Wednesday, October 4, 2023
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Type 2 diabetes mellitus (type 2 DM), which was once considered a rare condition in the pediatric population, now accounts for about 15% to 45% of all newly diagnosed cases of diabetes in children and teenagers.[1,2] The epidemic of type 2 DM in the pediatric age group is the result of a variety of factors, the most important of which appears to be an increase in the rate of obesity in children.
Depending on the clinical methodology employed, approximately one quarter to one third of children and teens are now overweight -- an increase of 2- to 3-fold over the past 2 to 3 decades.[3] Further, the increase in the prevalence of obesity in children and teens has closely paralleled the increase in the prevalence of type 2 DM in this age group. Particularly disturbing is the observation that 8- to 10-year-olds represent the fastest-growing group of overweight and obese children, indicating that our children are becoming more obese at an increasingly younger age.[4]
The principal factors responsible for the increase in the rates of obesity in children include an increase in their caloric intake and a more sedentary lifestyle. According to Lynne Levitsky, MD,[5] Massachusetts General Hospital, Boston, in a presentation at the 2002 Annual Meeting of the American Academy of Pediatrics, a net gain of 120 calories per day, either from physical inactivity or increased caloric intake, can lead to a weight gain of about 1 pound per month.
It is not surprising, therefore, that the availability of large quantities of calorically rich fast food, combined with more time spent watching TV, playing video games, and working on the computer, have produced a generation of overweight children. Many elementary and secondary schools, facing financial constraints, have limited their physical activity programs while at the same time offering calorically rich foods at lunch. Parental expectations of academic performance have further contributed to the sedentary lifestyle of many children and teens, who spend extra time studying in order to perform well in school.
Some investigators have postulated that childhood obesity may be determined prenatally as a result of fetal adaptation to nutritional deprivation. According to the "thrifty phenotype'' hypothesis,[6] substrate depletion in utero results in adaptive mechanisms designed to enhance energy conservation by the fetus. Postnatally, as calories become more plentiful, the adaptive mechanisms that cause greater efficiency in energy utilization produce greater weight gain relative to caloric intake. Despite its wide acceptance, the validity of the thrifty phenotype hypothesis remains to be determined.
Dr. Levitsky reported that other risk factors for the development of type 2 diabetes in children and teenagers include racial background, family history of type 2 diabetes, clinical evidence of insulin resistance, and female gender.[2,5] Girls are nearly twice as likely to develop type 2 DM as are boys. Type 2 DM has an especially high prevalence in ethnic minorities, including African Americans, Latinos, and American Indians. Despite the greater risk for the development of type 2 DM among ethnic minorities, a rise in the prevalence of type 2 DM has also recently been observed in white children -- about 25% of white children newly diagnosed with diabetes are diagnosed with type 2 DM, Dr. Levitsky pointed out. A family history of the condition in first- and second-degree relatives and clinical signs of insulin resistance, such as acanthosis nigricans, hypertension, and polycystic ovary syndrome (PCOS), are also important risk factors.
Clinical and biochemical findings indicate that the principal factor in the pathophysiology of type 2 DM in children is the development of insulin resistance.[2,5] The condition is associated with hyperlipidemia, hypertension, nonalcoholic hepatosteatosis, and PCOS. Whereas familial and nutritional factors are known to be important in the development of type 2 DM, the precise mechanisms by which genetic and environmental factors produce insulin resistance have yet to be determined. As in adults, progressive deterioration of insulin secretion as a result of "glucose toxicity," hypertriglyceridemia, or other, unknown factors ultimately contributes to the development of type 2 DM in children.
Whereas the relative importance of genetic and environmental influences on the development of obesity and type 2 DM is unknown, it is clear that modifications in dietary intake and physical activity can reduce the incidence of diabetes in individuals at risk for the condition. Dr. Levitsky cited a study[7] recently published by the Diabetes Prevention Program Research Group involving more than 3200 individuals at risk for type 2 DM because of increased body mass, glucose intolerance, and/or a strong family history of type 2 DM. Subjects were randomly assigned to receive routine care (placebo), metformin 850 mg twice daily, or lifestyle modification consisting of dietary intervention and increased physical activity at the level of at least 150 minutes per week.
After almost 3 years of follow-up, the incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and lifestyle modification groups, respectively. According to Dr. Levitsky, lifestyle modification reduced the incidence of type 2 DM by 58% and metformin reduced the incidence by 31%. Whereas similar data in children are lacking, Dr. Levitsky stressed that the message of this study is clear: Children need to eat less and exercise more.
Prevention of obesity needs to begin immediately after birth, according to Dr. Robert Schwartz, former Chair of the Pediatric Endocrinology Subsection of the American Academy of Pediatrics. Pediatricians need to counsel parents about appropriate types and amounts of food for their infants and children. Children need to be encouraged to take part in regular physical activity in order to stay healthy, avoid boredom, and prevent excessive accrual of calories. Weights, heights, weights for heights, and body mass indices (BMI) need to be obtained at regular intervals and plotted on appropriate charts in order to recognize patterns of excessive weight gain. When weight becomes excessive, appropriate intervention must be initiated early in order to increase the chances of success with treatment.
The treatment of type 2 DM in children and teenagers depends on clinical presentation. About one third to one half of youngsters will present with full-blown diabetic ketoacidosis and will require aggressive fluid and insulin therapy to reverse their metabolic decompensation.[1,2] Once stabilized, most individuals will require treatment with a combination of lifestyle modification and insulin and/or oral hypoglycemic agents, in any of a variety of possible combinations.
According to Dr. Levitsky and others,[1,2,4,5] the mainstay of treatment of type 2 DM in the pediatric population is dietary caloric restriction and increased physical activity. Unfortunately, compliance with dietary and exercise therapy in children and teenagers is often poor, even in the best of circumstances. Setting intermediate, attainable treatment goals, involving the entire family in the treatment program, and providing positive reinforcement for appropriate food choices and increased physical activity can help increase compliance with treatment.
In most cases, insulin and/or oral hypoglycemic agents are added to dietary and exercise therapy to improve blood glucose control.[2] Whereas insulin is effective in reducing blood glucose levels, it often promotes further weight gain and carries a higher risk of hypoglycemic reactions in youngsters with type 2 DM. Many physicians and patients are resistant to the need for insulin shots. Consequently, metformin, a biguanide approved by the US Food and Drug Administration for use in children older than 8 years of age, is considered by many to be the first-line treatment for type 2 DM in children and teens.
Metformin decreases hepatic glucose output and enhances primarily hepatic but also muscle insulin sensitivity.[4,8] When combined with dietary and exercise treatment, doses of 500 to 1000 mg twice daily can help reduce glucose concentrations to appropriate target levels. The most common side effects of metformin include gastrointestinal cramping and diarrhea. Serious reactions include metabolic acidosis in individuals with kidney or heart disease and in those requiring intravenous contrast material for radiologic studies.
Sulfonylureas, the most widely used agents in adults with type 2 DM, have not as yet been approved for use in the pediatric population. Nevertheless, reported Dr. Levitsky, they have been found by many pediatric endocrinologists to improve blood glucose levels in children when used alone or when combined with insulin and/or metformin. Likewise, thiazolidinediones, alone and in combination with other agents, have been found to be effective in children. The principal side effects of sulfonylureas and thiazolidinediones are hypoglycemia and liver abnormalities, respectively.[8] Both agents can result in weight gain.
Other therapeutic agents used in the treatment of type 2 DM are alpha-glucosidase inhibitors and anorectic agents such as orlistat and sibutramine.[8,9] According to Dr. Levitsky, alpha-glucosidase inhibitors have limited acceptance in children and teens because of their tendency to promote flatulence and gastrointestinal cramping. Anorectic agents may have a theoretical benefit in youngsters with type 2 DM, but experience with their use in this population is lacking.
Children require evaluation and treatment of other possible disorders associated with obesity and type 2 diabetes.[2] In particular, reported Dr. Levitsky, blood pressure needs to be monitored regularly and hypertension should be aggressively treated in order to prevent or delay the development of renal dysfunction. Likewise, hyperlipidemia requires dietary and/or drug therapy in order to prevent or delay cardiovascular disease. Nonalcoholic hepatosteatosis may produce liver enzyme abnormalities that may complicate drug therapy, on the one hand, and lead to liver dysfunction, on the other. Reproductive abnormalities, including PCOS, may require treatment.
The goals of treatment for type 2 DM in the pediatric population are similar to those in adults, namely, fasting plasma glucose 80-150 mg/dL and glycosylated hemoglobin level below 7%, with few or no episodes of symptomatic hypoglycemia.[2,9] Proper control of hypertension and hyperlipidemia, when present, are additional goals. In children, additional treatment goals include maintenance of normal growth and weight gain, academic advancement, and adequate social adjustment.
A recent report by David Nathan, MD,[9] raises concerns about the adequacy of "standard" therapy for adults with type 2 DM. According to Dr. Nathan, the elapsed time between the actual development of type 2 DM and its diagnosis is about 4 years. Single-drug oral therapy is typically used from about 4 to 7 years after onset (when many individuals are showing evidence of mild to more advanced microvascular disease) and combination oral therapy is used from about 10 to 16 years after onset (when many individuals are showing evidence of mild to more advanced cardiovascular disease). Insulin treatment is typically used 16 to 20 years after onset, when more advanced and life-threatening complications of the disease become established.
Like many other endocrinologists caring for adults with type 2 DM, Dr. Nathan suggests that patients need both more aggressive therapy and more immediate changes in their treatment program when blood glucose levels fail to reach target goals. In addition, many endocrinologists have pushed for tighter control of postprandial blood glucose levels, since there is evidence that this may help prevent the development of the complications associated with type 2 DM. Although children may benefit from similar strategies, aggressive treatment of type 2 DM has to be balanced against the potential risks of hypoglycemia, neurobehavioral abnormalities, and socialization problems that may arise in this patient population.
Recent data indicate that there may be a significant number of obese children with undiagnosed impaired glucose tolerance or frank type 2 DM. In a recently published report, Sinha and colleagues[10] evaluated 55 children (4-10 years of age) and 112 adolescents (11-18 years of age) of white (58%), African American (23%), or Latino (19%) ethnicity referred to the Yale Pediatric Obesity Clinic between 1999 and 2001. All youngsters had a BMI greater than the 95th percentile for age and sex, and 40% of adolescent girls had clinical and/or biochemical evidence of PCOS.
According to the diagnostic criteria of the American Diabetes Association (ADA), 14 of the children (9 white, 4 African American, 1 Latino) and 23 of the adolescents (10 white, 7 African American, 6 Latino) had impaired glucose tolerance. Four of the adolescents (2 African American and 2 Latino) were found to have frank diabetes. Interestingly, children and adolescents with impaired glucose tolerance had higher insulin and C-peptide levels than children and adolescents with normal glucose tolerance and diabetes. Adolescents with diabetes, however, had higher blood glucose levels but similar insulin and C-peptide levels compared with those of children with and without impaired glucose tolerance.
Together, these data support the concept that plasma insulin levels are increased early in the course of diabetes as a result of the compensation that occurs due to underlying insulin resistance. However, with the progression to frank diabetes, insulin secretion becomes insufficient to overcome the underlying insulin resistance, and hyperglycemia ensues.
According to Dr. Levitsky, the higher prevalence of childhood type 2 DM in certain ethnic groups, our knowledge of the natural course of the condition, and the reversal of impaired glucose tolerance in adults through lifestyle modifications have prompted the ADA to recommend screening for type 2 DM in individuals at risk for the disorder.[2] The ADA recommends testing in overweight children and teens (BMI > 85th percentile for age and sex, weight for height > 85th percentile, or > 120% of ideal body weight) who have any 2 of the following characteristics:
Further, the ADA recommends that testing begin at 10 years of age or at puberty (whichever occurs earlier), that testing be repeated every 2 years, and that fasting plasma glucose testing be performed. Whereas some individuals have favored testing by glycosylated hemoglobin measurements and others by urine glucose determinations, the ADA recommends fasting plasma glucose testing because of its ease of use. Although not explicitly stated in the ADA's recommendations, proper counseling of parents and patients geared toward the prevention of at-risk behaviors must be undertaken by all physicians and medical personnel caring for children and teenagers.
