INDEPENDENT CARDIOMETABOLIC RISK FACTORS IN CHILDREN

2.2.1 Overweight and obesity

Overweight and obesity have been considered as key factors in the pathogenesis of MetS (16,18,69,70). While the primary function of adipose tissue is to act as an energy storage, it is also an active endocrine organ (71). MetS is encountered almost exclusively among overweight and obese children and adolescents, and the

has been independently related to all components of MetS (18,74). An excessive amount of fat in the body not only evokes harmful changes in sugar and fat metabolism but it also elevates blood pressure (18). Visceral fat around the internal organs is believed to be particularly harmful for health (75–77), but there is still not unambiguous evidence of the independent significance of visceral fat in health and the effects of visceral fat on health among children (78). However, there is some evidence suggesting that increased visceral fat content could be a stronger predictor for cardiometabolic risk factors in children than in adults (78).

Obesity is indisputably a significant part of the clustering of cardiometabolic risk factors and the development of MetS already among children.

Intramyocellular and intra–abdominal fat accumulation is strongly associated with post-glucose hyperglycaemia in obese prediabetic youth (79). Adverse metabolic changes can be detected already among very young children, soon after the onset of overweight or obesity. Children aged 2-6 years who had become overweight within the last year exhibited metabolic abnormalities, including signs of non-alcoholic fatty liver disease (NAFLD) (80). Visceral fat accumulation may also increase hepatic insulin resistance (77). However, it is important to note that although obesity is one of the most important etiological factors in the

development of MetS, this does not mean that obesity inevitably leads to MetS (81). Nevertheless, many prospective studies have revealed that childhood obesity is associated with cardiovascular disease and its risk factors later in life (22,82–86).

2.2.2 Insulin resistance and impaired glucose metabolism

Insulin is a key factor in glucose metabolism and energy homeostasis in the human body. Normally after a glucose-containing meal, the plasma glucose level rises, and that triggers insulin release from the pancreatic β cells into the

circulation. The presence of insulin increases glucose uptake mainly in skeletal muscle and it also suppresses endogenous hepatic glucose production (87,88).

Insulin resistance refers to the situation where the pancreatic β cells still release insulin in response to glucose ingestion, but glucose uptake by skeletal muscle and other tissues of the human body is nonetheless inadequate (88).

Glucose and insulin metabolism disturbances, including impaired glucose tolerance and insulin resistance, are considered to be the major cardiometabolic risk factors and key components for the development of MetS among children and youth (81,89,90). It has been postulated that insulin resistance could be the most important trigger for the clustering of cardiometabolic risk factors (81,89–92), as well as being an independent predictor of MetS and its components (81,93).

The gold standard assessments of insulin resistance and impaired glucose metabolism are intravenous glucose and insulin tolerance tests. However, these invasive tests are complex and expensive to perform in large population-based studies. It is therefore common to assess insulin resistance and glucose

metabolism in such studies, particularly among children, by less invasive and less expensive surrogate measurements. The most common surrogate measurements are fasting plasma insulin and the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). HOMA-IR is a mathematical method to quantify insulin resistance that was first described by Matthews and coworkers (94).

2.2.3 Dyslipidemia

Dyslipidemia is associated with overweight and obesity in children and

adolescents (95–97). The Centers for Disease Control and Prevention in the United States analyzed the data from the National Health and Nutrition Examination Survey in 2010 and reported that 14.2% of normal weight, 22.3% of overweight and 42.9% of obese 12-19-year-old adolescents had at least one abnormal lipid level (98). Dyslipidemia is a disorder of blood lipoprotein metabolism where plasma or serum lipid concentrations or their relative proportions are abnormal (99). In essence, this means that the levels of low-density lipoprotein (LDL) cholesterol or triglycerides are elevated or the high-density lipoprotein (HDL) cholesterol concentration is too low in plasma or serum (100). Dyslipidemia is an independent risk factor for atherosclerosis and many studies have demonstrated its significant tracking from childhood into adulthood (23,101). Atherogenic

changes caused by dyslipidemia are already evident in the arterial walls of children and young adults (102). These changes rarely lead to illness during childhood, but their long-term effects on cardiovascular health in adulthood are significant (103).

Dyslipidemia could also lead to NAFLD in children (104). In this case, liver cells have accumulated an abundance of fat, especially triglycerides, and this interferes with normal liver function. NAFLD may, at worst, result in steatohepatitis, i.e., hepatic inflammation and hepatic cirrhosis (103).

2.2.4 Elevated blood pressure

Elevated blood pressure is relatively uncommon in general populations of children (105); in fact elevated blood pressure in children is usually associated with a secondary pathological factor for hypertension (106). Nonetheless, there is a clear

(107). Hypertension is twice as common in obese children, and even as many as every second hypertensive child is obese (108). The presence of elevated systolic blood pressure in childhood predicts hypertension and MetS later in life (109).

Therefore it is important to identify those children who are most at risk for the development of future hypertensive (110).

2.2.5 Other cardiometabolic risk factors

Circulating levels of biomarkers for low-grade inflammation, such as low

adiponectin concentrations, high high-sensitivity C-reactive protein concentrations, and elevated interleukin 6 (IL-6) concentrations, have been associated with

clustering of cardiometabolic risk factors and an increased risk of MetS in children and adolescents (18). C-reactive protein is an acute-phase protein whose

concentration reflects the inflammatory state of the body. Chronic low-grade inflammation is known to predict type 2 diabetes and cardiovascular diseases (111–113) and is believed to be an important factor in the pathogenesis of these diseases, particularly in the atheromatous process of arteriosclerosis and in the onset of diabetes and insulin resistance (111). Even a slightly elevated high-sensitivity C-reactive protein level has been associated with all components of MetS in adults (111) and children (18,111,114).

Adipose tissue, more specifically adipocytes, secrete many hormones, called adipokines, which have important roles in whole-body metabolism and in maintaining physiological homeostasis (115). Adiponectin is one of these

adipokines that has been found to be inversely associated with adiposity, insulin resistance, and the risk of MetS; this protein has both atherogenic and anti-inflammatory properties (116,117). Leptin is another adipokine that affects many metabolic processes, including body fat mass regulation, and higher serum levels of leptin have been related to insulin resistance (118). Low serum levels of

adiponectin and high serum levels of leptin have also been associated with insulin resistance and other cardiometabolic risk factors in overweight and obese children (118). Ghrelin is a somatotropic and orexigenic hormone that increases before eating a meal and declines afterwards. Lower serum levels of ghrelin have been associated with insulin resistance among overweight children (119).

Microalbuminuria has also been associated with overall and abdominal adiposity, insulin resistance, impaired fasting glucose, increased serum LDL cholesterol and triglycerides, elevated blood pressure and an increased prevalence of MetS, and a decreased serum HDL cholesterol concentration in obese children (120).