IX. Inflammation and the metabolic syndrome
The main parameters of the MetS (obesity, dyslipidemia i.e. a high TG level and low HDL), hypertension, increased fasting GLU and insulin resistance) increase the risk of various diseases.
The circulatory diseases (3 times) and the resultant death (6 times) are more frequent. The obesity develops during the syndrome facilitates and enhances the inflammatory processes.
The various components of systemic inflammation:
- a general immune response
- (production of T cells, B cells, immunoglobulins, cytokines)
- increased production of coagulation factors (fibrinogen, PAI-1, factors VII and VIII), CRP, serum amyloid A, albumin, transferrin by cytokines
- neuroendocrine response (fever, increases in glycocorticoid and epinephrine production, fatigue, depression)
- hematopoietic reactions (leukocytosis, thrombocytosis, anemia)
- metabolic reactions (lipolysis, a muscle mass decrease, a negative nitrogen balance, and a decrease in body weight).
The above-mentioned general processes are enhanced in several points by MetS-induced pathways.
Atherosclerosis is stimulated in various steps by inflammation: it increases lipid deposition, inhibits the endothelial function, decreases the amounts of NO and prostacyclin, and enhances the amounts of endothelin-1 and angiotensin-1.
Various other biomarkers level change in the MetS: serum amyloid A and CRP ↑, IL-6 ↑, TNF ↑, IL-10 ↓, adiponectin ↓ leptin ↑, serum amyloid A (SAA) ↑, PAI-1 ↑, resistin, and RBP-4 ↑.
In general, the MetS is characterized by enhanced insulin resistance and inflammatory pathways.
IL-1, IL-6 and TNF-α play important roles in the release of cytokines.
IL-1 and TNF-α stimulate IL-6 production. IL-6 plays a key role in the inflammatory processes: it inhibits the liver insulin sensitivity, increases CRP and fibrinogen release, and enhances the development of insulin resistance, increases monocyte efflux, and increases the adipocyte function. 30% of the circulating IL-6 is released from the adipose tissue. A decrease in IL-6 level leads to a weight loss. It is suggested that IL-6, together with FFAs and corticosteroids, plays an important role in the development of the MetS.
TNF-α is released from the monocytes, macrophages, endothelium and adipocytes. TNF-α influences the insulin sensitivity of the tissues. A decrease in TNF-α level leads to weight loss in animals. An increased TNF-α level correlates well with the BMI.
IL-10 is a well-known anti-inflammatory cytokine. Its level is increased in obese and in MetS patients, which reflects the reaction of the body to the systemic inflammatory processes.
The serum amyloid A and CRP levels are increased significantly in MetS patients (> 1 mg/l). Their levels correlate well with the HOMA values, hypertension, low HDL, high plasma Glu, LDL, TG, IL-6 and TNF-α levels. They also correlate with the BMI and waist-hip ratio. In contrast, the leptin and adiponectin levels do not change with respect to CRP, pointing to inflammatory processes.
CRP is produced mainly in the liver, the lymphocytes and the atherosclerotic plaques. CRP as a member of the immune system protects against infections, inflammation, autoimmune processes and cancers. It can bind to a damaged cell membrane, LDL/VLDL particles and lymphocytes. In physiological concentrations, it inhibits the PAF. Its increased level enhances thrombocyte aggregation, stimulates the uptake of oxidized LDL and hence the formation of foam cells, and increases cytokine and ET-1 production. It decreases the eNOS function, and hence increases vasoconstriction through the decrease of NO.
Its release is stimulated by cytokines (TNF-α, IL-6 and IL-1-β). Its normal range is about 1 µg/ml (<1.0 mg/l). Its level is enhanced by obesity, smoking, excessive alcohol consumption, and excessive physical activity. Interestingly, its level is increased in totally abstinent individuals.
The CRP level >3 mg/l in MetS patients correlates well with the development of circulatory disorders. It was therefore suggested that an increased CRP level should be one of the criteria of the MetS.
The changed adipose tissue plays an important role in the inflammatory processes. The increased adipose tissue starts to synthesize special signal molecules such as MCP-1, which stimulates macrophage infiltration into the adipose tissue. MCP-1 plays an important role in the development of atherosclerosis. Macrophage infiltration into the vessel wall is blocked by the CCR2 receptor, and the vessel wall lesion therefore decreases significantly. MCP-1 further decreases the Glu uptake induced by insulin.
The adiponectin released from the adipose tissue has many positive effects. It enhances insulin sensitivity in the liver, increases fat burning and decreases the release of Glu from the liver. It stimulates Glu uptake and utilization in the muscle, and inhibits monocyte adhesion in the vessel wall and macrophage infiltration. It increases endothelial NO production and angiogenesis. The level of MCP-1 is decreased the inflammation of the adipose tissue. T2DM and obese and/or MetS patients are characterized by low adiponectin levels. A significantly decreased adiponectin level increases the risk of the development of insulin resistance, infarcts and circulatory diseases.
SAA is expressed in the liver. Its role is not well understood. Enhanced SAA levels correlate well with insulin resistance and the increased fat mass. In T2DM patients, its level is high.
The effects of PAI-1, a serine protease inhibitor, have been proven extensively. Its main role is the inhibition of fibrinolysis, and it therefore stimulates coagulation. An enhanced PAI-1 level, a risk factor of circulatory diseases, correlates well with insulin resistance, obesity and the MetS. The PAI-1 production in the adipose tissues is enhanced in obese patients.
The structure and function of the endothelium are very important in the development of circulatory disorders. The medulla and the circulating blood contain special progenitor cells (endothelial progenitor cells, EPCs), which facilitate repair of the endothelium. Significantly decreased levels of EPCs are found in MetS patients.