Treating metabolic syndrome and Type 2 diabetes in children and adolescents

By Omar Ali, MD, FAAP

Background

Diabetes was known to ancient Egyptian and Chinese physicians, and the sweetness of urine in this condition was known to Claudius Galen (we can only imagine how he found out), but it was not until 1936 that Harold Percival Himsworth in London first discussed the possibility of two types of diabetes. It took another 40 years before this differentiation was well established and understood. We now differentiate between Type 1 diabetes (due to absolute deficiency of insulin, usually autoimmune) and Type 2 diabetes (due to insulin resistance and associated beta cell defects). There also are a few monogenic causes of diabetes (MODY) that are relatively rare. Type 2 diabetes is associated with obesity and has a strong hereditary component. In the past, it usually was diagnosed in older, obese individuals, but it now is being seen with increasing frequency in the young. This is thought primarily to be a consequence of the increasing prevalence of obesity, though other unknown environmental factors may play a role as well.

In 1988, Gerald Reaven and his colleagues put forward the hypothesis that insulin resistance not only underlays Type 2 diabetes, but also led to hypertension and hyperlipidemia in prediabetic insulin-resistant patients. This combination of insulin resistance, hypertension and hypertriglyceridemia initially was labeled syndrome X and then renamed the metabolic syndrome. The definition of this syndrome has been a matter of some controversy, and Reaven himself recently has proposed renaming it the insulin resistance syndrome. The bottom line is that in adults, there are certain clinical findings (obesity, dyslipidemia, hypertension and evidence of insulin resistance) that tend to cluster together and signify  an increased risk of morbidity and mortality, especially from cardiovascular disease.

Metabolic syndrome in children

The bulk of current evidence supports the supposition that the elements of metabolic syndrome are concerning for similar, if not identical, reasons in children as compared to adults. Several studies have documented the co-occurrence of syndrome components in obese children and adolescents, and the tracking of risk factor clusters from childhood into adult life. The tracking of these risk factors into adult life becomes stronger as the child gets older (a chubby 4-year-old may or may not be an overweight adult, a grossly overweight 16-year-old almost certainly will be an obese adult).

Other pathologies commonly associated with obesity and insulin resistance in children include:

1. Childhood tall stature with advanced bone age and normal final adult height.
2. Acanthosis nigricans. (See Figure 1.)
3. Primary and secondary amenorrhea. 
4. Hyperandrogenism (for example acne, hirsutism).
5. Non-alcoholic hepatic steatosis or fatty liver.

Figure 1 - Acanthosis nigricans

There is no universally accepted set of criteria for the diagnosis of metabolic syndrome in children, but certain clinical features may indicate a need for more aggressive intervention. (See Table 1.)

Obesity BMI >85th percentile for age/sex (CDC charts, www.cdc.gov). Accompanied by one or more of the following: Family History      Obesity, T2DM, metabolic syndrome, early atherosclerosclerotic disease. Hypertension >120/>80. Stature Non-syndromic childhood tall stature, associated with obesity and out of proportion to genetic potential. Advanced bone age with normal preditced adult height for genetic potential. Skin Childhood acne or unusually severe adolescent acne associated with obestiy. Acanthosis nigricans. Premature development of secondary sexual hair. Hirsutism. Menses Primary or secondary amenorrhea. Irregular or absent menses following a period of regular menses (rule out pregnancy in either case). Lab tests Otherwise unexplained elevations of AST and ALT. Fasting gluocose > 100. Glycated hemoglobin (total or HbA1c) above normal range. Total cholesterol > 180 (upper limit is debated). Low HDL (no standards for children). Triglycerides above lab normal range (for age, if available.)

Table 1

Type 2 diabetes mellitus in children

For all intents and purposes, Type 2 diabetes mellitus (T2DM) in children is the ultimate manifestation of obesity and insulin resistance. Most children with T2DM are obese, and the incidence and prevalence of childhood T2DM is increasing worldwide in proportion to the occurrence of obesity. In many clinics, the numbers of newly diagnosed cases of T2DM now equal or exceed the cases of new-onset Type 1 diabetes mellitus (T1DM), despite regional increases in the incidence of T1DM.

The presentation of childhood T2DM (excluding MODY and other syndromic T2DM) generally falls into three categories:

1. Obese, presents with acute weight loss, polyuria, polydipsia, hyperglycemia and ketosis (sometimes true diabetic ketoacidosis). This form can be very difficult to distinguish from T1DM in the initial stages of therapy; the presence of acanthosis nigricans, obesity and a strong family history of Type 2 tend to rule against T1DM. Some of these children have positive anti-GAD65 antibodies and require ongoing insulin treatment to prevent ketogenesis.

2. Obese, presents with mild polyuria/polydipsia, often during a minor unrelated illness. Lab tests show ±hyperglycemia and glucosuria, an elevated glycated hemoglobin and minimal or no ketosis.

3. Obese, asymptomatic, found to have elevated glycated hemoglobin, ±fasting hyperglycemia, no ketosis. This third category accounts for at least half of cases of T2DM in many pediatric diabetes clinics.

Treatment strategies

As with adults, the common pathogenic link for both the metabolic syndrome risk clusters and T2DM is obesity. Therefore, the focus of treatment should be on weight control, specifically aiming for maintenance of BMI below the 85th percentile for age/sex. T2DM may require additional treatment considerations, particularly if there is severe persistent hyperglycemia and/or in ketosis-prone cases.

The utility of specifically defining metabolic syndrome itself may or may not be useful in treating childhood obesity because obese children who do not have metabolic syndrome or T2DM at initial evaluation may later develop these conditions if the obesity is not controlled. Therefore, an argument can be made for treatment and prevention of childhood obesity regardless of the presence or absence of metabolic syndrome. On the other hand, if components of metabolic syndrome are identified, then specific monitoring and, in some cases, treatment may be necessary.

Treatment of asymptomatic obese children

Begin with a complete evaluation, focusing on the elements listed in the table. A simple initial intervention may consist of:

1. Elimination of simple sugars (>5 grams sugar/serving on the food label).
2. Limiting complex carbs to two servings (30 grams) three times daily (emphasizing label reading).
3. Increasing intake of lean proteins, vegetables and fresh fruit.
4. Using low- or non-carb snacks.
5. Avoiding fried or fatty foods.
6. Exercising: ¡Y30 minutes, three to five times per week. Coached activity is preferred (dance, martial arts, competitive sports, etc.).
7. In selected cases, and especially if there is evidence of insulin resistance, metformin is a useful adjunct. Pharmacologic treatment of persistent hypertension and hypercholesterolemia also may be considered.

Treatment of T2DM

This follows a similar approach, starting with diet, exercise and metformin therapy. In ketosis-prone cases, a low dose of long-acting insulin (usually glargine) is used to control ketogenesis. Rare cases benefit from sulfonylureas and insulin secretagogues (for example, repaglinide). Children's Hospital of Wisconsin physicians have not found it necessary to use PPAR agents (TZD's) in childhood T2DM at this time. Overuse of insulin should be avoided as insulin is lipogenic and the underlying pathology is different from Type 1 diabetes.

Conclusions

Pediatric obesity and associated morbidities, including T2DM and components of metabolic syndrome, are increasing worldwide. Risk-based definitions of metabolic syndrome currently have limited specificity in childhood, however, it is clear that the syndrome components cluster and track into adult life. The emphasis in pediatrics should be on treatment and prevention of obesity, emphasizing good dietary choices and regular exercise as integral parts of a healthy lifestyle. Pharmacotherapy may be useful for specific morbidities.

Although treatment of individual, motivated patients can be successful and gratifying, this approach addresses only the tip of the iceberg. On a larger scale, physicians have a responsibility to advocate for community-wide changes that may help to prevent obesity and associated morbidities in the population.

Omar Ali, MD, FAAP, is a pediatric endocrinologist at Children's Hospital of Wisconsin. He also is an assistant professor of Pediatrics (Endocrinology) at the Medical College of Wisconsin.

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