Metabolic syndrome pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Priyamvada Singh, M.B.B.S. [2]; Raviteja Guddeti, M.B.B.S. [3]; Aarti Narayan, M.B.B.S [4]

Overview

Metabolic syndrome is characterized by a cluster of conditions that greatly increase the risk of developing cardiovascular diseases, diabetes and stroke. By definition one is said to have a metabolic syndrome if they have 3 of the following 5 conditions: high blood pressure (>130/85), abnormal fasting blood glucose > 100 mg/dl, increased weight around the waist (women > 35 inches, male > 40 inches), triglycerides > 150 mg/dl and a low HDL (female < 50, male < 40).

Pathophysiology

The pathophysiology of metabolic syndrome is extremely complex and has only been partially elucidated. Most patients are older, obese, sedentary, and have a degree of insulin resistance. Metabolic syndrome can be defined as a chronic state of low-grade inflammation. Numerous factors which are believed to play a key role in the pathogenesis of metabolic syndrome includes:

• Insulin resistance
• Visceral adiposity
• Atherogenic dyslipidemia
• Endothelial dysfunction
• Genetic susceptibility
• Elevated blood pressure(Hypertension)
• Hypercoagulable state
• Chronic stress

Physical inactivity Smoking Energy dense food Stress

Positive energy balance resulting in Adipose tissue hyperplasia and hypertrophy

Altered FFA metabolism

Altered release of adipokines

↑ Portal FFA

Insulin resistance hyperinsulinemia

↑Leptin ↑AT-II ↑Aldosterone

↑ Factor VII ↑ Factor V ↑ PAI-I

↑ Lipoprotein synthesis ↑ Gluconeogenesis

Impairs 𝛽-cell function of pancreas

Activate RAAS and SNS

Oxidative stress endothelial dysfunction

Dyslipidemia

Hyperglycemia

↑ Sodium reabsorption Vasoconstriction

Proinflammatory state prothrombotic state

Hypertension

Hypercoagulable state

Metabolic syndrome WC,TCG,HDL Blood pressure, Fasting blood glucose

Atherosclerotic CVD

Diabetes Mellitus

Insulin Resistance

• Insulin resistance is considered the most acceptable hypothesis to describe the pathophysiology of metabolic syndrome.
• Free fatty acids, released from the expanding adipose tissue in obese patients, are the major contributors for the development of insulin resistance.
• In the liver elevated levels of these free fatty acids lead to increased production of glucose, triglycerides, VLDLs and LDLs.
• Free fatty acids inhibit insulin-mediated glucose uptake in the muscles.
• Increased circulating glucose stimulates increased pancreatic insulin secretion resulting in hyperinsulinemia.
• Excessive free fatty acids down regulate signaling pathways and lead to insulin resistance.
• Hyperinsulinemic state results in enhanced sodium reabsorption and increased sympathetic nervous system activity which in turn leads to hypertension.
• Obesity is a proinflammatory state and adipocytes enhance the secretion of interleukin-6, C-reactive protein and TNF which results in more insulin resistance and lipolysis of adipose tissue to FFAs.
• TNFα has been shown to not only cause the production of inflammatory cytokines, but may also trigger cell signaling by interaction with a TNFα receptor that may lead to insulin resistance.
• Cytokines and FFAs are also known to enhance the production of fibrinogen by the liver and plasminogen activator inhibitor-1 (PAI-1) resulting in a pro-thrombotic state. An experiment with rats that were fed a diet one-third of which was sucrose has been proposed as a model for the development of the metabolic syndrome. The sucrose first elevated blood levels of triglycerides, which induced visceral fat and ultimately resulted in insulin resistance. The progression from visceral fat to increased TNFα to insulin resistance has some parallels to human development of metabolic syndrome. Adiponectin is an anti-inflammatory cytokine produced by the adipose tissue. It enhances insulin sensitivity and glucose uptake in the muscles. Its levels are reduced in metabolic syndrome.

Adipose tissue

• Adipose tissue is a collection of adipocytes, stromal pre-adipocytes, immune cells, and endothelium.
• Adipocytes are dynamic in nature and respond to alterations in calorie intake through hypertrophy and hyperplasia.
• Obesity occurs when there is increased consumption of calorie-dense food with reduced physical activity.
• Combined with obesity and adipocyte hypertrophy results in decreased blood supply to adipocytes and subsequently hypoxia.
• Decreased blood supply along with hypoxia leads to necrosis and macrophage infiltration into adipose tissue.
• Infiltration by macrophages also attracts various inflammatory cells such as glycerol, free fatty acids (FFA), pro-inflammatory mediators (tumor necrosis factor alpha (TNF-𝛼) and interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), and C-reactive protein (CRP).

Inflammatory mediators	Productionction
Free Fatty Acids (FFA)	Produced by upper body subcutaneous adipocytes.	Acute exposure results in decreased glucose intake by smooth muscles Chronic exposure results in impairment of pancreatic 𝛽-cell function
Tumor necrosis factor alpha (TNF-𝛼)	Paracrine mediator in adipocytes	Reduce the insulin sensitivity of adipocytes Induces adipocytes apoptosis Inhibits insulin receptor substrate 1 signaling pathway
Interleukin-6 (IL-6)	Released by both adipose tissue and skeletal muscle	Systemic adipokine impairs insulin sensitivity by suppressing lipoprotein lipase activity. Major determinant of the hepatic production of CRP
CRP	Produced mainly by liver	Elevated levels of CRP are associated with an increased waist circumference, insulin resistance, BMI, and hyperglycemia.
Adiponectin	Adiponectin is inversely associated with CVD risk factors.	Increases glucose transport in muscles and enhances fatty acid oxidation. It inhibits hepatic gluconeogenic enzymes and the rate of an endogenous glucose production in the liver.
Leptin	Adipokine involved in the regulation of satiety and energy intake. Leptin receptors are located mostly in the hypothalamus and the brain stem Controls satiety, energy expenditure	Levels increase during the development of obesity and decline during the weight loss. Leptin resistance sets in obesity (no control over eating).

Oxidative Stress

Defects in the mitochondrial oxidative phosphorylation lead to an accumulation of TGs and lipid molecules in the muscles have been identified in elderly patients with type II diabetes or obesity. Accumulation of these lipids in the muscles is associated with insulin resistance. Some have pointed to oxidative stress due to a variety of causes including dietary fructose mediated increased uric acid levels.

Dyslipidemia

• Dyslipidemia is characterized by a spectrum of qualitative lipid abnormalities reflecting perturbations in the structure, metabolism, and biological activities of both atherogenic lipoproteins and antiatherogenic HDL-C which includes an elevation of lipoproteins containing apolipoprotein B (apoB), elevated TGs, increased levels of small particles of LDL, and low levels of HDL-C.
• Insulin resistance leads to an atherogenic dyslipidemia in several ways.
• First, insulin normally suppresses lipolysis in adipocytes, so an impaired insulin signaling increases lipolysis, resulting in increased FFA levels.
• In the liver, FFAs serve as a substrate for the synthesis of TGs.
• FFAs also stabilize the production of apoB, the major lipoprotein of very low density lipoprotein (VLDL) particles, resulting in a more VLDL production. Second, insulin normally degrades apoB through PI3K-dependent pathways, so an insulin resistance directly increases VLDL production.
• Third, insulin regulates the activity of lipoprotein lipase, the rate-limiting and major mediator of VLDL clearance.
• Thus, hypertriglyceridemia in insulin resistance is the result of both an increase in VLDL production and a decrease in VLDL clearance.
• VLDL is metabolized to remnant lipoproteins and small dense LDL, both of which can promote an atheroma formation.
• The TGs in VLDL are transferred to HDL by the Cholesterylester transferring protein (CETP) in exchange for cholesteryl esters, resulting in the TG-enriched HDL and cholesteryl ester enriched VLDL particles.
• Further, the TG-enriched HDL is a better substrate for hepatic lipase, so it is cleared rapidly from the circulation, leaving a fewer HDL particles to participate in a reverse cholesterol transport from the vasculature.
• Thus, in the liver of insulin-resistant patients, FFA flux is high, TGs synthesis and storage are increased, and excess TG is secreted as VLDL.
• For the most part, it is believed that the dyslipidemia associated with insulin resistance is a direct consequence of increased VLDL secretion by the liver.
• These anomalies are closely associatedwith an increased oxidative stress and an endothelial dysfunction, thereby reinforcing the proinflammatory nature of macrovascular atherosclerotic disease.

Hypertension

Insulin is a vasodilator under normal physiologic conditions with secondary effects on sodium reabsorption. In hyperinsulinemia and insulin resistance this vasodilatory effect of insulin is lost but the sodium reabsorption effect on the kidney is preserved. In caucasians this reabsorptive effect is increased in metabolic syndrome. Insulin also increases sympathetic nervous system activity and this effect is preserved in insulin resistance. Impairment of phosphatidylinositol-3-kinase signaling pathway causes imbalance between the production of NO and endothelin-1 resulting in reduced blood flow.

Glucose Intolerance

Due to defects in insulin, Glucose intolerance leads to increased production of insulin to maintain normal glucose levels. When this compensatory mechanism fails, the result is progression from glucose intolerance to diabetes.

Associated Conditions

• Type II diabetes
  • The risk of developing diabetes mellitus in patients with metabolic syndrome is very high.
• Polycystic ovarian syndrome (PCOS)
  • Women with PCOS are more likely to have metabolic syndrome than women without PCOS.
• Hemochromatosis (iron overload)
  • The dysmetabolic iron overload syndrome seen very commonly in metabolic syndrome can result in hemochromatosis.
• Obstructive sleep apnea
  • This condition is associated with obesity, hypertension, insulin resistance, glucose intolerance and increase in circulating inflammatory cytokines. Insulin resistance is greater in patients with obstructive sleep apnea in comparison to weight matched controls.
• Hyperuricemia
  • Increase in serum uric acid levels is a result of defective action of insulin on the renal tubular cells. An increase in asymmetric methylarginine signifies endothelial dysfunction secondary to an insulin resistant state.
• Gout
• Nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH)
  • Inflammation and triglyceride accumulation coexists in this condition. This condition can result in fibrosis or cirrhosis of the liver, ultimately causing hepatic failure.