Aetiology
It is unclear whether a single primary abnormality triggers a cascade of diverse events that lead to the manifestation of the components of metabolic syndrome. However, the condition is certainly closely linked to insulin resistance and abdominal obesity.[4][12][13]
The 'obesity epidemic', resulting from overnutrition, atherogenic diets (high in total or saturated fats), and sedentary lifestyles, is primarily responsible for the increased prevalence of metabolic syndrome. In addition to excess adiposity, a metabolic susceptibility seems to play a fundamental role in the development of the condition. Factors predisposing to this susceptibility are genetic defects in insulin signalling pathways, various disorders of adipose tissue (e.g., lipodystrophy caused by mutations in lamin A/C, AGPAT, and seipin), physical inactivity, and mitochondrial dysfunction. Advancing age and certain drugs (e.g., corticosteroids, antipsychotics, antidepressants, and protease inhibitors used to treat HIV) are also predisposing factors but lack specificity for metabolic syndrome.[13][14]
Specific genes, especially those that encode 11-beta-hydroxysteroid dehydrogenase, adiponectin, beta-3-adrenergic receptor, endocannabinoid receptors, and peroxisome proliferator-activated receptor-alpha, may predispose to metabolic syndrome.[4][13] Hyperandrogenaemia has also been associated with insulin resistance in women with polycystic ovary syndrome.[14] Patients with metabolic syndrome also have mild hypercortisolism and increased activity of the hypothalamus-pituitary-adrenal axis compared with healthy controls.[15]
Pathophysiology
There is increasing evidence that insulin resistance is the main defect linking the individual components of metabolic syndrome, although the strength of this correlation varies between, and even within, different populations.
Insulin resistance is a physiological change in the action of insulin manifesting as a resistance to insulin-mediated glucose disposal.[12] People with insulin resistance have impaired glucose metabolism or tolerance demonstrated by an abnormal response to a glucose challenge, indicated by elevated fasting glucose levels and decreased insulin-mediated glucose clearance. This phenotype is mainly present in overweight or obese people and those with a sedentary lifestyle and atherogenic diet.[4] The visceral adiposity in metabolic syndrome is characterised by increased turnover of free fatty acids. In the insulin-resistant state, insulin is incapable of suppressing free fatty acid mobilisation (lipolysis) from stored adipose tissue. This results in a higher plasma concentration of free fatty acids, which impairs insulin secretion by pancreatic beta-cells and inhibits insulin-stimulated glucose uptake, particularly in muscle.[4][16]
In skeletal muscle, increased accumulation of triglycerides impairs translocation of the glucose transporter GLUT-4, resulting in resistance to insulin-stimulated glucose uptake.[17] Furthermore, the high flux of free fatty acids to the liver increases storage and synthesis of triglycerides, which are secreted as very low-density lipoprotein (VLDL)-cholesterol.[18] Hypertriglyceridaemia is associated with low high-density lipoprotein (HDL)-cholesterol levels due to the role of cholesteryl ester transfer protein (CETP), a key enzyme that mediates the transfer of triglycerides from triglyceride-rich lipoproteins to HDL and low-density lipoprotein (LDL) particles in exchange for cholesteryl esters. In the insulin-resistant state, CETP generates small, triglyceride-rich HDL-cholesterol particles, which are easily disintegrated by hepatic lipase and therefore cleared by the kidney. Insulin resistance is also characterised by small, dense LDL-cholesterol particles that are highly atherogenic.[4] Metabolic syndrome has been associated with an increase in CETP mass (especially in men), which may be responsible for reduced HDL-cholesterol and LDL-cholesterol particle diameters.[19]
Another important enzyme in lipid metabolism is lipoprotein lipase (LPL), which plays a key role in partitioning lipoprotein-derived free fatty acids between different tissues. An accumulating body of evidence from both human studies and animal models suggests that insulin resistance is associated with overexpression of LPL in skeletal muscle, and decreased LPL activity in liver and adipose tissue.[20][21] LPL deletion in mouse skeletal muscle reduces lipid storage and increases insulin sensitivity, but increases insulin resistance in liver and adipose tissue.[20]
Insulin resistance and compensatory hyperinsulinaemia are also strongly related to hypertension. The possible pathogenetic mechanisms include increased sodium reabsorption in the kidney, an imbalance between pressor (through increased sympathetic neural flow) and depressor (through vasodilation) actions of insulin, vasoconstriction effects of free fatty acids, and activation of the sympathetic nervous system, as well as an increase in endothelin 1 and a decrease in nitric oxide, which have been found in obese people.[4][22] Another potential mechanism that links obesity to hypertension is the high level of the adipokine leptin and concurrent leptin resistance in obese patients.[22] Leptin affects central circuits in the hypothalamus, thereby suppressing food intake and stimulating energy expenditure. Increased food intake and insulin resistance has been shown to substantially increase tissue leptin resistance and to rapidly enhance plasma leptin levels, which are independently associated with cardiovascular risk in humans.[23] Hypertension in patients with metabolic syndrome has also been associated with high resistin levels and low levels of adiponectin, an adipokine that exerts anti-atherogenic and insulin-sensitising effects.[24]
Metabolic syndrome is also considered to be a proinflammatory and prothrombotic state.[14] It is associated with high levels of C-reactive protein, increased secretion of cytokines (adipokines such as leptin, resistin, tumour necrosis factor-alpha, and interleukins 6, 10, and 18) by adipose cells, and decreased levels of adiponectin.[25][26][27] It is also associated with higher levels of fibrinogen, homocysteine, and plasminogen activator 1 concentrations than in healthy controls.[12][28][29]
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