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]


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.[1] Numerous factors which are believed to play a key role in the pathogenesis of metabolic syndrome includes:

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
↑ Factor VII
↑ Factor V
↑ Lipoprotein synthesis
↑ Gluconeogenesis
Impairs 𝛽-cell function
of pancreas
Activate RAAS and SNS
Oxidative stress
endothelial dysfunction
↑ Sodium reabsorption
Proinflammatory state
prothrombotic state
Hypercoagulable state
Metabolic syndrome
Blood pressure, Fasting blood glucose
Atherosclerotic CVD
Diabetes Mellitus

Insulin Resistance

Adipose tissue

Inflammatory mediators Productionction
Free Fatty Acids


Produced by upper body subcutaneous adipocytes.
Tumor necrosis factor alpha


Interleukin-6 (IL-6)

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.[4][5][6]



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. [9]

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


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  2. 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.
  3. 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.
  4. 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.
  5. Hallfrisch J (1990). "Metabolic effects of dietary fructose". FASEB J. 4 (9): 2652&ndash, 2660. PMID 2189777.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. Takata H, Fujimoto S (2013). "[Metabolic syndrome]". Nihon Rinsho. Japanese Journal of Clinical Medicine (in Japanese). 71 (2): 266–9. PMID 23631204. Unknown parameter |month= ignored (help)
  11. 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 |month= ignored (help)
  12. 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 |month= ignored (help)
  13. 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 |month= ignored (help)
  14. 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 |month= ignored (help)

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