Insulin resistance and its association with the components of the metabolic syndrome among obese children and adolescents

The World Health Organization recognizes overweight and obesity in children and adolescents as worldwide public health problems. Mexico is one of the countries which suffer most from these.

Indeed, according to Mexican National Health and Nutrition Surveys, in 1999 [1] the combined prevalence of overweight and obesity in school-age children was 18.6%; by 2006, such prevalence had increased to 26%, which represents an average increase of 1.1 percentage points per year [2].

Insulin resistance (IR) is the primary metabolic disorder associated with obesity and is defined as a diminished ability of insulin to stimulate glucose uptake by skeletal muscle and adipose tissue, in addition to reducing insulin's ability to suppress hepatic glucose production and output [3]. Some of the several disorders associated with IR that have been described include systemic inflammation, increases in fibrinolysis, endothelial dysfunction, and atherosclerosis [4], all of which can first appear during childhood in obese individuals [5]. Although the hyperinsulinemic-euglycemic clamp is considered the gold standard for evaluating and measuring IR, the technical difficulties associated with this method have led to the development of less invasive methods. Among these, the homeostasis model assessment of insulin resistance index (HOMA-IR) is one of the most commonly used [6]. It is worth noting that no consensus exists concerning the HOMA-IR cut-off points that define IR among the pediatric population, although there is general agreement that IR is a common pathway for the development of glucose metabolism disorders, dyslipidemias, and high blood pressure, all of which are components of the metabolic syndrome (MS) [7–9]. In turn, MS is a risk factor for the subsequent development of type-2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) [10].

Among children, MS is not well characterized, and there is a lack of agreement as to its components and cut-off points, though most authors include among the former abdominal obesity, high blood pressure, glucose abnormalities, and dyslipidemias [11, 12]. Due to this lack of consensus, the reported prevalence of MS among children and adolescents shows a great deal of variability [13, 14]. For instance, in studies including children and adolescents with varying nutritional conditions, the prevalence lies between 2.5% and 12.9% [13]. However, when only overweight and obese children and adolescents are included, the prevalence increases and falls within the range 26% -31.2% [13–15].

In children and adolescents, a direct relationship between the degree of obesity and the prevalence of MS has been reported [16, 17]; however, it is not exactly known how and to what extent IR is associated with each of the components of MS. In this context, this study aims to elucidate the prevalence of IR and to evaluate the association of IR with each of the components of MS among obese children and adolescents.

The study was conducted in all of the forty-four schools that compose the public school system in Campeche City, Mexico.

Prior to the study, ethical clearance was obtained from Campeche State research ethics committees and school authorities. The study consisted of two stages, the first of which aimed to identify children suffering from obesity. For this purpose, weight and height were measured by four nurses previously trained to follow international anthropometric guidelines. The study included 4,937 children between 11 and 13 years of age attending the 5^th and 6^th grades. Obesity was defined as a body mass index (BMI) percentile ≥95^th for the child's age and gender according to the Centers for Disease Control (CDC) 2000 references [18]. Following this criterion, 1,475 children were classified as obese. Out of this total, written parental and child informed consent was obtained from 600 randomly selected children. From this group, complete blood samples were collected from 466 children.

During the second stage, blood pressure (BP) was obtained using the auscultatory method, and waist circumference (WC) was measured with children in the standing position, placing the metric strip at the midpoint between the lower rib and the iliac crest after a normal exhalation. In addition, a sample of venous blood was obtained after a 12-hour fast in order to determine concentrations of insulin by chemiluminescence immunoassay (Access Beckman Coulter Instruments, Brea California), glucose, and plasma lipids by an enzymatic method, and high density lipoprotein cholesterol (HDL-C) assayed by the addition of magnesium ions (Synchron CX^® Beckman Instruments, Brea California). In all cases, commercial enzymatic kits were employed. Low density lipoprotein cholesterol (LDL-C) levels were estimated using the Friedewald formula, as modified by De Long [19].

No difference was observed between sexes in the values of systolic and diastolic BP. However, in both sexes systolic BP fell into the 49.5^th percentile, whereas diastolic BP fell into the 60.9^th percentile, according to the reference values for gender, age, and height [20] (these data are not shown in the tables).

The same table summarizes the values of glucose, insulin, and lipids in the investigated children and adolescent population. Girls exhibited a higher concentration of fasting insulin and higher HOMA-IR values compared to boys, but smaller concentrations of fasting glucose, total cholesterol, and LDL-C.

Our results show that higher levels of IR are associated with a greater degree of alterations in the components of the MS in the population studied, half of which presented IR.

The apparently normal fasting glucose levels in this population are maintained by a compensatory mechanism based on hyperinsulinism, which is reflected in HOMA-IR values [25]. However, when impaired fasting glucose prevalence is analyzed through ORs, it is possible to observe that increased levels of IR are associated with rising OR.

Girls presented the highest insulin levels and HOMA-IR values, along with lower glucose concentrations. This pattern could be a consequence of the fact that, at equal ages, girls can enter puberty up to two years earlier than boys [26, 27] - therefore, more girls would have reached higher pubertal stages. However - and this is a limitation of this study - no information was collected about either pubertal stage or growth and sexual hormones, factors which could influence the prevalence of the rise in IR [28].

In accordance with previous studies on adolescents and adults, the IR reported in this study is associated with the primary alterations in the lipid profile; hyperinsulinism increases the free fatty acid release and the triglyceride synthesis, which results in hypertriglyceridemia [29, 30]. Likewise increased hepatic lipase activity can account for the rise in high-density lipoprotein depuration, producing hypoalphalipoproteinemia [31]. However, the high prevalence of low C-HDL levels observed in this study is one of the highest reported in the literature [13, 30, 32]. Regardless of its cause, it is a risk factor for the development of cardiovascular events during adulthood. Such events stem from both genetic and environmental factors. Indeed, it has been reported that individuals of Turkish descent display greater hepatic lipase activity, which augments the depuration of this lipoprotein and is associated with lower levels of HDL-C [33]. However, it is not known whether population of Mexican descent could have a polymorphism such as that identified among their Turkish counterparts that may explain the higher prevalence of low HDL-C observed in this study. What is known is that, among individuals of Mexican descent, an association has been described between a variant of gene ABCA1 and lower HDL-C levels, along with a greater risk of developing obesity, MS, and early onset T2DM [34]. As far as environmental factors are concerned, lower levels of this lipoprotein can be explained in terms of changing eating habits [35]. The diet of Mexican children resembles ever more that of their North American counterparts [36], a diet rich in simple sugars and animal fats, but with limited amounts of fiber [37].

Although the association between IR and OR of suffering high blood pressure was not statistically significant, the observed trend in this population can be associated with the different disorders stemming from obesity [7] among which IR stands out [38]. Hyperinsulinism increases renal sodium absorption and sympathetic tone [39], which combines with altered vasodilatation, which in turn is a secondary effect of nitric oxide deficient secretion by the vascular endothelium [40]. Therefore, it is to be expected that if such IR-induced hyperinsulinism continues, permanent alterations such as atherosclerosis and hypertension will eventually develop.

Furthermore, the prevalence of MS reported in this study - around 20% - might stem from the employed definition, which relied on stricter cut-off points than those used in other studies [11]. In studies where Cook's criteria was applied, the prevalence of MS among North American obese adolescents was 27% [16], in others following the III Adult Treatment Panel criteria, the prevalence was 26.1% [15].

In order to ascertain the real prevalence of this syndrome among children, agreement is needed concerning the cut-off points for each of the syndrome's components; likewise, categories for pubertal stage and gender need to be established [41]. Notwithstanding the heterogeneity of current definitions, the notion of MS has been useful for identifying individual children at risk of developing CVD and T2DM [42].

As mentioned above, 87% of the study participants presented at least some kind of functional or metabolic disorder. Nevertheless, in spite of being obese, almost 13% of the study population did not present any kind of disorder, a phenotype known as "metabolically healthy but obese individuals" [43]. Among adults, a 9.7% prevalence of this phenotype has been reported in the literature; interestingly, within this group no family history of T2DM has been found [44]. This suggests that protection against cardiometabolic disorders, even in the presence of obesity, can have genetic features [45].

A further limitation of this study derives from the fact that cross-sectional studies are not able to establish causality, only associations between different variables.

However, given the close relationship between obesity, IR, and MS - with its attendant risk of developing co-morbidities, such as T2DM and CVD - it is imperative to implement prevention, diagnosis, and early treatment measures for obesity involving all sectors of society.

This study has confirmed that among obese children and adolescents, regardless of age and gender, an increased degree of insulin resistance is associated with a higher prevalence of disorders in each of the components of the metabolic syndrome and with a heightened risk of suffering MS.

HOMA-IR values above 3.4, which correspond to the 50^th percentile of this population, were associated with an increased risk of having MS, compared to the lowest percentile of HOMA-IR values.