Editing Metabolic syndrome (section)

==Causes==
The mechanisms of the complex pathways of metabolic syndrome are under investigation. The [[pathophysiology]] is very complex and has been only partially elucidated. Most people affected by the condition are older, obese, sedentary, and have a degree of insulin resistance. [[Stress (biology)|Stress]] can also be a contributing factor. The most important [[risk factors]] are diet (particularly sugar-sweetened beverage consumption),<ref name="PMID20693348">{{Cite journal |vauthors=Malik VS, Popkin BM, Bray GA, Després JP, Willett WC, Hu FB |date=November 2010 |title=Sugar-sweetened beverages and risk of metabolic syndrome and type 2 diabetes: a meta-analysis |journal=Diabetes Care |volume=33 |issue=11 |pages=2477–83 |doi=10.2337/dc10-1079 |pmc=2963518 |pmid=20693348}}</ref> genetics,<ref>{{Cite journal |vauthors=Pollex RL, Hegele RA |date=September 2006 |title=Genetic determinants of the metabolic syndrome |journal=Nature Clinical Practice Cardiovascular Medicine |volume=3 |issue=9 |pages=482–89 |doi=10.1038/ncpcardio0638 |pmid=16932765 |s2cid=24558150}}</ref><ref>{{Cite journal |vauthors=Poulsen P, Vaag A, Kyvik K, Beck-Nielsen H |date=May 2001 |title=Genetic versus environmental aetiology of the metabolic syndrome among male and female twins |journal=Diabetologia |volume=44 |issue=5 |pages=537–43 |doi=10.1007/s001250051659 |pmid=11380071 |s2cid=26582450 |doi-access=free}}</ref><ref name="Groop2000">{{Cite journal |vauthors=Groop L |date=March 2000 |title=Genetics of the metabolic syndrome |journal=The British Journal of Nutrition |volume=83 |issue=Suppl 1 |pages=S39–S48 |doi=10.1017/S0007114500000945 |pmid=10889791 |s2cid=8974554 |doi-access=free}}</ref><ref name="Bouchard1995">{{Cite journal |vauthors=Bouchard C |date=May 1995 |title=Genetics and the metabolic syndrome |journal=International Journal of Obesity and Related Metabolic Disorders |volume=19 |issue=Suppl 1 |pages=S52–59 |pmid=7550538}}</ref> aging, sedentary behavior<ref name="PMID22514690">{{Cite journal |vauthors=Edwardson CL, Gorely T, Davies MJ, Gray LJ, Khunti K, Wilmot EG, Yates T, Biddle SJ |year=2012 |title=Association of sedentary behaviour with metabolic syndrome: a meta-analysis |journal=PLOS ONE |volume=7 |issue=4 |pages=e34916 |bibcode=2012PLoSO...734916E |doi=10.1371/journal.pone.0034916 |pmc=3325927 |pmid=22514690 |doi-access=free}}</ref> or low physical activity,<ref name="katzmaryk">{{Cite journal |vauthors=Katzmarzyk PT, Leon AS, Wilmore JH, Skinner JS, Rao DC, Rankinen T, Bouchard C |date=October 2003 |title=Targeting the metabolic syndrome with exercise: evidence from the HERITAGE Family Study |journal=Medicine and Science in Sports and Exercise |volume=35 |issue=10 |pages=1703–09 |doi=10.1249/01.MSS.0000089337.73244.9B |pmid=14523308 |s2cid=25598917 |doi-access=free}}</ref><ref>{{Cite journal |vauthors=He D, Xi B, Xue J, Huai P, Zhang M, Li J |date=June 2014 |title=Association between leisure time physical activity and metabolic syndrome: a meta-analysis of prospective cohort studies |journal=Endocrine |volume=46 |issue=2 |pages=231–40 |doi=10.1007/s12020-013-0110-0 |pmid=24287790 |s2cid=5271746}}</ref> disrupted [[chronobiology]]/sleep,<ref name="PMID23890470">{{Cite journal |vauthors=Xi B, He D, Zhang M, Xue J, Zhou D |date=August 2014 |title=Short sleep duration predicts risk of metabolic syndrome: a systematic review and meta-analysis |journal=Sleep Medicine Reviews |volume=18 |issue=4 |pages=293–97 |doi=10.1016/j.smrv.2013.06.001 |pmid=23890470}}</ref> mood disorders/psychotropic medication use,<ref name="PMID24262678">{{Cite journal |vauthors=Vancampfort D, Correll CU, Wampers M, Sienaert P, Mitchell AJ, De Herdt A, Probst M, Scheewe TW, De Hert M |date=July 2014 |title=Metabolic syndrome and metabolic abnormalities in patients with major depressive disorder: a meta-analysis of prevalences and moderating variables |url=https://lirias.kuleuven.be/handle/123456789/398044 |journal=Psychological Medicine |volume=44 |issue=10 |pages=2017–28 |doi=10.1017/S0033291713002778 |pmid=24262678 |s2cid=206253750}}</ref><ref name="PMID23361837">{{Cite journal |vauthors=Vancampfort D, Vansteelandt K, Correll CU, Mitchell AJ, De Herdt A, Sienaert P, Probst M, De Hert M |date=March 2013 |title=Metabolic syndrome and metabolic abnormalities in bipolar disorder: a meta-analysis of prevalence rates and moderators |journal=The American Journal of Psychiatry |volume=170 |issue=3 |pages=265–74 |doi=10.1176/appi.ajp.2012.12050620 |pmid=23361837}}</ref> and excessive alcohol use.<ref name="PMID24315622">{{Cite journal |vauthors=Sun K, Ren M, Liu D, Wang C, Yang C, Yan L |date=August 2014 |title=Alcohol consumption and risk of metabolic syndrome: a meta-analysis of prospective studies |journal=Clinical Nutrition |volume=33 |issue=4 |pages=596–602 |doi=10.1016/j.clnu.2013.10.003 |pmid=24315622}}</ref> The pathogenic role played in the syndrome by the excessive expansion of adipose tissue occurring under sustained [[overeating]], and its resulting [[lipotoxicity]] was reviewed by [[Antonio Vidal-Puig|Vidal-Puig]].<ref>{{Cite journal |vauthors=Vidal-Puig A |date=2013 |title=Adipose tissue expandability, lipotoxicity and the metabolic syndrome |journal=Endocrinologia y Nutricion |volume=60 |issue=Suppl 1 |pages=39–43 |doi=10.1016/s1575-0922(13)70026-3 |pmid=24490226}}</ref>

Recent studies have highlighted the global prevalence of metabolic syndrome, driven by the rise in obesity and type 2 diabetes. The World Health Organization (WHO) and other major health organizations define metabolic syndrome with criteria that include central obesity, insulin resistance, hypertension, and dyslipidemia. As of 2015, metabolic syndrome affects approximately 25% of the global population, with rates significantly higher in urban areas due to increased consumption of high-calorie, low-nutrient diets and decreased physical activity. This condition is associated with a threefold increase in the risk of type 2 diabetes and cardiovascular disease, accounting for a substantial burden of non-communicable diseases globally (Saklayen, 2018).<ref>{{Cite journal |last=Saklayen |first=M.G. |date=2018 |title=The Global Epidemic of the Metabolic Syndrome |journal=Current Hypertension Reports |volume=20 |issue=2 |pages=12 |doi=10.1007/s11906-018-0812-z |pmc=5866840 |pmid=29480368}}</ref>

There is debate regarding whether obesity or insulin resistance is the cause of the metabolic syndrome or if they are consequences of a more far-reaching metabolic derangement. Markers of systemic [[inflammation]], including [[C-reactive protein]], are often increased, as are [[fibrinogen]], [[interleukin 6]], [[tumor necrosis factor-alpha]]&nbsp;(TNF-α), and others. Some have pointed to a variety of causes, including increased [[uric acid]] levels caused by dietary [[fructose]].<ref>{{Cite journal |vauthors=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 |date=March 2006 |title=A causal role for uric acid in fructose-induced metabolic syndrome |journal=American Journal of Physiology. Renal Physiology |volume=290 |issue=3 |pages=F625–31 |doi=10.1152/ajprenal.00140.2005 |pmid=16234313}}</ref><ref>{{Cite journal |vauthors=Hallfrisch J |date=June 1990 |title=Metabolic effects of dietary fructose |journal=FASEB Journal |volume=4 |issue=9 |pages=2652–60 |doi=10.1096/fasebj.4.9.2189777 |pmid=2189777 |s2cid=23659634 |doi-access=free}}</ref><ref>{{Cite journal |vauthors=Reiser S, Powell AS, Scholfield DJ, Panda P, Ellwood KC, Canary JJ |date=May 1989 |title=Blood lipids, lipoproteins, apoproteins, and uric acid in men fed diets containing fructose or high-amylose cornstarch |journal=The American Journal of Clinical Nutrition |volume=49 |issue=5 |pages=832–39 |doi=10.1093/ajcn/49.5.832 |pmid=2497634 |doi-access=free}}</ref>

Research shows that Western diet habits are a factor in the development of metabolic syndrome, with high consumption of food that is not biochemically suited to humans.<ref name="PMID22351884">{{Cite journal |vauthors=Bremer AA, Mietus-Snyder M, Lustig RH |date=March 2012 |title=Toward a unifying hypothesis of metabolic syndrome |journal=Pediatrics |volume=129 |issue=3 |pages=557–70 |doi=10.1542/peds.2011-2912 |pmc=3289531 |pmid=22351884}}</ref>{{page needed|date=September 2020}} Weight gain is associated with metabolic syndrome. Rather than total adiposity, the core clinical component of the syndrome is visceral and/or ectopic fat (i.e., fat in organs not designed for fat storage) whereas the principal metabolic abnormality is insulin resistance.<ref>{{Cite journal |vauthors=Ali ES, Hua J, Wilson CH, Tallis GA, Zhou FH, Rychkov GY, Barritt GJ |date=September 2016 |title=The glucagon-like peptide-1 analogue exendin-4 reverses impaired intracellular Ca(2+) signalling in steatotic hepatocytes |journal=Biochimica et Biophysica Acta (BBA) - Molecular Cell Research |volume=1863 |issue=9 |pages=2135–46 |doi=10.1016/j.bbamcr.2016.05.006 |pmid=27178543}}</ref> The continuous provision of energy via dietary [[Carbohydrate metabolism|carbohydrate]], [[Lipid metabolism|lipid]], and [[Protein metabolism|protein]] fuels, unmatched by physical activity/energy demand, creates a backlog of the products of [[Oxidative phosphorylation|mitochondrial oxidation]], a process associated with progressive mitochondrial dysfunction and insulin resistance.<ref>{{Cite journal |last=Bremer |first=A. A. |last2=Mietus-Snyder |first2=M. |last3=Lustig |first3=R. H. |date=2012 |title=Toward a Unifying Hypothesis of Metabolic Syndrome |url=https://pmc.ncbi.nlm.nih.gov/articles/PMC3289531/ |journal=Pediatrics |volume=129 |issue=3 |pages=557–570 |doi=10.1542/peds.2011-2912 |via=PubMed Central|pmc=3289531 }}</ref>

===Stress===
Recent research indicates prolonged [[chronic stress]] can contribute to metabolic syndrome by disrupting the hormonal balance of the [[hypothalamic-pituitary-adrenal axis]] (HPA-axis).<ref name="Gohill">{{Cite journal |vauthors=Gohil BC, Rosenblum LA, Coplan JD, Kral JG |date=July 2001 |title=Hypothalamic-pituitary-adrenal axis function and the metabolic syndrome X of obesity |journal=CNS Spectrums |volume=6 |issue=7 |pages=581–86, 589 |doi=10.1017/s1092852900002121 |pmid=15573024 |s2cid=22734016}}</ref> A dysfunctional HPA-axis causes high [[cortisol]] levels to circulate, which results in raising [[glucose]] and [[insulin]] levels, which in turn cause insulin-mediated effects on adipose tissue, ultimately promoting [[visceral adiposity]], insulin resistance, dyslipidemia and hypertension, with direct effects on the bone, causing "low turnover" [[osteoporosis]].<ref name="tsigos">{{Cite journal |vauthors=Tsigos C, Chrousos GP |date=October 2002 |title=Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress |url=https://zenodo.org/record/1259653 |journal=Journal of Psychosomatic Research |volume=53 |issue=4 |pages=865–71 |doi=10.1016/S0022-3999(02)00429-4 |pmid=12377295}}</ref> HPA-axis dysfunction may explain the reported risk indication of abdominal obesity to [[cardiovascular disease]] (CVD), type 2 diabetes and [[stroke]].<ref name="rosmond">{{Cite journal |vauthors=Rosmond R, Björntorp P |date=February 2000 |title=The hypothalamic-pituitary-adrenal axis activity as a predictor of cardiovascular disease, type 2 diabetes and stroke |journal=Journal of Internal Medicine |volume=247 |issue=2 |pages=188–97 |doi=10.1046/j.1365-2796.2000.00603.x |pmid=10692081 |s2cid=20336259 |doi-access=free}}</ref> [[Psychosocial]] stress is also linked to heart disease.<ref name="brunner">{{Cite journal |vauthors=Brunner EJ, Hemingway H, Walker BR, Page M, Clarke P, Juneja M, Shipley MJ, Kumari M, Andrew R, Seckl JR, Papadopoulos A, Checkley S, Rumley A, Lowe GD, Stansfeld SA, Marmot MG |date=November 2002 |title=Adrenocortical, autonomic, and inflammatory causes of the metabolic syndrome: nested case-control study |journal=Circulation |volume=106 |issue=21 |pages=2659–65 |doi=10.1161/01.cir.0000038364.26310.bd |pmid=12438290 |s2cid=5992769 |doi-access=free}}</ref>

===Obesity===
Central obesity is a key feature of the syndrome, as both a sign and a cause, in that the increasing adiposity often reflected in high [[waist circumference]] may both result from and contribute to insulin resistance. However, despite the importance of obesity, affected people who are of normal weight may also be insulin-resistant and have the syndrome.<ref name="isbn0-07-147692-X">{{Cite book |last=Fauci, Anthony S. |title=Harrison's principles of internal medicine |publisher=McGraw-Hill Medical |year=2008 |isbn=978-0-07-147692-8}}{{page needed|date=October 2017}}</ref>

===Sedentary lifestyle===
Physical inactivity is a predictor of CVD events and related [[Death|mortality]]. Many components of metabolic syndrome are associated with a [[sedentary lifestyle]], including increased adipose tissue (predominantly central); reduced HDL cholesterol; and a trend toward increased triglycerides, blood pressure, and glucose in the genetically susceptible. Compared with individuals who watched television or videos or used their computers for less than one hour daily, those who carried out these behaviors for greater than four hours daily have a twofold increased risk of metabolic syndrome.<ref name="isbn0-07-147692-X" />

===Aging===
Metabolic syndrome affects 60% of the U.S. population older than age 50. With respect to that demographic, the percentage of women having the syndrome is higher than that of men. The age dependency of the syndrome's prevalence is seen in most populations around the world.<ref name="isbn0-07-147692-X" />

===Diabetes mellitus type 2===
{{main|Diabetes mellitus|Diabetes mellitus type 2}}

The metabolic syndrome quintuples the risk of type 2 diabetes mellitus. Type 2 diabetes is considered a [[complication (medicine)|complication]] of metabolic syndrome.<ref name="Mayo-metabolic" /> In people with impaired glucose tolerance or impaired fasting glucose, presence of metabolic syndrome doubles the risk of developing type 2 diabetes.<ref name="PMID22895669">{{Cite journal |vauthors=Goldberg RB, Mather K |date=September 2012 |title=Targeting the consequences of the metabolic syndrome in the Diabetes Prevention Program |journal=Arteriosclerosis, Thrombosis, and Vascular Biology |volume=32 |issue=9 |pages=2077–90 |doi=10.1161/ATVBAHA.111.241893 |pmc=3901161 |pmid=22895669}}</ref> It is likely that prediabetes and metabolic syndrome denote the same disorder, defining it by the different sets of biological markers.{{citation needed|date=June 2022}}

The presence of metabolic syndrome is associated with a higher prevalence of CVD than found in people with type 2 diabetes or [[impaired glucose tolerance]] without the syndrome.<ref name="isbn0-07-147692-X" /> [[Adiponectin#Hypoadiponectinemia|Hypoadiponectinemia]] has been shown to increase insulin resistance<ref name="pmid17495599">{{Cite journal |vauthors=Lara-Castro C, Fu Y, Chung BH, Garvey WT |date=June 2007 |title=Adiponectin and the metabolic syndrome: mechanisms mediating risk for metabolic and cardiovascular disease |journal=Current Opinion in Lipidology |volume=18 |issue=3 |pages=263–70 |doi=10.1097/MOL.0b013e32814a645f |pmid=17495599 |s2cid=20799218}}</ref> and is considered to be a risk factor for developing metabolic syndrome.<ref name="pmid19258676">{{Cite journal |vauthors=Renaldi O, Pramono B, Sinorita H, Purnomo LB, Asdie RH, Asdie AH |date=January 2009 |title=Hypoadiponectinemia: a risk factor for metabolic syndrome |journal=Acta Medica Indonesiana |volume=41 |issue=1 |pages=20–24 |pmid=19258676}}</ref>

===Coronary heart disease===
The approximate prevalence of the metabolic syndrome in people with [[coronary artery disease]] (CAD) is 50%, with a prevalence of 37% in people with premature coronary artery disease (age 45), particularly in women. With appropriate [[Cardiopulmonary rehabilitation|cardiac rehabilitation]] and changes in lifestyle (e.g., nutrition, physical activity, weight reduction, and, in some cases, drugs), the prevalence of the syndrome can be reduced.<ref name="isbn0-07-147692-X" />

===Lipodystrophy===
[[Lipodystrophy|Lipodystrophic disorders]] in general are associated with metabolic syndrome. Both genetic (e.g., [[Berardinelli-Seip congenital lipodystrophy]], [[Dunnigan familial partial lipodystrophy]]) and acquired (e.g., [[HIV]]-related lipodystrophy in people treated with [[highly active antiretroviral therapy]]) forms of lipodystrophy may give rise to severe insulin resistance and many of metabolic syndrome's components.<ref name="isbn0-07-147692-X" />

===Rheumatic diseases===
There is research that associates comorbidity with rheumatic diseases. Both [[psoriasis]] and [[psoriatic arthritis]] have been found to be associated with metabolic syndrome.<ref>{{Cite journal |vauthors=Quilon III A, Brent L |year=2010 |title=The primary care physician's guide to inflammatory arthritis: diagnosis |url=http://www.musculoskeletalnetwork.com/display/article/1145622/1579185 |journal=The Journal of Musculoskeletal Medicine |volume=27 |pages=223–31}}</ref>

===Chronic obstructive pulmonary disease===
Metabolic syndrome is seen to be a comorbidity in up to 50 percent of those with [[chronic obstructive pulmonary disease]] (COPD). It may pre-exist or may be a consequence of the lung pathology of COPD.<ref name="Chan">{{Cite journal |vauthors=Chan SM, Selemidis S, Bozinovski S, Vlahos R |date=June 2019 |title=Pathobiological mechanisms underlying metabolic syndrome (MetS) in chronic obstructive pulmonary disease (COPD): clinical significance and therapeutic strategies |journal=Pharmacol Ther |volume=198 |pages=160–88 |doi=10.1016/j.pharmthera.2019.02.013 |pmc=7112632 |pmid=30822464}}</ref>