Metabolic syndrome pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. ; Associate Editor(s)-in-Chief: Priyamvada Singh, M.B.B.S. ; Raviteja Guddeti, M.B.B.S. ; Aarti Narayan, M.B.B.S 
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).
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 |
Energy dense food
|Positive energy balance resulting in |
Adipose tissue hyperplasia and hypertrophy
|Altered FFA metabolism||Altered release of adipokines|
|↑ Portal FFA||Insulin resistance hyperinsulinemia||↑Leptin|
|↑ Factor VII|
↑ Factor V
|↑ Lipoprotein synthesis|
|Impairs 𝛽-cell function|
|Activate RAAS and SNS||Oxidative stress|
|Dyslipidemia||Hyperglycemia||↑ Sodium reabsorption|
Blood pressure, Fasting blood glucose
|Atherosclerotic CVD||Diabetes Mellitus|
- 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 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).
|Free Fatty Acids
|Produced by upper body subcutaneous adipocytes.||
|Tumor necrosis factor alpha
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 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.
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. 
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.
- Type II diabetes
- The risk of developing diabetes mellitus in patients with metabolic syndrome is very high.
- Polycystic ovarian syndrome (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.
- 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.
- 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.
- ↑ Cornier MA, Dabelea D, Hernandez TL; et al. (2008). "The metabolic syndrome". Endocrine Reviews. 29 (7): 777–822. doi:10.1210/er.2008-0024. PMID 18971485. Unknown parameter
- ↑ Després JP, Lemieux I, Bergeron J, Pibarot P, Mathieu P, Larose E; et al. (2008). "Abdominal obesity and the metabolic syndrome: contribution to global cardiometabolic risk". Arterioscler Thromb Vasc Biol. 28 (6): 1039–49. doi:10.1161/ATVBAHA.107.159228. PMID 18356555.
- ↑ Fukuchi S, Hamaguchi K, Seike M, Himeno K, Sakata T, Yoshimatsu H. (2004). "Role of Fatty Acid Composition in the Development of Metabolic Disorders in Sucrose-Induced Obese Rats". Exp Biol Med. 229 (6): 486&ndash, 493. PMID 15169967.
- ↑ Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, Glushakova O, Ouyang X, Feig DI, Block ER, Herrera-Acosta J, Patel JM, Johnson RJ (2006). "A causal role for uric acid in fructose-induced metabolic syndrome". Am J Phys Renal Phys. 290 (3): F625&ndash, F631. PMID 16234313.
- ↑ Hallfrisch J (1990). "Metabolic effects of dietary fructose". FASEB J. 4 (9): 2652&ndash, 2660. PMID 2189777.
- ↑ Reiser S, Powell AS, Scholfield DJ, Panda P, Ellwood KC, Canary JJ (1989). "Blood lipids, lipoproteins, apoproteins, and uric acid in men fed diets containing fructose or high-amylose cornstarch". Am J Clin Nutr. 49 (5): 832&ndash, 839. PMID 2497634.
- ↑ Lewis GF, Steiner G (1996). "Acute effects of insulin in the control of VLDL production in humans. Implications for the insulin-resistant state". Diabetes Care. 19 (4): 390–3. PMID 8729170.
- ↑ Borggreve SE, De Vries R, Dullaart RP (2003). "Alterations in high-density lipoprotein metabolism and reverse cholesterol transport in insulin resistance and type 2 diabetes mellitus: role of lipolytic enzymes, lecithin:cholesterol acyltransferase and lipid transfer proteins". Eur. J. Clin. Invest. 33 (12): 1051–69. PMID 14636288.
- ↑ Zimmet P, Boyko EJ, Collier GR, de Courten M (1999). "Etiology of the metabolic syndrome: potential role of insulin resistance, leptin resistance, and other players". Ann. N. Y. Acad. Sci. 892: 25–44. PMID 10842650.
- ↑ Takata H, Fujimoto S (2013). "[Metabolic syndrome]". Nihon Rinsho. Japanese Journal of Clinical Medicine (in Japanese). 71 (2): 266–9. PMID 23631204. Unknown parameter
- ↑ Teede HJ, Hutchison S, Zoungas S, Meyer C (2006). "Insulin resistance, the metabolic syndrome, diabetes, and cardiovascular disease risk in women with PCOS". Endocrine. 30 (1): 45–53. doi:10.1385/ENDO:30:1:45. PMID 17185791. Unknown parameter
- ↑ Cussons AJ, Stuckey BG, Watts GF (2007). "Metabolic syndrome and cardiometabolic risk in PCOS". Current Diabetes Reports. 7 (1): 66–73. PMID 17254520. Unknown parameter
- ↑ Dongiovanni P, Fracanzani AL, Fargion S, Valenti L (2011). "Iron in fatty liver and in the metabolic syndrome: a promising therapeutic target". Journal of Hepatology. 55 (4): 920–32. doi:10.1016/j.jhep.2011.05.008. PMID 21718726. Unknown parameter
- ↑ Sogabe M, Okahisa T, Tsujigami K, Fukuno H, Hibino S, Yamanoi A (2013). "Visceral fat predominance is associated with nonalcoholic fatty liver disease in Japanese women with metabolic syndrome". Hepatology Research : the Official Journal of the Japan Society of Hepatology. doi:10.1111/hepr.12146. PMID 23617326. Unknown parameter