ka (Mohawk) children age 6–11 years old: Eight-year results from the Kahnawake Schools Diabetes Prevention Project. Pediatrics 2005;115:333–339.
  124. Carrell A, Meinen A, Garry C, Storandt R: Effects of nutrition education and exercise in obese children: the Ho-Chunk Youth Fitness Program. WMJ 2005;104:44–47.

    External Resources

  125. Caballero B, Clay T, Davis SM, Ethelbah B, Rock BH, Lohman T, Norman J, Story M, Stone EJ, Stevens J: Pathways: a school based randomized controlled trial for the prevention of obesity in American-Indian school children. Am J Clin Nutr 2003;78:1030–1038.
  126. Teufel NI, Ritenbaugh CK: Development of a primary prevention program: insight gained in the Zuni Diabetes Prevention Program. Clin Pediatr (Phila) 1998;37:131–141.
  127. Trevino RP, Yin Z, Hernandez A, Hale DE, Garcia OA, Mobley C: Impact of the Bienestar school-based diabetes mellitus prevention program on fasting capillary glucose levels: a randomized controlled trial. Arch Pediatr Adolesc Med 2004;158:911–917.
  128. Campbell K, Waters E, O’Meara S, Kelly S, Summerbell C: Interventions for preventing obesity in children. Cochrane Database Syst Rev 2004;3.
  129. White NH, Pyle LL, Tamborlane WV, Geffner ME, Guandalini C: Clinical characteristics and co-morbidities in a large cohort of youth with type 2 diabetes mellitus (T2DM) who volunteered for the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) Study (abstract). Diabetes 2006;55:A67.

 goto top of outline Author Contacts

Silva A. Arslanian, MD
Divisions of Weight Management & Wellness and Pediatric Endocrinology, Metabolism and Diabetes Mellitus, Children’s Hospital of Pittsburgh
3705 Fifth Avenue, Pittsburgh, PA 15213 (USA)
Tel. +1 412 692 6565, Fax +1 412 692 5834, E-Mail silva.arslanian@chp.edu

 goto top of outline Article Information

Published online: September 28, 2006
Number of Print Pages : 13
Number of Figures : 3, Number of Tables : 2, Number of References : 129

 goto top of outline Publication Details

Hormone Research (From Developmental Endocrinology to Clinical Research)

Vol. 67, No. 1, Year 2007 (Cover Date: February 2007)

Journal Editor: Czernichow, P. (Paris)
ISSN: 0301–0163 (print), 1423–0046 (Online)

For additional information: http://www.karger.com/HRE

Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.