Childhood obesity is a significant health problem that has reached epidemic proportions around the world (1). Recent data from the United States indicate that 31.7% of children and adolescents ages 2 to 19 years have a high body mass index (BMI) (≥85th percentile) and 16.9% are frankly obese (BMI ≥95th percentile) (1). Similar data have been reported for many European countries, where a BMI ≥85th percentile has been found in 31.8% of school-age children (2).
Childhood obesity is associated with an increased risk for several metabolic and cardiovascular complications, such as insulin resistance, dyslipidemia, hypertension, glucose intolerance, and type 2 diabetes mellitus (T2D) (3), therefore highlighting the burden of this condition.
CHILDHOOD OBESITY AS A MAJOR DETERMINANT OF INSULIN RESISTANCE
Insulin resistance is characterized by a decrease in the ability of insulin to stimulate the use of glucose by muscles and adipose tissue and to suppress hepatic glucose production and output. Furthermore, it accounts for a resistance to insulin action on protein and lipid metabolism and on vascular endothelial function and gene expression (3).
Insulin resistance is a complex condition with genetic and environmental factors implicated in its etiology (3). Several environmental factors can influence insulin sensitivity: obesity, ethnicity, sex, perinatal factors, puberty, sedentary lifestyle, and diet (3).
Obesity represents the major risk factor for the development of insulin resistance during childhood and adolescence (3). Approximately 55% of the variance in insulin sensitivity in children can be explained by total adiposity, after adjusting for other confounders such as age, sex, ethnicity, and pubertal stage (3). Several factors are implicated in the pathogenesis of obesity-related insulin resistance, including increased free fatty acids and many hormones and cytokines released by adipose tissue (3).
An altered partitioning of fat between subcutaneous and visceral or ectopic sites has been associated with insulin resistance (4). Independent of the relation between total body fat and insulin resistance, increased abdominal visceral adipose tissue in obese youth is associated with lower insulin sensitivity and higher acute insulin response (4). Ectopic deposition of fat in the liver or muscles can also be responsible for insulin resistance in subjects with obesity (4).
The available data so far suggest that diet composition may be an additional factor contributing to insulin resistance. In particular, animal and human studies suggest that a high energy intake as well as a diet rich in saturated and trans fatty acids and carbohydrates and low in fiber could increase the risk of developing insulin resistance. In contrast, micronutrients, such as magnesium, zinc, chromium, and vanadium, can improve insulin sensitivity (5).
COMPLICATIONS OF INSULIN RESISTANCE
Insulin resistance is associated with the development of hypertension, dyslipidemia, impaired glucose tolerance, T2D, and steatosis. Furthermore, insulin resistance is associated with systemic inflammation, endothelial dysfunction, early atherosclerosis, and disordered fibrinolysis (3).
The fundamental role of insulin resistance in human disease was already recognized in 1988 by Reaven, who emphasized its role in the development of a grouping of metabolic abnormalities, defined as syndrome X or metabolic syndrome and including insulin resistance/hyperinsulinemia, dyslipidemia, hypertension, and glucose intolerance (3). The prevalence of the metabolic syndrome is about 4% in the overall pediatric population, but it is as high as 30% to 50% among overweight children and adolescents (3).
In children and adolescents with obesity, insulin resistance has been also associated with the development of impaired glucose tolerance and T2D (3,4). During the last decade, there has been an alarming increase in T2D in youth, concomitant with the rise of obesity in this age group, and in the United States, T2D now accounts for between 8% and 45% of all of the cases of childhood and adolescent diabetes (3).
It is alarming that these complications are already found in prepubertal children and adolescents with obesity, given that insulin resistance and related complications may be further exacerbated by the influence of puberty, due to the physiological decrease in insulin sensitivity associated with normal pubertal development.
ASSESSING INSULIN RESISTANCE
Several methods to assess insulin resistance are available and they include fasting measurements of insulin and glucose, the oral glucose tolerance test (OGTT), the insulin tolerance test, the hyperinsulinemic euglycemic clamp, and the frequently sampled intravenous glucose tolerance test (FSIVGTT) (6).
The hyperinsulinemic euglycemic clamp and the FSIVGTT are 2 well-accepted methods to assess insulin sensitivity; however, both these tests are difficult to perform, time-consuming, expensive, and invasive (6). Simpler methods based on surrogate markers derived from fasting insulin and glucose or from an OGTT have been suggested as potential alternatives. These surrogate measures include fasting insulin, fasting glucose to fasting insulin ratio, the homeostasis model assessment of insulin resistance, and the quantitative insulin sensitivity check index. These indices have been validated and proposed for the purpose of screening in large populations of adults (6).
Validation studies have also been performed in children and adolescents with normal glucose tolerance, with good correlation coefficient with insulin sensitivity measures derived from the clamp or FSIVGTT (7). In children and adolescents, the simple use of fasting insulin, in the presence of normoglycemia, could be an estimate of insulin resistance as good as the homeostasis model assessment of insulin resistance, quantitative insulin sensitivity check index, or fasting glucose to fasting insulin ratio (8). However, it is important to acknowledge that there are some limitations in the use of these surrogate indexes related to the variability in insulin measurements across laboratories, with a consequent difficulty in comparing results obtained in different centers (6). Indexes derived from the OGTT have also been developed. Some of them, such as the whole-body insulin sensitivity index and the insulin sensitivity index, have been validated also in children and adolescents with obesity, with a good correlation with the euglycemic clamp (9).
CONCLUSIONS FROM THE 2009 CONSENSUS ON INSULIN RESISTANCE IN CHILDREN
Emerging data indicate that insulin resistance is common among children and adolescents, therefore requiring consideration early in life. However, there is still confusion on how to define insulin resistance, how to measure it, what are its risk factors, and whether there are effective strategies to prevent and treat it.
In 2009, the Consensus Conference on Insulin Resistance in Children was held to clarify these points (10). The Consensus highlighted the lack of a clear cutoff to define insulin resistance in children and that surrogate measures, such as fasting insulin, are poor estimates of insulin sensitivity. In addition, it emerged that based on current screening criteria and methodology, there is no justification for screening children for insulin resistance, even in those who are obese (10). However, it appears that prevention strategies should be started early in life and, with regard to treatment, lifestyle intervention, including diet and exercise, should be included, whereas metformin should be limited to selected patients (10).
The Consensus also highlighted the need for future research aimed at the careful evaluation of childhood risk factors for insulin resistance and their short- and long-term complications, including morbidity and mortality. Longitudinal studies are required to determine the best way to assess insulin sensitivity during childhood and adolescence. In particular, it is important to standardize insulin measurements and to try to identify strong surrogate biomarkers of insulin resistance that are valuable throughout childhood and adolescence (10). There is a need for high-quality studies looking at interventions starting during pregnancy and preconception and extending throughout childhood and adolescence to prevent the development of insulin resistance. Additional studies are also required to explore the potential role of both lifestyle intervention and medications in the treatment of insulin resistance (10).
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