A Clinical Guide to Pediatric Weight Management and Obesity, 1st Edition


Insulin Resistance, the Metabolic Syndrome, and Type 2 Diabetes


A major metabolic implication of the obesity epidemic is the rapid rise in the number of children and adolescents in whom type 2 diabetes is diagnosed or is developing. Type 2 diabetes evolves over time along a continuum of metabolic derangement beginning with insulin resistance.

Obesity in childhood and adolescence has been shown to increase the risk of insulin resistance (1). Insulin resistance has been linked to hypertension, dyslipidemia, polycystic ovarian syndrome (PCOS), and nonalcoholic steatohepatitis (NASH) in children and adolescents with obesity (2). Insulin resistance is a signal feature in the metabolic syndrome, a phenotype first defined by Reaven (3) as “syndrome X.” The metabolic syndrome is defined as obesity, elevated blood pressure, elevated triglyceride, decreased HDL cholesterol levels, and impaired glucose tolerance (IGT). Specific definitions vary, and long-term studies are needed to establish the nature of the link between these risk factors and later morbidity (4,5,6).

As a result of the obesity-driven rise in insulin resistance, the incidence of IGT is increased in obese children. As insulin resistance increases, the first-phase insulin response is lost, resulting in IGT. In one study, 25% of children and 21% of adolescents presenting to an obesity clinic for treatment had IGT, and 4% of adolescents were newly diagnosed with diabetes (7). In these patients, insulin and C-peptide levels were elevated and IGT was associated with insulin resistance, the first phase of the evolution of type 2 diabetes.

State of the Problem

The increase of type 2 diabetes in adults has paralleled the rising prevalence of obesity. Diabetes now affects 7.7% of the adult American population, or 16 million individuals. Adults with a body mass index (BMI) greater than 40 are 7.4 times


more likely to develop diabetes than their normal weight counterparts (8). Type 2 diabetes may range from a predominantly insulin-resistant form treatable with oral agents to a predominantly secretory defect requiring insulin treatment (9).

Paralleling this increase in adults, children and adolescents are also being affected, and the occurrence of type 2 diabetes in childhood is no longer a rarity. Driven by the rise in obesity, type 2 diabetes, in some series (10), comprises 30% of all newly diagnosed cases of diabetes in 10- to 20-year-old patients. Increases in incidence among Native American, African American, and Hispanic children have been particularly striking in the United States (11).

This escalating incidence has been mirrored across the globe, particularly in populations shifting from relative undernutrition to overnutrition (12). In the 1970s and 1980s, type 2 diabetes in children was reported in the Native American (1979) and Canadian First Nation (1984) populations. By the mid 1990s ethnic minorities (African Americans, Hispanic Americans) were experiencing rapidly rising rates of disease, as were children in Japan and Asian populations, and by 2000 cases were emerging in Europe (13).

The onset of diabetes in childhood and adolescence substantially increases the risk of significant morbidity and mortality from retinopathy, nephropathy, neuropathy, and cardiovascular disease at a younger age. Diabetes-associated microvascular and macrovascular complications evolve based on duration of disease and extent of hyperglycemia. Early signs of microvascular change, dyslipidemia, and hypertension are already present at diagnosis in some populations of children (14).


  • Insulin resistance—An impaired ability of plasma insulin at usual concentrations to adequately promote peripheral glucose disposal, suppress hepatic glucose, and inhibit very low density lipoprotein output (8).
  • Prediabetes—A period of either elevated fasting glucose levels or IGT occurring before the development of type 2 diabetes (15). Prediabetes is defined as fasting glucose greater than or equal to 100 mg/dL and less than 126 mg/dL, or a 2-hour post–glucose load plasma glucose level greater than or equal to 140 mg/dL and less than 200 mg/dL (16).
  • GLUT4—A glucose transporter isoform that is the major insulin-responsive transporter. It is located in striated muscle and adipose tissue. GLUT4 transporter proteins are enclosed in intracellular storage vesicles that respond to rising postprandial glucose levels by migrating to the plasma membrane, allowing tissues to respond to fluctuations in circulating insulin levels (17).


The evolution of type 2 diabetes involves the development of both insulin resistance and beta cell failure and progresses over time with a gradual decline in beta cell function (18). First-phase insulin secretion is initially lost, with an inability of


endogenous insulin secretion to compensate for the evolving insulin resistance (19). The cause of insulin resistance, insulin resistance syndrome, and type 2 diabetes is multifactorial.

Type 2 diabetes develops in the setting of genetic predisposition and a permissive nutritional and activity environment. The addition of obesity to genetic risk factors is undoubtedly fueling the current rise in the incidence of type 2 diabetes. Further evidence for the influence of genetics on diabetes risk comes from the wide variation of diabetes prevalence in different ethnic groups when all share similar environments (20).

Obesity in adults can modulate insulin sensitivity secondary to an increase in visceral fat (21). Visceral fat correlates with insulin levels in children (22). Children with greater central adiposity develop metabolic syndrome more frequently than children with peripheral body fat distribution (23). In this same study, waist circumference correlated more strongly to metabolic syndrome than either BMI or skin fold thickness (23). In a study of Hispanic children with increased waist-to-hip ratios, visceral fat measurements were positively correlated to both fasting insulin and acute insulin response to glucose. In the same study, visceral fat measurement was negatively related to insulin sensitivity (24).

Obese children and adolescents with IGT have increased intramyocellular lipid levels and visceral-to-subcutaneous-abdominal-fat ratios when compared with obese nonimpaired individuals (18). Intramyocellular accumulation of lipid causes abnormalities in insulin signaling (18, 25).

The presence of high levels of triglycerides in muscle cells impairs glucose oxidation and insulin response (26).

In a study of obese children and adolescents, intramyocellular lipid and visceral-to-subcutaneous-fat ratio were positively related to the 2-hour plasma glucose level during an oral glucose tolerance test (OGTT) (18). Leptin, which is increased in obesity, may be involved in the regulation of insulin sensitivity and triglyceride levels (26).

Type 2 diabetes is more common in African American children than in white children. During hyperglycemic clamp studies in normal weight children, African American children exhibited higher insulin levels than did their white peers (27). The Bogalusa Heart Study showed increased insulin response to the oral glucose tolerance test in African American versus white children after adjusting for Tanner stage and weight (28).

Collectively, more than 600 genes, markers, and chromosomal regions have been associated or linked with human obesity phenotypes (29). Genetic and familial findings that relate to diabetes include the following:

  • Individual genetic predispositions to type 2 diabetes exist; 75% to 100% of children and adults with type 2 diabetes have a first- or second-degree relative with type 2 diabetes (30).



  • Insulin sensitivity in nondiabetic children from families with a history of type 2 diabetes has been found to be decreased by 20% (31).
  • β-Adrenergic receptor subtypes have been associated with obesity and type 2 diabetes (32).
  • In adults, the concordance rate of type 2 diabetes in monozygotic twins is approximately 90%, and the lifetime risk of type 2 diabetes in a first-degree relative is approximately 40% (33).

Interactions between shifts in energy balance and predisposition to insulin resistance and type 2 diabetes may occur. Such interactions may involve population risk, as when Neal (12) noted in 1962 that an unexpectedly high rate of type 2 diabetes was found in populations shifting from a history of relative undernutrition to overnutrition. He proposed that a “thrifty genotype” of energy conservation had developed to confer a survival advantage in these groups. This hypothesis may be true for several of the ethnic groups with high rates of type 2 diabetes, such as the Pima Indians.

Energy availability in the intrauterine environment may be another determinant of diabetes risk. Children who were infants of diabetic mothers were found to have increased rates of IGT as young as 2 to 5 years of age (34). Exposure to hyperinsulinemia and increased glucose in utero during pregnancy in a diabetic woman can result in macrosomia at birth and an increased risk of obesity, IGT in childhood, and future diabetes (35,36). In addition, infants of diabetic mothers who had a greater intake of breast milk from their mothers had a higher relative body weight at 2 years and a correlation of breast milk intake with postprandial glucose levels (37).The significance of this finding has yet to be determined.

Low birth weight has also been associated with increased rates of type 2 diabetes later in life (38).

The “thrifty phenotype” hypothesis was advanced to propose that early exposure of the fetus to poor nutrition leads to permanent changes in insulin metabolism and body fat distribution (35).

Low birth weight has also been associated with increased central fat deposition in children (39) and higher rates of type 2 diabetes later in life (40). In a Finnish study, children who later developed type 2 diabetes had lower birth weight, lower weight at 1 year, and an early tendency to develop adiposity (41). These findings fit with animal models of prenatal growth restriction followed by postnatal ad lib feeding, which results in insulin resistance and diabetes (42).

The increase in insulin resistance during normal puberty may also enhance the risk of type 2 diabetes because the predominant defect in type 2 diabetes is peripheral resistance to the effects of insulin with a variable insulin secretory deficit (43). In one study, insulin-mediated glucose disposal was 30% lower in pubertal versus prepubertal children and young adults (44). This is thought to be due to the pubertal increase in growth hormone secretion (43). It is worth noting that African American children


do not have the same level of compensatory increase in insulin secretion that white children do in response to high levels of growth hormone during puberty. This may explain their increased risk for type 2 diabetes during this phase of growth (14).

TABLE 8.1. Glucose tolerance test results

·         FPG <100 mg/dL(5.6 mmol/L) = normal fasting glucose

·         FPG 100–125 mg/dL(5.6–6.9 mmol/L) = impaired fasting glucose (IFG)

·         FPG ≥126 mg/dL(7.0 mmol/L) = provisional diagnosis of diabetes (the diagnosis must be confirmed, as described below)

The corresponding categories when the OGTTis used are the following:

·         2-hr post load glucose <140 mg/dL(7.8 mmol/L) = normal glucose tolerance

·         2-hr post load glucose 140–199 mg/dL(7.8–11.1 mmol/L) = impaired glucose tolerance (IGT)

·         2-hr post load glucose ≥200 mg/dL(11.1 mmol/L) = provisional diagnosis of diabetes (the diagnosis must be confirmed, as described below)

FPG, fasting plasma glucose; OGTT, oral glucose tolerance test.

Note that many individuals with IGTare euglycemic in their daily lives. Individuals with IFG or IGT may have normal or near normal glycosylated hemoglobin levels. Individuals with IGToften manifest hyperglycemia only when challenged with the oral glucose load used in the standardized OGTT (1,2).

Reprinted with permission from American Diabetes Association Position Statements Original Article Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2005;28:S37–S42.

Clinical Manifestations

Impaired Glucose Tolerance and Impaired Fasting Glucose

Patients with impaired fasting glucose (IFG) and/or IGT are now referred to as having “prediabetes,” indicating the relatively high risk for development of diabetes in these patients. IFG and IGT are associated with the metabolic syndrome, which includes obesity (especially abdominal or visceral obesity), dyslipidemia [of the high-triglyceride and/or low–high-density lipoprotein (HDL) type], and hypertension (45,46). IFG reference limits were decreased to greater than 100 mg/dL by the Expert Committee on Diagnosis and Classification of Diabetes Mellitus (46). However, the correlation between IFG and IGT is still not perfect, and the OGTT remains the defining test for IGT (47) (Table 8.1). With appropriate changes in lifestyle, progression from IGT to diabetes can be delayed or prevented (48).

Risk Factors

The current rise in the rates of type 2 diabetes can be thought of as the unmasking of underlying individual genetic susceptibility by social, behavioral, and environmental risk factors (14).

Risk factors for type 2 diabetes include the following:

  • Ethnicity
  • Obesity
  • Puberty



  • Positive family history
  • Polycystic ovarian syndrome (PCOS)
  • Acanthosis nigricans
  • Decreased physical activity (49)
  • Maternal diabetes
  • Maternal gestational diabetes (50)

Acanthosis Nigricans

Acanthosis nigricans is associated with insulin resistance and hyperinsulinemia and features of the metabolic syndrome. Prevalence in the general population has been reported as follows:

  • 13.3% in African American children
  • 5.5% in Hispanic children
  • 0.5% in white children (51)

Insulin Resistance

The American Heart Association (52) defines

  • Normal fasting insulin in children as insulin <15 µU/mL (following a 12-hour fast)
  • Borderline high fasting insulin as 15 to 20 µU/mL
  • High fasting insulin as >20 µU/mL

Type 2 Diabetes

The presentation of type 2 diabetes can range from asymptomatic glycosuria to ketonuria or ketoacidosis with dehydration and weight loss (30). However, individuals with type 2 diabetes often present with obesity, glycosuria but no ketonuria, mild or absent polyuria and polydipsia, and little or no recent weight loss. Most will also have acanthosis nigricans (53). In one study, 25% of girls diagnosed with type 2 diabetes presented with vaginal candidiasis (54). Type 2 diabetes should be suspected in the presence of obesity-related comorbidities, such as acanthosis nigricans, hypertension, sleep apnea, PCOS, and NASH.

Recommendations by the American Diabetic Association (ADA) consensus panel of experts for screening for type 2 diabetes include any patient who has a BMI greater than the 85th percentile for age and gender and two of the following risk factors: (a) family history of type 2 diabetes in first- or second-degree relatives; (b) belonging to an ethnic group of African Americans, Hispanic Americans, American Indians, or Asians/South Pacific Islanders; and (c) having insulin resistance or conditions associated with insulin resistance such as PCOS, acanthosis nigricans, hypertension, or dyslipidemia. If the requirements for BMI and two other criteria are met, testing should start at age 10 years (or at onset of pubertal development if it


occurs earlier than age 10) and be continued every 2 years. The expert panel also recommended that clinical judgment be used in testing any other patients believed to be at high risk for diabetes. Fasting plasma glucose is the preferred screen (9).


The ADA diagnostic criteria for type 2 diabetes in children are listed in Table 8.2. Patients with type 2 diabetes can present with diabetic ketoacidosis, and there has also been a recent report of adolescents who presented with hyperglycemic hyperosmolar state (HHS) as the first recognized manifestation of type 2 diabetes. In several patients, this condition resulted in death. These patients had initial clinical symptoms that included the following:

  • Vomiting
  • Abdominal pain
  • Dizziness
  • Weakness
  • Polyuria
  • Polydipsia
  • Weight loss
  • Diarrhea

These patients presented acutely with what was thought to be diabetic ketoacidosis but was eventually recognized as HHS. The diagnostic criteria for HHS include a plasma glucose level of more than 600 mg/dL, serum carbon dioxide level of more than 15 mmol/L, small ketonuria, absent to low ketonemia, an effective serum osmolality of more than 320 mOsm/kg, and stupor or coma (55,56).

Along with diabetic ketoacidosis, HHS represents an acute emergency.

TABLE 8.2. Criteria for the diagnosis of diabetes mellitus

1. Symptoms of diabetes plus casual plasma glucose concentration ≥200 mg/dL (11.1 mmol/L). Casual is defined as any time of day without regard to time since the last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss.

2. FPG ≥126 mg/dL(7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 hr.

3. 2-hr post load glucose ≥200 mg/dL(11.1 mmol/L) during an OGTT. The test should be performed as described by WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.

In the absence of unequivocal hyperglycemia, these criteria should be confirmed by repeat testing on a different day. The third measure (OGTT) is not recommended for routine clinical use.

OGTT, oral glucose tolerance test; WHO, World Health Organization.

Reprinted with permission from American Diabetes Association Position Statements Original Article Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2005;28:S37–S42.



Goals of Treatment

The goals of treatment for type 2 diabetes in children and adolescents are to achieve normal growth and development and include the following:

  1. Physical well-being (15)
  2. Weight loss or no further weight gain (30)
  3. Continued normal linear growth (30)
  4. Psychological well-being (15)
  5. Long-term glycemic control (30,49)
  6. HgbA1Cshould be maintained at minimum less than 7%
  7. Lifestyle intervention (diet, exercise, and weight control) initially
  8. Pharmacotherapy if lifestyle change does not achieve glycemic control with metformin as initial therapy
  9. The addition of insulin if control is not achieved with metformin and lifestyle change (15)
  10. Control of hypertension and hyperlipidemia (30)

Prevention of Microvascular and Macrovascular Complications of Diabetes

In adults, intensive blood glucose control with oral hypoglycemic agents and insulin has been demonstrated to substantially decrease the risk of microvascular complications (57). This study also found that treatment of hypertension in adults with type 2 diabetes significantly lowered the risk of cardiovascular disease (57).

Treatment of hyperlipidemia in patients with diabetes, as in nondiabetic patients, decreases the risk of macrovascular complications and should be part of the treatment regimen (58).


The management of type 2 diabetes should be family based and include diabetes self-management, which encompasses the following (13):

  1. Family involvement
  2. Education, including a basic knowledge of pathophysiology and short- and long-term complications of diabetes
  3. Nutrition and meal planning
  4. Exercise
  5. Pharmacologic management
  6. Self-monitoring

Family Involvement

It cannot be overstated how important family involvement is in treating type 2 diabetes and obesity and their related comorbidities. In a study of children and adolescents with type 2 diabetes, direct supervision by adult family members had a positive effect on blood sugar control (59).




It is vital for patients and families to understand the causes of type 2 diabetes and the impact of family history, obesity, and lifestyle on the course of the disease. Families should be encouraged to work together for lifestyle change. Education about nutrition, activity, and the effect of sedentary behavior can lay the groundwork for such change. Because most children and adolescents with type 2 diabetes will have family members with type 2 diabetes, it is important to understand how the family has approached this diagnosis. If older members of the family have developed a more passive approach to the disease, it is important to help the child and adolescent, along with their family, take a more proactive approach.


Even modest (10%) weight loss can improve glycemic control.

Generally, a balanced dietary approach with reduction of total calories, usually starting with the elimination of excess sugar, will begin to reverse the tendency toward weight gain and deterioration in glycemic control. The ADA position statement on nutritional recommendations in diabetes suggests use of the non-nutritive sweeteners approved by the Food and Drug Administration (FDA) (saccharin, aspartame, acesulfame potassium, sucralose) as long as they are consumed within the acceptable daily intake levels established by the FDA (60). If dyslipidemia is present, normalization of lipids is also a dietary goal. Less than 10% of the energy intake should be from saturated fats, and patients with low-density lipoprotein (LDL) cholesterol greater than or equal to 100 mg/dL may benefit from lowering saturated fat intake to less than 7% of energy intake. Dietary cholesterol intake should be less than 300 mg/day, and if LDL cholesterol is greater than 100 mg/dL, dietary cholesterol should be lowered to 200 mg/day (60). Protein intake should follow age-specific requirements. Although very large amounts of fiber may benefit insulin resistance, glycemic control, and plasma lipids, it is unclear if these benefits are achievable because of poor palatability and the gastrointestinal side effects of a large fiber load (60). Children and families should work with a nutritionist whenever possible to optimize and individualize dietary planning.

Weight loss decreases insulin resistance, reduces the tendency toward hyperglycemia and dyslipidemia, and lowers blood pressure. As in all cases of weight loss, a structured, intensive lifestyle program involving education, individualized counseling, reduced fat and energy intake, regular physical activity, and frequent patient contact is needed (60).

Physical Activity

Physical activity has been shown to correlate with lower fasting insulin and greater insulin sensitivity in children (61). In adults, low levels of physical activity


have been associated with the future risk of type 2 diabetes (62). Because regular activity may not have been a part of the obese child's or adolescent's lifestyle before the diagnosis, scheduling a time for exercise or enrolling in a structured exercise program is beneficial. Clearly, reduction in television watching is important for both increasing activity and decreasing excess snacking (63,64).


The ADA suggests pharmacotherapy if the HgbA1C is greater than 7% (30). The first line of pharmacotherapy is metformin. Of the oral pharmacologic agents used in adults with type 2 diabetes, only metformin has been approved for use in children who are older than 10 years (53). Metformin decreases hepatic gluconeogenesis, increases insulin sensitivity, and lowers triglycerides and LDL cholesterol. Metformin raises insulin sensitivity in muscle by upregulating GLUT 4 activity and increasing insulin receptor tyrosine kinase activity. It has no effect on pancreatic insulin secretion but requires the presence of insulin to be effective (13). In a 5-year retrospective review of African American and Hispanic pubertal patients who presented with type 2 diabetes, 45% were able to keep their HgbA1C levels less than 7% with oral medications, which included metformin, 18% required insulin in addition to oral medications, and 37% did not require medication (65).

The most common side effect is gastrointestinal disturbance, including nausea, vomiting, a sense of fullness, constipation, and heartburn, which may diminish over time. The most serious side effect is lactic acidosis, occurring in patients with renal impairment or liver failure.

Patients with renal insufficiency, liver disease, alcohol abuse, hypoxemia and hypoperfusion, and sepsis should not use metformin. Metformin must be discontinued when the patient receives contrast dye and during serious illness (53). Temporary insulin therapy may be needed for severe symptoms at diagnosis, during acute intercurrent illness or steroid therapy, and perioperatively (53).

Vitamin B12 deficiency has been reported in adults in association with long-term use of metformin. Patients with this deficiency present with mild anemia, and some report having asthenia, peripheral neuropathy, and lower limb edema (66,67).

Additional oral agents used in adults are undergoing study in the pediatric age group. These agents include thiazolidinediones, sulfonylurea, meglitinides, acarbose, and α-glucosidase inhibitors.

Insulin therapy is often necessary to re-establish metabolic control. Combinations of long-acting and rapid-acting insulin are part of intensive insulin therapy in which both basal and bolus insulin are used to simulate normal insulin secretion. Insulin pump therapy may be used to accomplish this goal (53). Studies in adults show that beta cell function gradually deteriorates because of hyperglycemia, to the point at which oral agents can no longer induce insulin production, and that this occurs on average about 6 to 10 years after diagnosis. Therefore, supplementing oral agents with insulin, as soon as necessary to re-establish metabolic control, is recommended (53).




Ongoing monitoring should include measurements of the following:

  • Glucose and HgbA1C
  • Blood urea nitrogen (BUN)/creatinine (Crt), liver function tests (if on metformin)
  • Microalbuminuria
  • Lipid levels
  • Dilated eye examination
  • Blood pressure
  • Neurologic and foot examinations (49)

Diabetes-Associated Complications

The degree and duration of hyperglycemia are associated with the risk for and development of diabetic microvascular and macrovascular complications. Certain populations of children have presented at diagnosis with evidence of increased cardiovascular risk (68). In adults, risk of the microvascular complications of retinopathy, nephropathy, and neuropathy can be decreased by intensive blood glucose control (57). Furthermore, the treatment of hypertension and hyperlipidemia lowered the risk of cardiovascular disease (57).

Cardiovascular Complications

The insulin resistance syndrome has been associated with risk factors for cardiovascular disease (69) and type 2 diabetes is considered amajor risk factor for coronary artery disease. In obese children, dyslipidemia correlates with the degree of insulin resistance (70).

Elevated insulin levels increase renal sodium retention while increasing free water clearance and are linked with greater sympathetic nervous system activity and stimulation of avascular smooth muscle growth (71), increasing the risk for hypertension.

Lipid-Lowering Therapy

The ADA recommends that children and adolescents with type 2 diabetes should be screened for hyperlipidemia at diagnosis and early in the course of the disease after glycemic control is achieved. The most common cause of hyperlipidemia is continuing poor control of hyperglycemia. Optimal levels of lipids for children and adolescents with diabetes are as follows (72):

  • Total cholesterol <170 mg/dL
  • LDL cholesterol <100 mg/dL
  • HDL cholesterol >35 mg/dL
  • Triglycerides <150 mg/dL



  • Borderline levels are defined as
  • Total cholesterol 170–199 mg/dL
  • LDL cholesterol 110–129 mg/dL
  • Elevated levels are defined as
  • Total cholesterol >200 mg/dL
  • LDL cholesterol >130 mg/dL

It is now suggested that treatment for hyperlipidemia begin with the American Heart Association Step 2 diet. This diet holds dietary cholesterol below 200 mg/dL and saturated fat at less than 7% of total calories (72). Laboratory follow-up with fasting lipid profiles should be performed in the first 3 to 6 months after the initiation of treatment to monitor effectiveness of the dietary interventions and then yearly thereafter (72).

Pharmacotherapy has been recommended by the ADA in children older than 10 years to optimize the LDL cholesterol, if LDL levels stay greater than or equal to 160 mg/dL in children with obesity and a high risk of cardiovascular disease (diabetes, hypertension, and positive family history) (72).

Bile acid sequestrants can be used as treatment, but compliance may be low. The ADA (72) refers to two studies of statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) in adolescents. In the first study, sponsored by the drug company manufacturing the agent, simvastatin was used in postmenarchal girls and boys classified as Tanner II or greater with heterozygous familial hypercholesterolemia in a 48-week randomized controlled trial. None of these children had diabetes. The average BMI was 21 in boys and 22 in girls. LDL values were lowered by an average of 41%. Transient elevations of liver enzymes occurred in one case thought to be due to the drug and in one child with infectious mononucleosis. Elevated creatine phosphokinase (CPK) also was noted in a child taking erythromycin. Cholesterol is a precursor of the adrenal hormones cortisol and dihydroepiandrosterone (DHEAS) and the gonadal hormones testosterone and estradiol; in this study, significant reductions in DHEAS were found (73).

The second study was performed in boys with heterozygous familial hypercholesterolemia (74). LDL decreased 17% to 27%, depending on the dose, over 48 weeks. The authors note that

Growth and sexual maturation assessed by Tanner staging and testicular volume were not significantly different between the lovastatin and placebo groups at 24 weeks (P 5 .85) and 48 weeks (P 5 .33); neither were serum hormone levels or biochemical parameters of nutrition. However, the study was underpowered to detect significant differences in safety parameters. Serum vitamin E levels were reduced with lovastatin treatment consistent with reductions in LDL-C, the major carrier of vitamin E in the circulation.

The funding for this second study was not identified. The ADA recommends that when

… statins are used, treatment should begin at the lowest available dose and dose increases should be based on LDL levels and side effects. Liver function tests (LFTs)


should be monitored and medication should be discontinued if LFTs are greater than three times the upper limit of normal. If there is any persistent complaint of significant muscle pain/muscle soreness, the medication should be discontinued to see if symptoms resolve. Routine monitoring of creatine phosphokinase levels is not felt to be helpful. In addition, the use of statins in sexually active adolescent females must be very carefully considered and the risks explicitly discussed, as these drugs are not approved in pregnancy (68).

If triglyceride levels are greater than 150 mg/dL, dietary therapy and glycemic control are the first line of treatment. Specific recommendations for triglyceride values greater than 1,000 mg/dL are to consider treating with a fibric acid medication. Smoking cessation, blood pressure control, and physical activity are also important in managing cardiac risk reduction (68).


Hypertension is a major risk factor for cardiovascular and renal disease. Treatment of hypertension is important and does not differ in children and adolescents with type 2 diabetes (see Chapter 7 for discussion of treatment) (68).

Polycystic Ovarian Syndrome

The prevalence of type 2 diabetes and IGT is increased in polycystic ovarian syndrome (PCOS) (75). Adolescent girls with PCOS have a 50% reduction in peripheral insulin sensitivity, abnormal first-phase insulin response, and lack of beta cell compensation with compensatory hyperinsulinemia (76).

Psychological Well-Being

Ensuring psychological well-being is a component of all therapeutic efforts involved in the treatment of type 2 diabetes. Depression has been associated with obesity in children and adolescents (77). In one study of a hospital-based urban pediatric population with type 2 diabetes, an increased frequency of neuropsychiatric disorders was found. Just over 19% of type 2 diabetes patients presenting for treatment had a diagnosed mental health disorder (78). More females than males were affected, but there was no ethnic, BMI, or demographic difference between affected and unaffected patients. Diagnoses included neurodevelopmental disorders, psychiatric illness, and behavioral disorders, with two thirds of patients prescribed psychotropic medications (78).

Additional Obesity-Related Comorbidities

It is worth noting that obese patients with type 2 diabetes are also at risk for other obesity-related comorbidities, such as sleep apnea and upper airway obstruction and NASH. In fact, a high prevalence of elevated liver function studies has been reported


in a population of children with type 2 diabetes. Forty-eight percent had elevated serum transaminase levels, with 60% of these being more than twice the upper limit of normal. These elevations did not correlate with age, BMI, or HgbA1C (79).

Ongoing Support: Case of HJ

Initial Presentation

HJ is a 14-year-old African American young lady who is brought to your office by her mother because of the family's concern about diabetes. HJ's mother developed type 2 diabetes as a young adult and is now treated with insulin and has early diabetic retinopathy. HJ is not very happy about being at the doctor's, but you have some history with her because you have been struggling to help get her asthma under control.

You note that her weight is 152 lb (91st percentile) and height is 5 ft 1 in. (10th percentile). Her calculated BMI is 28.7, which places her above the 95th percentile and she has gained about 20 lb over the past year. You begin by asking about her eating and activity. She says little, so you discuss her daily routine with her. She is skipping breakfast and having lunch at school, which consists of a snack and soda. When HJ comes home from school, her mother notes, she is “starving” and eating “anything,” which turns out to be leftovers or snack food. She drinks soda between meals. After school, she sometimes watches television and sometimes naps, working on her homework in between. The family sometimes cooks, sometimes orders takeout food, and the family members frequently eat separately. HJ says that she doesn't eat before bed, but her mother says she often finds dishes and snack wrappers in HJ's room. HJ had physical education last term in school, but she does not really spend time outside and has no extracurricular activities.

Catching up on the rest of the family history, you find that the maternal grandmother also has diabetes, as does the paternal grandfather. Numerous aunts and uncles have hypertension, and several great uncles have had coronary artery disease.

In the review of systems, you note she has asthma, which is poorly controlled, and an irregular menstrual cycle. On physical examination, you note her elevated BMI and a blood pressure of 128/86 mm Hg, which is greater than the 95th percentile for systolic and diastolic pressure. She has moderate acanthosis nigricans of her neck and axilla. Besides slight wheezing, she has no other positive physical findings.

You check HJ's blood glucose on the office glucometer and it is 105 mg/dL, and she has not eaten breakfast. You order a 2-hour glucose tolerance test with insulin; laboratory studies to evaluate her metabolic status with regard to her obesity [total cholesterol, HDL cholesterol, triglycerides, aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyltransferase (GGT)] and her possible PCOS (total testosterone, free testosterone, DHEAS, sex hormone binding globulin); and a metabolic panel.

You tell HJ and her mother about the risk for diabetes and PCOS as well as the blood pressure elevation. Her mother is upset and asks what they can do; HJ looks somewhat concerned and asks if she will need “shots.”



You ask HJ what she knows about diabetes. She knows it concerns high “sugar.” You explain insulin resistance and diabetes and inform HJ and her mother that with diet and activity change HJ can dramatically lower her risk for diabetes. You mention several things they might consider changing, such as eliminating or decreasing sugar-containing beverages, eating healthier after school snacks, and cooking at home. The mother says that HJ should stop drinking soda; you mention that it would be easier for HJ to stop if there were no sugar-containing beverages in the house. The mother says she thinks she can eliminate them, but HJ's father “won't like it.” You ask HJ's mother to invite her father to come to the next visit.

You ask HJ if there is anything she can do to increase her activity; she says she does not know but mentions she likes to dance. You start with this and ask her to play a dance tape for 15 minutes/day and keep an activity log. You arrange to see HJ again in the clinic in 1 month.

About 1 week later, you receive a laboratory report for HJ. HJ's 2-hour glucose was 152 mg/dL, indicating IGT; her 2-hour insulin was 296 µU/mL, showing marked insulin resistance. As is typical of the lipid profile in insulin resistance, her cholesterol was mildly elevated at 186 mg/dL and her triglycerides were 215 mg/dL, with a low HDL cholesterol of 32 mg/dL. The results for liver function studies were normal. But her testosterone, free testosterone, and DHEAS were mildly elevated. Your nurse gives HJ's mother a call to report the results and to check on how the family is doing with eliminating soda and juice and increasing HJ's activity. The mother reports that all sugar-containing beverages are out of the house and HJ has been doing “some” dancing and has also gone out with her friends and walked the mall.

Second Visit

When HJ comes back for her visit, her weight has decreased by 1.5 lb and her blood pressure is 122/79 mm Hg (systolic between the 90% and 95% and diastolic <90%). Her fasting glucose is 99 mg/dL. HJ and her mother report that HJ has not had any soda or juice, and the mother has removed sugared drinks from the house. HJ's father has been supportive (he is drinking his regular soda at his work). HJ has done some dancing and gone out with friends a little more, and you discuss other possible activity options, such as a dance class, after school activity, and/or a volunteer job. You give them diet and activity records to monitor, asking them to fax the records weekly, and arrange to see HJ again in 1 month. You also notice that HJ is more communicative, and she and her mother are less irritable with each other; you comment on this and congratulate them on making these lifestyle changes.

Follow-up Visits

You tell HJ and her mother that you plan to see HJ monthly until her laboratory studies and menstrual cycle normalize and they feel they have made changes they can sustain.




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