Metabolic Syndrome Pathophysiology and Predisposing Factors

António Bovolini; Juliana Garcia; Maria Amparo Andrade; José Alberto Duarte

doi:10.1055/a-1263-0898

International Journal of Sports Medicine, Inhaltsverzeichnis

Int J Sports Med 2021; 42(03): 199-214
DOI: 10.1055/a-1263-0898

Review

Metabolic Syndrome Pathophysiology and Predisposing Factors

António Bovolini

¹CIAFEL Faculty of Sport, University of Porto, Porto

,

Juliana Garcia

²Centre for the Research and Technology of Agro-Environmental and Biological Sciences, University of Trás-os-Montes and Alto Douro, Vila Real

,

Maria Amparo Andrade

³Federal University of Pernambuco, Federal University of Pernambuco, Recife

,

José Alberto Duarte

¹CIAFEL Faculty of Sport, University of Porto, Porto

⁴University Institute of Health Sciences (IUCS), Rua Central de Gandra, 1317 4585-116 Gandra Paredes, Portugal

› Institutsangaben

Abstract

Metabolic syndrome (MetS) is a cluster of cardiometabolic risk factors with high prevalence among adult populations and elevated costs for public health systems worldwide. Despite the lack of consensus regarding the syndrome definition and diagnosis criteria, it is characterized by the coexistence of risk factors such as abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, a prothrombotic and pro-inflammatory state, insulin resistance (IR), and higher glucose levels, factors indubitably linked to an increased risk of developing chronic conditions, such as type 2 diabetes (T2D) and cardiovascular disease (CVD). The syndrome has a complex and multifaceted origin not fully understood; however, it has been strongly suggested that sedentarism and unbalanced dietary patterns might play a fundamental role in its development. The purpose of this review is to provide an overview from the syndrome epidemiology, costs, and main etiological traits from its relationship with unhealthy diet patterns and sedentary lifestyles.

Key words

metabolic syndrome - sedentary lifestyle - diet - cardiovascular disease - type 2 diabetes

Volltext

Referenzen

References
1 Gurka MJ, Guo Y, Filipp SL. et al. Metabolic syndrome severity is significantly associated with future coronary heart disease in Type 2 diabetes. Cardiovasc Diabetol 2018; 17: 17
2 Lopez-Candales A, Hernández Burgos PM, Hernandez-Suarez DF. et al. Linking chronic inflammation with cardiovascular disease: From normal aging to the metabolic syndrome. J Nat Sci 2017; 3: e341
3 Rochlani Y, Pothineni NV, Kovelamudi S. et al. Metabolic syndrome: Pathophysiology, management, and modulation by natural compounds. Ther Adv. Cardiovasc Dis 2017; 11: 215-225
4 Alberti K, Eckel RH, Grundy SM. et al. Harmonizing the metabolic syndrome. Circulation 2009; 120: 1640-1645
5 Balkau B, Vernay M, Mhamdi L. et al. The incidence and persistence of the NCEP (National Cholesterol Education Program) metabolic syndrome. The French D.E.S.I.R. study. Diabetes Metab 2003; 29: 526-532
6 Kolovou GD, Anagnostopoulou KK, Salpea KD. et al. The prevalence of metabolic syndrome in various populations. Am J Med Sci 2007; 333: 362-371
7 Desroches S, Lamarche B. The evolving definitions and increasing prevalence of the metabolic syndrome. Appl Physiol Nutr Metab 2007; 32: 23-32
8 Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: Findings from the Third National Health and Nutrition Examination Survey. JAMA 2002; 287: 356-359
9 Ervin RB. Prevalence of metabolic syndrome among adults 20 years of age and over, by sex, age, race and ethnicity, and body mass index: United States, 2003-2006. Natl Vital Stat Report 2009; 13: 1-7
10 Beltran-Sanchez H, Harhay MO, Harhay MM. et al. Prevalence and trends of metabolic syndrome in the adult U.S. population, 1999-2010. J Am Coll Cardiol 2013; 62: 697-703
11 Sullivan PW, Ghushchyan V, Wyatt HR. et al. The medical cost of cardiometabolic risk factor clusters in the United States. Obesity 2007; 15: 3150-3158
12 Boudreau D, Malone D, Raebel M. et al. Health care utilization and costs by metabolic syndrome risk factors. Metab Syndr Relat Disord 2009; 7: 305-314
13 American Heart Association, American Stroke Association. Cardiovascular disease: a costly burden for America (projections through 2035). Washington, DC: American Heart Association; 2017. Available at https://healthmetrics.heart.org/wp-content/uploads/2017/10/Cardiovascular-Disease-A-Costly-Burden.pdf
14 Wilkins E, Wilson L, Wickramasinghe K. et al. European Cardiovascular Disease Statistics 2017. Brussels: European Heart Network; 2017
15 International Diabetes Federation. IDF Diabetes Atlas Seventh Edition 2015. Available at https://idf.org/e-library/epidemiology-research/diabetes-atlas/13-diabetes-atlas-seventh-edition.html
16 Bays H, Ballantyne C. Adiposopathy: Why do adiposity and obesity cause metabolic disease?. Future Lipidol 2006; 1: 389-420
17 Longo D, Fauci A, Kasper D. et al. Harrison’s Principles of Internal Medicine. 18. McGraw-Hill Education; 2011
18 Kaur J. A comprehensive review on metabolic syndrome. Cardiol Res Pract 2014; 2014: 1-20
19 Rizvi AA. Cytokine biomarkers, endothelial inflammation, and atherosclerosis in the metabolic syndrome: emerging concepts. Am J Med Sci 2009; 338: 310-318
20 Monda KL, North KE, Hunt SC. et al. The genetics of obesity and the metabolic syndrome. Endocr Metab Immune Disord Drug Targets 2010; 10: 86-108
21 Joy T, Hegele RA. Genetics of metabolic syndrome: is there a role for phenomics?. Curr Atheroscler Rep 2008; 10: 201-208
22 Blüher M. The distinction of metabolically ‘healthy’ from ‘unhealthy’ obese individuals. Curr Opin Lipidol 2010; 21: 38-43
23 Ferrannini E, Natali A, Bell P. et al. Insulin resistance and hypersecretion in obesity. European Group for the Study of Insulin Resistance (EGIR). J Clin Invest 1997; 100: 1166-1173
24 Banerji MA, Lebovitz HE. Insulin-sensitive and insulin-resistant variants in NIDDM. Diabetes 1989; 38: 784-792
25 Conway JM, Yanovski SZ, Avila NA. et al. Visceral adipose tissue differences in black and white women. Am J Clin Nutr 1995; 61: 765-771
26 Lovejoy JC, Jacques A, Klemperer M. et al. Abdominal fat distribution and metabolic risk factors: Effects of race. Metabolism 1996; 45: 1119-1124
27 Crowther N, Ferris W, Ojwang P. et al. The effect of abdominal obesity on insulin sensitivity and serum lipid and cytokine concentrations in African women. Clin Endocrinol 2006; 64: 535-541
28 Jennings CL, Lambert EV, Collins M. et al. Determinants of insulin-resistant phenotypes in normal-weight and obese Black African women. Obesity 2008; 16: 1602-1609
29 Haffner SM, D’Agostino R, Goff D. et al. LDL size in African Americans, Hispanics, and non-Hispanic whites: The insulin resistance atherosclerosis study. Arterioscler Thromb Vasc Biol 1999; 19: 2234-2240
30 Karter AJ, Mayer-Davis EJ, Selby JV. et al. Insulin sensitivity and abdominal obesity in African-American, Hispanic, and non-Hispanic white men and women: the Insulin Resistance and Atherosclerosis Study. Diabetes 1996; 45: 1547-1555
31 Meis SB, Schuster D, Gaillard T. et al. Metabolic syndrome in nondiabetic, obese, first-degree relatives of African American patients with type 2 diabetes: African American triglycerides-HDL-C and insulin resistance paradox. Ethn Dis 2006; 16: 830-836
32 Hall W, Clark LT, Wenger NK. et al. The metabolic syndrome in African Americans: a review. Ethn Dis 2003; 13: 414-428
33 Harris MM, Stevens J, Thomas N. et al. Associations of fat distribution and obesity with hypertension in a bi-ethnic population: The ARIC study. Obes Res 2000; 8: 516-524
34 Park Y-W, Zhu S, Palaniappan L. et al. The metabolic syndrome: Prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988-1994. Arch Intern Med 2003; 163: 427-436
35 Taylor H, Liu J, Wilson G. et al. Distinct component profiles and high risk among African Americans with metabolic syndrome: the Jackson Heart Study. Diabetes Care 2008; 31: 1248-1253
36 Gaillard T, Schuster D, Osei K. Metabolic syndrome in Black people of the African diaspora: The paradox of current classification, definition and criteria. Ethn Dis 2009; 19 S2- 1-7
37 Gaillard T. Consequences of Abdominal adiposity within the metabolic syndrome paradigm in Black People of African Ancestry. J Clin Med 2014; 3: 897-912
38 Carr DB, Utzschneider KM, Hull RL. et al. Intra-Abdominal Fat Is a Major Determinant of the National Cholesterol Education Program Adult Treatment Panel III Criteria for the Metabolic Syndrome. Diabetes 2004; 53: 2087-2094
39 Amato MC, Giordano C, Galia M. et al. Visceral Adiposity Index: A reliable indicator of visceral fat function associated with cardiometabolic risk. Diabetes Care 2010; 33: 920-922
40 Polimeni L, Baratta F, Pastori D. et al. Visceral fat evaluated by ultrasound is associated with insulin resistance and liver damage in patients with non-alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis 2017; 27: e32
41 Caprio S, Perry R, Kursawe R. Adolescent obesity and insulin resistance: roles of ectopic fat accumulation and adipose inflammation. Gastroenterology 2017; 152: 1638-1646
42 Darbre PD. Endocrine disruptors and obesity. Curr Obes Rep 2017; 6: 18-27
43 Saltiel AR, Olefsky JM. Inflammatory mechanisms linking obesity and metabolic disease. J Clin Invest 2017; 127: 1-4
44 Zmora N, Bashiardes S, Levy M. et al. The role of the immune system in metabolic health and disease. Cell Metab 2017; 25: 506-521
45 Rodriguez A, Catalan V, Gomez-Ambrosi J. et al. Visceral and subcutaneous adiposity: Are both potential therapeutic targets for tackling the metabolic syndrome?. Curr Pharm Des 2007; 13: 2169-2175
46 Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism 2016; 65: 1038-1048
47 Tan HW, Zhao NQ, Yu YR. et al. Pancreatic beta-cell dysfunction and apoptosis induced by elevated free fatty acids synergize with hyperglycemia. Sichuan Da Xue Xue Bao Yi Xue Ban 2017; 48: 71-75
48 Tumova J, Andel M, Trnka J. Excess of free fatty acids as a cause of metabolic dysfunction in skeletal muscle. Physiol Res 2016; 65: 193-207
49 Ginsberg HN, Zhang Y-L, Hernandez-Ono A. Regulation of plasma triglycerides in insulin resistance and diabetes. Arch Med Res 2005; 36: 232-240
50 Sharma RB, Alonso LC. Lipotoxicity in the pancreatic beta cell: not just survival and function, but proliferation as well?. Curr Diab Rep 2014; 14: 492
51 Cerf ME. Beta cell dysfunction and insulin resistance. Front Endocrinol (Lausanne) 2013; 4: 37
52 Brøns C, Grunnet LG. Mechanisms in Endocrinology: Skeletal muscle lipotoxicity in insulin resistance and type 2 diabetes: A causal mechanism or an innocent bystander?. Eur J Endocrinol 2017; 176: R67-R78
53 Samuel VT, Petersen KF, Shulman GI. Lipid-induced insulin resistance: unravelling the mechanism. Lancet 2010; 375: 2267-2277
54 Dresner A, Laurent D, Marcucci M. et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest 1999; 103: 253-259
55 Roden M, Price TB, Perseghin G. et al. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest 1996; 97: 2859-2865
56 Sakaguchi M, Fujisaka S, Cai W. et al. Adipocyte dynamics and reversible metabolic syndrome in mice with an inducible adipocyte-specific deletion of the insulin receptor. Cell Metab 2017; 25: 448-462
57 Jialal I, Adams-Huet B, Major A. et al. Increased fibrosis and angiogenesis in subcutaneous gluteal adipose tissue in nascent metabolic syndrome. Diabetes Metab 2017; 43: 364-367
58 Lindberg S, Jensen JS, Bjerre M. et al. Low adiponectin levels at baseline and decreasing adiponectin levels over 10 years of follow-up predict risk of the metabolic syndrome. Diabetes Metab 2017; 43: 134-139
59 Canas JA, Lochrie A, McGowan AG. et al. Effects of mixed carotenoids on adipokines and abdominal adiposity in children: A pilot study. J Clin Endocrinol Metab 2017; 102: 1983-1990
60 Furukawa S, Fujita T, Shimabukuro M. et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 2017; 114: 1752-1761
61 Wisse BE. The inflammatory syndrome: The role of adipose tissue cytokines in metabolic disorders linked to obesity. Clin J Am Soc Nephrol 2004; 15: 2792-2800
62 Leal VdO, Mafra D. et al. Adipokines in obesity. Clin Chim Acta 2013; 419: 87-94
63 Farr OM, Gavrieli A, Mantzoros CS. Leptin applications in 2015: What have we learned about leptin and obesity?. Curr Opin Endocrinol Diabetes Obes 2015; 22: 353-359
64 Jung CH, Kim M-S. Molecular mechanisms of central leptin resistance in obesity. Arch Pharm Res 2013; 36: 201-207
65 Diez JJ, Iglesias P. The role of the novel adipocyte-derived hormone adiponectin in human disease. Eur J Endocrinol 2003; 148: 293-300
66 Yamauchi T, Kamon J, Waki H. et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001; 7: 941-946
67 Aslam M, Madhu SV. Development of metabolic syndrome in high-sucrose diet fed rats is not associated with decrease in adiponectin levels. Endocrine 2017; 58: 59-65
68 Yamauchi T, Kamon J, Minokoshi Ya. et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 2002; 8: 1288-1295
69 Ouchi N, Kihara S, Arita Y. et al. Novel modulator for endothelial adhesion molecules. Circulation 1999; 100: 2473-2476
70 Ouchi N, Kihara S, Arita Y. et al. Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-κB signaling through a cAMP-dependent pathway. Circulation 2000; 102: 1296-1301
71 Achari AE, Jain SK. Adiponectin, a therapeutic target for obesity, diabetes, and endothelial dysfunction. Int J Mol Sci 2017; 18: 1321
72 Karnati HK, Panigrahi MK, Li Y. et al. Adiponectin as a potential therapeutic target for prostate cancer. Curr Pharm Des 2017; 23: 4170-4179
73 Hotamisligil GS, Arner P, Caro JF. et al. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest 1995; 95: 2409-2415
74 Pologe L, de Bruin D, Ravetch J. et al. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-ac-and obesity-induced insulin resistance. Science 1996; 271: 665-668
75 Wang S, Leonard SS, Castranova V. et al. The role of superoxide radical in TNF-alpha induced NF-kappaB activation. Ann Clin Lab Sci 1999; 29: 192-199
76 Taylor AW, Ku NO, Mortensen RF. Regulation of cytokine-induced human C-reactive protein production by transforming growth factor-beta. J Immunol 1990; 145: 2507-2513
77 Stenlof K, Wernstedt I, Fjallman T. et al. Interleukin-6 levels in the central nervous system are negatively correlated with fat mass in overweight/obese subjects. J Clin Endocrinol Metab 2003; 88: 4379-4383
78 Xu E, Pereira MM, Karakasilioti I. et al. Temporal and tissue-specific requirements for T-lymphocyte IL-6 signalling in obesity-associated inflammation and insulin resistance. Nat Commun 2017; 8: 1-16
79 Aroor AR, McKarns S, Demarco VG. et al. Maladaptive immune and inflammatory pathways lead to cardiovascular insulin resistance. Metabolism 2013; 62: 1543-1552
80 Timper K, Denson JL, Steculorum SM. et al. IL-6 improves energy and glucose homeostasis in obesity via enhanced central IL-6 trans-Signaling. Cell Rep 2017; 19: 267-280
81 Li L, Duan C, Zhao Y. et al. Preventive effects of interleukin-6 in lipopolysaccharide/d-galactosamine induced acute liver injury via regulating inflammatory response in hepatic macrophages. Int Immunopharmacol 2017; 51: 99-106
82 Kraja AT, Province MA, Arnett D. et al. Do inflammation and procoagulation biomarkers contribute to the metabolic syndrome cluster?. Nutr Metab (Lond) 2007; 4: 28
83 Holzberg JR, Jin R, Le N-A. et al. Pai-1 predicts quantity of hepatic steatosis independent of insulin resistance and body weight. J Pediatr Gastroenterol Nutr 2016; 62: 819-823
84 Carratala A, Martinez-Hervas S, Rodriguez-Borja E et al. PAI-1 levels are related to insulin resistance and carotid atherosclerosis in subjects with familial combined hyperlipidemia. J Investig Med 2018; 66: 17-21
85 Grundy SM, Brewer HB, Cleeman JI. et al. Definition of Metabolic Syndrome. Report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues Related to Definition. 2004; 109: 433-438
86 Alessi M-C, Juhan-Vague I. PAI-1 and the metabolic syndrome. Arterioscler Thromb Vasc Biol 2006; 26: 2200-2207
87 Roberts CK, Hevener AL, Barnard RJ. Metabolic syndrome and insulin resistance: underlying causes and modification by exercise training. Compr Physiol 2013; 3: 1-58
88 Reaven G. The metabolic syndrome or the insulin resistance syndrome? Different names, different concepts, and different goals. Endocrinol Metab Clin North Am 2004; 33: 283-303
89 Grundy SM, Cleeman JI, Daniels SR. et al. Diagnosis and management of the metabolic syndrome. Circulation 2005; 112: 2735-2752
90 Lackey DE, Olefsky JM. Regulation of metabolism by the innate immune system. Nat Rev Endocrinol 2016; 12: 15-28
91 Cancello R, Clement K. Is obesity an inflammatory illness? Role of low-grade inflammation and macrophage infiltration in human white adipose tissue. BJOG 2006; 113: 1141-1147
92 Wu H, Ballantyne CM. Skeletal muscle inflammation and insulin resistance in obesity. J Clin Invest 2017; 127: 43-54
93 Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 2011; 11: 98-107
94 Robinson MW, Harmon C, O’Farrelly C. Liver immunology and its role in inflammation and homeostasis. Cell Mol Immunol 2016; 13: 267-276
95 Grundy SM. Obesity, metabolic syndrome, and cardiovascular disease. J Clin Endocrinol Metab 2004; 89: 2595-2600
96 Maury E, Brichard SM. Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome. Mol Cell Endocrinol 2010; 314: 1-16
97 Blokhin IO, Lentz SR. Mechanisms of thrombosis in obesity. Curr Opin Hematol 2013; 20: 437-444
98 Contractor AS, Gordon TL, Gordon NF. Hypertension. In: Ehrman JK, Gordon PM, Visich PS et al., Eds. Clinical Exercise Physiology. Third edition. Human Kinetics, Champaign, IL; 2013: 137-153
99 Yanai H, Tomono Y, Ito K. et al. The underlying mechanisms for development of hypertension in the metabolic syndrome. Nutr J 2008; 7: 10
100 Mulè G, Calcaterra I, Nardi E. et al. Metabolic syndrome in hypertensive patients: An unholy alliance. World J Cardiol 2014; 6: 890-907
101 Duvnjak L, Bulum T, Metelko Z. Hypertension and the metabolic syndrome. Diabetol Croat 2008; 37: 83-89
102 Schinzari F, Tesauro M, Rovella V. et al. Generalized impairment of vasodilator reactivity during hyperinsulinemia in patients with obesity-related metabolic syndrome. Am J Physiol Endocrinol Metab 2010; 299: E947-E952
103 Smith MM, Minson CT. Obesity and adipokines: Effects on sympathetic overactivity. J Physiol 2012; 590: 1787-1801
104 Campese VM, Ye S, Zhong H. et al. Reactive oxygen species stimulate central and peripheral sympathetic nervous system activity. Am J Physiol Heart Circ Physiol 2004; 287: H695-H703
105 Han Y, Zhang Y, Wang H-J. et al. Reactive oxygen species in paraventricular nucleus modulates cardiac sympathetic afferent reflex in rats. Brain Res 2005; 1058: 82-90
106 Duvnjak L, Duvnjak M. The metabolic syndrome: an ongoing story. J Physiol Pharmacol 2009; 60: 19-24
107 Reaven G, Laws A. Insulin resistance, compensatory hyperinsulinaemia, and coronary heart disease. Diabetologia 1994; 37: 948-952
108 Wang CCL, Goalstone ML, Draznin B. Molecular mechanisms of insulin resistance that impact cardiovascular biology. Diabetes 2004; 53: 2735-2740
109 Sowers JR, Frohlich ED. Insulin and insulin resistance: Impact on blood pressure and cardiovascular disease. Med Clin North Am 2004; 88: 63-82
110 Rahmouni K, Correia ML, Haynes WG. et al. Obesity-associated hypertension: New insights into mechanisms. Hypertension 2005; 45: 9-14
111 Grundy SM. Hypertriglyceridemia, atherogenic dyslipidemia, and the metabolic syndrome. Am J Cardiol 1998; 81: 18b-25b
112 Gazi I, Tsimihodimos V, Filippatos T. et al. Concentration and relative distribution of low-density lipoprotein subfractions in patients with metabolic syndrome defined according to the National Cholesterol Education Program criteria. Metabolism 2006; 55: 885-891
113 Huang PL. A comprehensive definition for metabolic syndrome. Dis Model Mech 2009; 2: 231-237
114 Devi SA, Jyothi B. Dyslipidemia in metabolic syndrome: An overview of lipoprotein-related disorders. Int J Cardiol Lipid Res 2017; 4: 7
115 Stefan N, Kantartzis K, Machann J. et al. Identification and characterization of metabolically benign obesity in humans. Arch Intern Med 2008; 168: 1609-1616
116 Deepa M, Papita M, Nazir A. et al. Lean people with dysglycemia have a worse metabolic profile than centrally obese people without dysglycemia. Diabetes Technol Ther 2014; 16: 91-96
117 Raji A, Seely EW, Arky RA. et al. Body fat distribution and insulin resistance in healthy Asian Indians and Caucasians. J Clin Endocrinol Metab 2001; 86: 5366-5371
118 Wang C, Wang B, He H. et al. Association between insulin receptor gene polymorphism and the metabolic syndrome in Han and Yi Chinese. Asia Pac J Clin Nutr 2012; 21: 457-463
119 Chiefari E, Tanyolaç S, Iiritano S. et al. A polymorphism of HMGA1 is associated with increased risk of metabolic syndrome and related components. Sci Rep 2013; 3: 1491
120 Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabetes mellitus: The thrifty phenotype hypothesis. Diabetologia 1992; 35: 595-601
121 Neel JV. Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”?. Am J Hum Genet 1962; 14: 353-362
122 van Dongen J, Willemsen G, Chen W-M et al. The heritability of metabolic syndrome traits in a large population-based sample. J Lipid Res 2013; 54: 2914-2923
123 Musani SK, Martin LJ, Woo JG. et al. Heritability of the severity of the metabolic syndrome in whites and blacks in 3 large cohorts. Circ Cardiovasc Genet 2017; 10: e001621
124 Schmidt MI, Watson RL, Duncan BB. et al. Clustering of dyslipidemia, hyperuricemia, diabetes, and hypertension and its association with fasting insulin and central and overall obesity in a general population. Metabolism 1996; 45: 699-706
125 Schmidt MI, Duncan BB, Watson RL. et al. A metabolic syndrome in whites and African-Americans: The Atherosclerosis Risk in Communities baseline study. Diabetes Care 1996; 19: 414-418
126 Ferrannini E. Syndrome x. Horm Res 1993; 39: 107-111
127 Poulsen P, Vaag A, Kyvik K. et al. Genetic versus environmental aetiology of the metabolic syndrome among male and female twins. Diabetologia 2001; 44: 537-543
128 Freeman M, Mansfield M, Barrett J. et al. Heritability of features of the insulin resistance syndrome in a community-based study of healthy families. Diabet Med 2002; 19: 994-999
129 Mills G, Avery P, McCarthy M. et al. Heritability estimates for beta cell function and features of the insulin resistance syndrome in UK families with an increased susceptibility to type 2 diabetes. Diabetologia 2004; 47: 732-738
130 Beck-Nielsen H. General characteristics of the insulin resistance syndrome. Drugs 1999; 58: 7-10
131 Mitchell BD, Kammerer CM, Mahaney MC. et al. Genetic analysis of the IRS: pleiotropic effects of genes influencing insulin levels on lipoprotein and obesity measures. Arterioscler Thromb Vasc Biol 1996; 16: 281-288
132 Selby JV, Newman B, Quiroga J. et al. Concordance for dyslipidemic hypertension in male twins. JAMA 1991; 265: 2079-2084
133 Carmelli D, Cardon LR, Fabsitz R. Clustering of hypertension, diabetes, and obesity in adult male twins: Same genes or same environments?. Am J Hum Genet 1994; 55: 566-573
134 Hong Y, Pedersen NL, Brismar K. et al. Genetic and environmental architecture of the features of the insulin-resistance syndrome. Am J Hum Genets 1997; 60: 143-152
135 Loos RJF, Katzmarzyk PT, Rao DC. et al. Genome-Wide Linkage Scan for the Metabolic Syndrome in the HERITAGE Family Study. J Clin Endocrinol Metab 2003; 88: 5935-5943
136 Aron-Wisnewsky J, Clément K. The gut microbiome, diet, and links to cardiometabolic and chronic disorders. Nat Rev Nephrol 2016; 12: 169-181
137 Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol 2011; 29: 415-445
138 Rodríguez-Monforte M, Sánchez E, Barrio F. et al. Metabolic syndrome and dietary patterns: A systematic review and meta-analysis of observational studies. Eur J Nutr 2017; 56: 925-947
139 Ristic-Medic D, Vucic V. Dietary fats and metabolic syndrome.. J Nutrition Health Food Sci 2013; 1: 8
140 Erion DM, Shulman GI. Diacylglycerol-mediated insulin resistance. Nat Med 2010; 16: 400-402
141 Meyer C, Dostou JM, Welle SL. et al. Role of human liver, kidney, and skeletal muscle in postprandial glucose homeostasis. Am J Physiol Endocrinol Metab 2002; 282: E419-E427
142 Adams JM, Pratipanawatr T, Berria R. et al. Ceramide content is increased in skeletal muscle from obese insulin-resistant humans. Diabetes 2004; 53: 25-31
143 Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell 2012; 148: 852-871
144 Yu C, Chen Y, Cline GW. et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem 2002; 277: 50230-50236
145 Erion DM, Shulman GI. Diacylglycerol-mediated insulin resistance. Nat Med 2010; 16: 400-402
146 Hernández EÁ, Kahl S, Seelig A. et al. Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance. J Clin Invest 2017; 127: 695-708
147 Mihalik SJ, Goodpaster BH, Kelley DE. et al. Increased levels of plasma acylcarnitines in obesity and type 2 diabetes and identification of a marker of glucolipotoxicity. Obesity (Silver Spring) 2010; 18: 1695-1700
148 Rinaldo P, Cowan TM, Matern D. Acylcarnitine profile analysis. Genet Med 2008; 10: 151-156
149 Koves TR, Ussher JR, Noland RC. et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab 2008; 7: 45-56
150 Morino K, Petersen KF, Shulman GI. Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 2006; 55: S9-S15
151 Schooneman MG, Vaz FM, Houten SM. et al. Acylcarnitines: Reflecting or inflicting insulin resistance?. Diabetes 2013; 62: 1-8
152 Prentki M, Joly E, El-Assaad W. et al. Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity: Role in beta-cell adaptation and failure in the etiology of diabetes. Diabetes 2002; 51: S405-S413
153 El-Assaad W, Buteau J, Peyot M-L. et al. Saturated fatty acids synergize with elevated glucose to cause pancreatic β-cell death. Endocrinology 2003; 144: 4154-4163
154 Jacqueminet S, Briaud I, Rouault C. et al. Inhibition of insulin gene expression by long-term exposure of pancreatic beta cells to palmitate is dependent on the presence of a stimulatory glucose concentration. Metabolism 2000; 49: 532-536
155 Briaud I, Harmon JS, Kelpe CL. et al. Lipotoxicity of the pancreatic beta-cell is associated with glucose-dependent esterification of fatty acids into neutral lipids. Diabetes 2001; 50: 315-321
156 Kaneto H, Xu G, Fujii N. et al. Involvement of c-Jun N-terminal kinase in oxidative stress-mediated suppression of insulin gene expression. J Biol Chem 2002; 277: 30010-30018
157 Prentki M, Corkey BE. Are the β-cell signaling molecules malonyl-CoA and cystolic long-chain acyl-CoA implicated in multiple tissue defects of obesity and NIDDM?. Diabetes 1996; 45: 273-283
158 Poitout V, Amyot J, Semache M. et al. Glucolipotoxicity of the pancreatic beta cell. Biochim Biophys Acta Mol Basis Dis 2010; 1801: 289-298
159 Poitout V, Robertson RP. Minireview: Secondary β-cell failure in type 2 diabetes—a convergence of glucotoxicity and lipotoxicity. Endocrinology 2002; 143: 339-342
160 Ruderman N, Prentki M. AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome. Nat Rev Drug Discov 2004; 3: 340-351
161 Foufelle F, Ferré P. New perspectives in the regulation of hepatic glycolytic and lipogenic genes by insulin and glucose: a role for the transcription factor sterol regulatory element binding protein-1c. Biochem J 2002; 366: 377-391
162 Hoyas I, Leon-Sanz M. Nutritional challenges in metabolic syndrome. J Clin Med 2019; 8: 1301
163 Grundy SM. Metabolic Syndrome. Springer; 2020
164 Grundy SM. Overnutrition, ectopic lipid and the metabolic syndrome. J Investig Med 2016; 64: 1082-1086
165 Lionetti L, Mollica MP, Lombardi A. et al. From chronic overnutrition to insulin resistance: The role of fat-storing capacity and inflammation. Nutr Metab Cardiovasc Dis 2009; 19: 146-152
166 Williams KJ, Wu X. Imbalanced insulin action in chronic over nutrition: clinical harm, molecular mechanisms, and a way forward. Atherosclerosis 2016; 247: 225-282
167 Grundy SM. Adipose tissue and metabolic syndrome: too much, too little or neither. Eur J Clin Invest 2015; 45: 1209-1217
168 Ikramuddin S, Buchwald H. How bariatric and metabolic operations control metabolic syndrome. Br J Surg 2011; 98: 1339-1341
169 Ainsworth BE, Haskell WL, Whitt MC. et al. Compendium of physical activities: an update of activity codes and MET intensities. Med Sci Sports Exerc 2000; 32: S498-S504
170 Cong Y, Gan Y, Sun H. et al. Association of sedentary behaviour with colon and rectal cancer: a meta-analysis of observational studies. Br J Cancer 2014; 110: 817-826
171 Owen N, Healy GN, Matthews CE. et al. Too much sitting: The population-health science of sedentary behavior. Exerc Sport Sci Rev 2010; 38: 105-113
172 Network SBR Letter to the editor: standardized use of the terms “sedentary” and “sedentary behaviours”. Appl Physiol Nutr Metab 2012; 37: 540-542
173 Ekelund U, Steene-Johannessen J, Brown WJ. et al. Does physical activity attenuate, or even eliminate, the detrimental association of sitting time with mortality? A harmonised meta-analysis of data from more than 1 million men and women. Lancet 2016; 388: 1302-1310
174 Teychenne M, Costigan SA, Parker K. The association between sedentary behaviour and risk of anxiety: A systematic review. BMC Public Health 2015; 15: 513
175 Katzmarzyk PT, Church TS, Craig CL. et al. Sitting time and mortality from all causes, cardiovascular disease, and cancer. Med Sci Sports Exerc 2009; 41: 998-1005
176 Hamilton MT, Hamilton DG, Zderic TW. Role of low energy expenditure and sitting in obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease. Diabetes 2007; 56: 2655-2667
177 Thorp AA, Healy GN, Owen N. et al. Deleterious associations of sitting time and television viewing time with cardiometabolic risk biomarkers: Australian Diabetes, Obesity and Lifestyle (AusDiab) Study 2004-2005. Diabetes Care 2010; 33: 327-334
178 Hamilton MT, Hamilton DG, Zderic TW. Exercise physiology versus inactivity physiology: an essential concept for understanding lipoprotein lipase regulation. Exerc Sport Sci Rev 2004; 32: 161-166
179 Daneshmandi H, Choobineh A, Ghaem H. et al. Adverse effects of prolonged sitting behavior on the general health of office workers. J Lifestyle Med 2017; 7: 69-75
180 Inoue S, Sugiyama T, Takamiya T. et al. Television viewing time is associated with overweight/obesity among older adults, independent of meeting physical activity and health guidelines. J Epidemiol 2012; 22: 50-56
181 Dunstan DW, Barr EL, Healy GN. et al. Television viewing time and mortality: The Australian Diabetes, Obesity and Lifestyle Study (AusDiab). Circulation 2010; 121: 384-391
182 Chau JY, van der Ploeg HP, Merom D. et al. Cross-sectional associations between occupational and leisure-time sitting, physical activity and obesity in working adults. Prev Med 2012; 54: 195-200
183 Loyen A, Verloigne M, Van Hecke L. et al. Variation in population levels of sedentary time in European adults according to cross-European studies: a systematic literature review within DEDIPAC. Int J Behav Nutr Phys Act 2016; 13: 71
184 Owen N, Sparling PB, Healy GN. et al. Sedentary behavior: Emerging evidence for a new health risk. Mayo Clin Proc 2010; 85: 1138-1141
185 World Health Organization. Physical Inactivity: A Global Public Health Problem. World Health Organization; 2019. Available at https://www.who.int/dietphysicalactivity/factsheet_inactivity/en/
186 Warren TY, Barry V, Hooker SP. et al. Sedentary behaviors increase risk of cardiovascular disease mortality in men. Med Sci Sports Exerc 2010; 42: 879-885
187 Dunstan D, Barr E, Healy G. et al. Television viewing time and mortality: the Australian diabetes, obesity and lifestyle study (AusDiab). Circulation 2010; 121: 384-391
188 Barazzoni R, Gortan Cappellari G, Ragni M et al. Insulin resistance in obesity: An overview of fundamental alterations. Eat Weight Disord 2018; 23: 149-157
189 Myers J, Kokkinos P, Nyelin E. Physical activity, cardiorespiratory fitness, and the metabolic syndrome. Nutrients 2019; 11: 1652
190 Kim YJ, Hwang J-Y, Kim H. et al. Diet quality, physical activity, and their association with metabolic syndrome in Korean Adults. Nutrition 2019; 59: 138-144
191 Anderson E, Durstine JL. Physical activity, exercise, and chronic diseases: A brief review. Sports Medicine and Health Science 2019; 1: 3-10
192 Golbidi S, Mesdaghinia A, Laher I. Exercise in the metabolic syndrome. Oxid Med Cell Longev 2012; 2012: 349710
193 Rees-Punia E, Evans EM, Schmidt MD. et al. Mortality risk reductions for replacing sedentary time with physical activities. Am J Prev Med 2019; 56: 736-741
194 Swisher AK. Yes, “Exercise is Medicine”…. but It Is So Much More!. Cardiopulm Phys Ther J 2010; 21: 4
195 McGrath S, Brazel D, Dugas L. et al. Physical activity and central adiposity in a cohort of African-American adults. BMC Obes 2017; 4: 34
196 Richter EA, Hargreaves M. Exercise, GLUT4, and skeletal muscle glucose uptake. Physiol Rev 2013; 93: 993-1017
197 Kumar R. The influence of physical exercise on lipid profile. Curr Sci 2018; 19: 1-5
198 Gordon B, Chen S, Durstine JL. The effects of exercise training on the traditional lipid profile and beyond. ACSMs Health Fit J 2016; 1: 159-164
199 Wang Y, Xu D. Effects of aerobic exercise on lipids and lipoproteins. Lipids Health Dis 2017; 16: 132
200 Larsen MK, Matchkov VV. Hypertension and physical exercise: The role of oxidative stress. Medicina (Kaunas) 2016; 52: 19-27
201 Lelbach A, Koller A. Mechanisms underlying exercise-induced modulation of hypertension. J Hypertens Res 2017; 3: 35-44
202 Ramirez-Jimenez M, Morales-Palomo F, Pallares JG. et al. Ambulatory blood pressure response to a bout of HIIT in metabolic syndrome patients. Eur J Appl Physiol 2017; 117: 1403-1411
203 Gremeaux V, Drigny J, Nigam A. et al. Long-term lifestyle intervention with optimized high-intensity interval training improves body composition, cardiometabolic risk, and exercise parameters in patients with abdominal obesity. Am J Phys Med Rehabil 2012; 91: 941-950
204 Matsuo T, So R, Shimojo N. et al. Effect of aerobic exercise training followed by a low-calorie diet on metabolic syndrome risk factors in men. Nutr Metab Cardiovasc Dis 2015; 25: 832-838
205 Kessler HS, Sisson SB, Short KR. The potential for high-intensity interval training to reduce cardiometabolic disease risk. Sports Med 2012; 42: 489-509
206 Lee S, Kuk JL, Davidson LE. et al. Exercise without weight loss is an effective strategy for obesity reduction in obese individuals with and without type 2 diabetes. J Appl Physiol (1985) 2005; 99: 1220-1225
207 Vella CA, Allison MA, Cushman M. et al. Physical activity and adiposity-related inflammation: The MESA. Med Sci Sports Exerc 2017; 49: 915-921
208 You T, Arsenis NC, Disanzo BL. et al. Effects of exercise training on chronic inflammation in obesity. Sports Med 2013; 43: 243-256
209 Gleeson M, Bishop NC, Stensel DJ. et al. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat Rev Immunol 2011; 11: 607-615
210 Jennersjö P, Ludvigsson J, Länne T. et al. Pedometer-determined physical activity is linked to low systemic inflammation and low arterial stiffness in type 2 diabetes. Diabet Med 2012; 29: 1119-1125
211 Harriss DJ, Macsween A, Atkinson G. ethical standards in sport and exercise science research: 2020 update. Int J Sports Med 2019; 40: 813-817