ReviewPathophysiology of metabolic syndrome X and its links to the perinatal period
Introduction
Metabolic syndrome X is characterized by abdominal obesity, atherosclerosis, insulin resistance and hyperinsulinemia, hyperlipidemias, essential hypertension, type 2 diabetes mellitus, and coronary heart disease (CHD). Other features of metabolic syndrome X are hyperfibrinogenemia, increased plasminogen activator inhibitor-1, decreased tissue plasminogen activator, nephropathy, microalbuminuria, and hyperuricemia. Although the incidence of metabolic syndrome X is assuming epidemic proportions in almost all countries around the globe, the cause for this increasing incidence is not clear. Genetics of various populations have not changes in the past 100 y, so a dominant role for environmental factors in the increasing incidence of metabolic syndrome X is suspected. Identification of causes and/or etiologic factors for the development of metabolic syndrome X is important so that suitable measures can be instituted to prevent and cure the syndrome.
Section snippets
Incidence of metabolic syndrome X
By the year 2010, in the United States alone there may be about 50 to 75 million or more people who have metabolic syndrome X. It is more common on the Indian subcontinent and has been attributed to genetic factors. One common feature of metabolic syndrome X is the presence of insulin resistance and consequent hyperinsulinemia. Many subjects with abdominal obesity, hypertension, type 2 diabetes, hyperlipidemias, CHD, and stroke show insulin resistance and impaired glucose tolerance (IGT). It is
Different depots of fat display wide differences in their biochemical properties
Adipose tissue distribution is an important predictor of obesity-associated morbidity and mortality. Abdominal obesity is common in subjects with metabolic syndrome X and is a risk factor for CHD. Adipose tissue distribution is dependent on genetic, environmental, and hormonal factors. There are distinct differences in the distribution of adipose tissue in males and females, and adipose tissue in different regions of the body is functionally different. Females have more subcutaneous and
11β-Hydroxysteroid dehydrogenase type 1 and abdominal obesity
Mice that overexpress the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) enzyme selectively in adipose tissue develop abdominal obesity and exhibit insulin resistance, type 2 diabetes, hyperlipidemia, hyperphagia, and hyperleptinemia [6], [7], features that are similar to those seen in subjects with metabolic syndrome X. This indicates that abdominal obesity is akin to localized Cushing’s syndrome. Increased activity of 11β-HSD-1 in the abdominal adipose tissue compared with subcutaneous
Metabolic syndrome X as a low-grade systemic inflammatory condition: obesity, insulin resistance, and type 2 diabetes mellitus
There is evidence to suggest that low-grade systemic inflammation occurs in metabolic syndrome X [8], [9], [10]. Plasma levels of C-reactive protein (CRP), TNF-α, and IL-6, markers of inflammation, are higher in subjects who have obesity, insulin resistance, essential hypertension, type 2 diabetes, and CHD [8], [9], [10], [11], [12], [13], [14], [15], [16]. A direct positive correlation exists between body mass index and CRP in otherwise healthy children and adults. Higher plasma concentrations
Free radicals, nitric oxide, and metabolic syndrome X
Superoxide anion interacts with nitric oxide (NO) and inactivates it, thus producing peroxynitrite radical, which has cytotoxic actions. Increased superoxide production accounts for a significant proportion of the NO deficit seen in diabetes, hypertension, and consequent vascular dysfunction [26], [27]. Decreased endothelial NO (eNO) and increased free radical generation (especially superoxide anion) is seen not only in diabetes and hypertension but also in insulin resistance, obesity, and CHD
Adiponectin and metabolic syndrome X
Adiponectin is a 29-kDa adipocyte protein that is secreted by adipose cells. Plasma adiponectin levels are decreased in subjects with obesity and type 2 diabetes mellitus. An inverse association exists between plasma adiponectin levels and insulin resistance, with lower concentrations of adiponectin indicating greater resistance to the actions of insulin [35]. Women have higher plasma adiponectin levels than do men despite the fact that women have larger amounts of adipose tissue. A significant
Essential hypertension is an inflammatory condition
High circulating IL-6 levels in women with hypertension and insulin resistance in men has been described [46]. A significant graded relation between blood pressure and levels of intercellular adhesion molecule-1 and IL-6 was noted [47]. Increased pulse pressure is associated with high CRP levels among healthy U.S. adults [48]. A direct correlation between plasma CRP levels and advancing age, body mass index, systolic blood pressure, HDL, smoking, and hormone replacement therapy was reported in
Metabolic syndrome X is a low-grade systemic inflammatory condition
Increased concentrations of proinflammatory cytokines, CRP, and free radicals and decreased concentrations of eNO, antioxidants, anti-inflammatory cytokines, and adiponectin are common in abdominal obesity, insulin resistance, type 2 diabetes mellitus, hypertension, CHD, and hyperlipidemia [53], [54], [55]. This implies that metabolic syndrome X is an inflammatory condition [8]. TNF-α and IL-6 increase, whereas insulin-like growth factor-I (IGF-I) and insulin, suppress the activity of 11β-HSD-1
Perinatal origins of metabolic syndrome X
Cardiovascular disease and type 2 diabetes may have their origins early in life [7], [8], [9], [58], [67], [68]. Low birth weight leads to a high prevalence of metabolic syndrome X in later life [58], [69]. Babies with low birth weights have 10 times greater chance of developing metabolic syndrome X than do those whose birth weights are normal. However, this relation has been disputed. It was suggested that postnatal nutrition and growth are equally important in the development of metabolic
ω-3 and ω-6 long-chain polyunsaturated fatty acids and metabolic syndrome X
The ω-3 and ω-6 fatty acids are essential for fetal growth and development including that of the brain [73], [74], [75]. Dietary linoleic acid and α-linolenic acid are essential fatty acids that are desaturated and elongated to form their respective long-chain metabolites [76], [77], [78] (Figure 2 illustrates the metabolism of essential fatty acids). Newborn infants, especially preterm infants, have limited capacity to form eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and
Maternal malnutrition, LCPUFAs, and metabolic syndrome X
Malnutrition can be defined as undernutrition and as overnutrition. Maternal protein restriction or increased consumption of saturated and/or trans-fatty acids and energy-rich diets (maternal overnutrition) during pregnancy decrease the activity of Δ-6 and Δ-5 desaturase enzymes that are essential for the conversion of dietary essential fatty acids linoleic acid and α-linolenic acid to their respective LCPUFAs. Hence, maternal malnutrition (undernutrition and overnutrition) leads to maternal
What sequence of events lead to metabolic syndrome X?
I propose that the physiologic response to even normal food intake (containing carbohydrates, proteins, and fats and mixed meals) is an increase in the production of TNF-α and IL-6 and consequent increase in plasma CRP and decreases in anti-inflammatory cytokines IL-4 and IL-10 and in adiponectin. TNF-α and IL-6 induce oxidative stress and activate nuclear factor-κB, which induces insulin resistance and, hence, hyperinsulinemia. Insulin secreted in response to food intake is not only intended
Conclusions and therapeutic implications
It is evident from the preceding discussion that LCPUFAs, cytokines, and 11β-HSD-1 interact with each other and play an important role in the pathobiology of metabolic syndrome X (Figure 3). This suggests that these indices can be used as markers to predict future development of metabolic syndrome X and its prognosis. In addition, these indices may be used to predict the response to the interventions employed in the prevention or postponement of metabolic syndrome X. Thus, I propose the
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