Metabolic syndrome: a puppeteer of multiple diseases

‍Highlights:

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• Metabolic syndrome (MtS) presents a constellation of symptoms, including insulin resistance, visceral obesity, hypertension, and dyslipidemia
• MtS significantly increases the risks of further development of type 2 diabetes and cardiovascular disease
• MtS is prevalent in the aging population and strongly correlates with mortality
• Lifestyle changes, such as physical activity, a healthy diet, and abstaining from harmful habits, are the key to fighting the MtS

Introduction

Known as syndrome X, the insulin resistance syndrome, and the deadly quartet, metabolic syndrome can manifest in various ways and be notoriously hard to diagnose. During the past two decades, the number of people suffering from metabolic syndrome strikingly increased due to the global obesity epidemic and the aging of the world population. The abnormalities connected with metabolic syndrome include insulin resistance, obesity, and hypertension. As metabolic syndrome significantly increases the risk for diabetes and cardiovascular disease – one of the leading risks of death and disability in developed countries – there is an urgent need to address and prevent it in as many cases as possible.

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Three out of five: diagnosis of metabolic syndrome

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Though several definitions of metabolic syndrome (MtS) exist, the most widely used criteria were systematized and formulated in 2001 by the National Cholesterol Education Program (1) and updated in 2005 by the American Heart Association and the National Heart Lung and Blood Institute (2). According to this definition, metabolic syndrome is present when three or more of these five criteria are met:

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• waist circumference over 40 inches/102 cm (for men) or 35 inches/89 cm (for women),
• heightened blood pressure over 130/85 mmHg,
• elevated fasting triglyceride level over 150 mg/dl,
• reduced fasting high-density lipoprotein (HDL) cholesterol level less than 40 mg/dl (for men) or 50 mg/dl for women,
• elevated fasting blood sugar over 100 mg/dl.

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These diagnostic criteria rely on accessible measurements, and they are easy to apply. The exact numbers may vary depending on the ethnicity or age of the target group.

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Key features of MtS

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Behind the diagnostics stand four main features of MtS:

• insulin resistance, 
• visceral obesity, 
• dyslipidemia (abnormal levels of lipids in the blood), 
• and hypertension. 

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The first two features appear to be essential for the manifestation of the MtS. For example, some patients are obese but do not show any of the other components of the MtS (3). So, both insulin resistance and obesity are prerequisites for the MtS phenotype. Dyslipidemia and hypertension follow insulin resistance and visceral obesity.

Insulin resistance is a major contributor to the MtS, caused by an overabundance of circulating fatty acids. When fatty acids reach insulin-sensitive tissues, they modify downstream signaling by impairing a range of kinases related to glucose disposal (4). The consequence of this is increased hepatic glucose production and diminished inhibition of glucose production by insulin (5).

Another syndrome included in diagnostics is waist circumference, mainly due to its correlation to the ratio between subcutaneous adipose tissue and visceral fat. Generally, fat tissue works as secretory organ and can be of two main types. Subcutaneous adipose tissue is fat tissue located beneath the skin, while visceral fat is adipose tissue lining internal organs. Though a strict distinction can be made using computer tomography and magnetic resonance imaging, a large waist is a commonly mechanistically accepted indication of visceral obesity (6). An increase in visceral fat leads to a higher flux rate of adipose tissue-derived fatty acids and adipokines (adipose cell signaling proteins), launching the insulin resistance mechanism described above. The flux of fatty acids is targeted mainly at liver, where it induces increased secretion of triglycerides, reduces degradation of apolipoprotein B (protein responsible for lipids accumulation) and insulin. 

The elevated levels of fatty acids and adipokines consequently lead to dyslipidemia, which is characterized by low serum HDL levels and high triglyceride levels. The mechanism behind dyslipidemia is likely a loss of lipolysis (mechanism through which fatty acids are released) and breakage of fatty acid storage in adipocytes due to impaired insulin signaling (7). The excess provision of high-density lipids further results in the formation and accumulation of very-low-density lipid particles connected with atherosclerosis. 

Hypertension is the “fourth pillar” of the MtS and is also closely related to insulin resistance. In healthy individuals, insulin plays a dual role – as a vascular dilator (8) and as a sodium reabsorption regulator in the kidneys (9). In the case of insulin resistance, the vasodilatory effect can be lost, but the renal effect is preserved or reinforced. Insulin resistance causes microvascular damage, which results in endothelial dysfunction. Moreover, fatty acids can additionally induce vasoconstriction (10). All of these combined leads to the development of hypertension.

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Consequences of MtS 

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The constant MtS exposure adversely affects several bodily systems and leads to the development of connected diseases. Endothelial damage and dyslipidemia cause atherosclerotic disease. Furthermore, hypertension leads to increased vascular resistance and stiffness, resulting in a range of cardiovascular conditions, including peripheral vascular disease, structural heart disease, and cardiomyopathy. Accumulated damage from endothelial dysfunction and hypertension further can lead to ischemic heart disease (11). 

The second major risk linked to the MtS is the development of diabetes. If the patient has the MtS, it serves as a reliable predictor for the further development of diabetes (12). But, since both impaired fasting glucose and insulin resistance are part of the diabetes definition, this connection is hardly surprising.  Frequently, nowadays, from medical perspective, obesity, metabolic syndrome, and diabetes are considered as a single condition under the name of metabesity.

Several large studies were conducted to explore the MtS as a predictor of connected health disorders. The DECODE study of non-diabetic men and women of European descent showed that the people with the MtS had an increased risk of death from all causes, including cardiovascular disease (13). In two other studies (14,15), the presence of the MtS was connected with increased cardiovascular disease and coronary heart disease mortality. As for diabetes, the meta-study on more than 42 thousand participants demonstrated that the MtS incidence (especially in cases with higher levels of fasting blood sugar) serves as a reliable predictor for the development of type 2 diabetes (16). 

The MtS has been connected with the development of multiple other diseases, including, but not limited to, non-alcoholic steatohepatitis (NASH), osteoarticular disease, and cancer (17). Research also shows that metabolic syndrome can adversely affect neurocognitive performance and accelerate cognitive aging (18).

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MtS, aging, and longevity

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The occurrence of the MtS is age-related and has been shown to reach 40% of the US population above 60 (19). However, the data show that the quantity of younger people with the MtS have grown six-fold during the last twenty years (20). These tendencies are highly alarming since the MtS is strongly associated with accelerated aging (21).

The MtS is linked to aging through multiple biochemical pathways (22) – particularly those connected with nutrient availability, metabolism, and lifespan regulation. One of the key mechanisms is the mTOR (mammalian target of rapamycin)/AMPK (adenosine monophosphate-activated kinase) pathway. mTOR influences body weight and food intake through hormone regulation and has been connected to insulin resistance. Other mechanisms include FOXO (forkhead transcription box O) factors and insulin/IGF-1 (insulin growth factor 1) pathways, which are strongly associated with longevity and aging. Metabolic syndrome has a detrimental influence on each of these pathways, hormone balance (i.e., estrogens, TSH), and, consequentially, on health- and lifespan. 

The development of insulin resistance has also been linked to age-related mitochondrial dysfunction (23). Age-related damage to mitochondrial DNA leads to a vicious cycle of an increase in reactive oxygen species (ROS) production with subsequent additional mitochondrial DNA damage. Mitochondrial dysfunction through increased ROS production further manifests in increased senescence levels and chronic inflammation, both factors leading to accelerated aging.

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Strategies for prevention 

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The perspectives of the MtS are dire, but the good news is that they can be prevented and addressed with lifestyle changes. The special focus lies in keeping a balanced weight as excessive caloric intake has been labeled one of the most important determinants of the MtS development. Overnutrition combined with a sedentary lifestyle leads directly to visceral fat accumulation (24). Caloric restriction, however, was shown to prevent the development of alterations linked to the MtS. The next option for prevention is the inclusion of physical activity, as higher cardiorespiratory fitness has been shown to improve both glucose metabolism and cardiovascular diseases mortality. Employing aerobic and progressive endurance exercises proved to be effective in decreasing the risk of developing the MtS and subsequent diabetes and NASH (25). In those cases when a person is limited in their ability to do exercises, or diet-induced changes fail to happen, the suggested options are either exercise mimetics (drugs like metformin that can “emulate” the effect of exercise) or bariatric surgery.

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Briefly, the tips you can give to your patient or client can be summarized as follows:

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• Inform them about risks and health consequences connected to the MtS,
• Suggest them an urgent modification of their diet with the purpose of including more plant-based food, exclusion of processed food and excessive amounts of sugar,
• Introduce you patient to caloric restriction,
• Introduce progressively more exercises into their daily routine (including lifestyle choices like using stairs instead of elevator); high-intensity aerobic training is preferred,
• Plan regular monitoring of their blood biomarkers, weight and waist circumference,
• Strongly advise your patient or client to abstain from unhealthy habits, such as smoking, soft drinks, and alcohol, which may worsen their condition.

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Conclusions

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Metabolic syndrome can be hard to define and diagnose due to it being rather a range of symptoms than a single disease. Nevertheless, the latest definitions prove to be quite robust and useful in clinical practice. Due to it being a prerequisite for the development of multiple diseases, it is drastically important to monitor and intervene in the health parameters of the patients prone to obesity. Careful prevention and treatment of metabolic syndrome is a feasible and impactful path to a healthier and longer life.

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References

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2.         Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and Management of the Metabolic Syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005 Oct 25;112(17):2735–52.

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4.         Kim Y-B, Shulman GI, Kahn BB. Fatty Acid Infusion Selectively Impairs Insulin Action on Akt1 and Protein Kinase C λ/ζ but Not on Glycogen Synthase Kinase-3. J Biol Chem. 2002 Sep;277(36):32915–22.

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9.         Tiwari S, Riazi S, Ecelbarger CA. Insulin’s impact on renal sodium transport and blood pressure in health, obesity, and diabetes. Am J Physiol-Ren Physiol. 2007 Oct;293(4):F974–84.

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11.       Cӑtoi A, Pârvu A, Andreicuț A, Mironiuc A, Crӑciun A, Cӑtoi C, et al. Metabolically Healthy versus Unhealthy Morbidly Obese: Chronic Inflammation, Nitro-Oxidative Stress, and Insulin Resistance. Nutrients. 2018 Sep 1;10(9):1199.

12.       Hanson RL, Imperatore G, Bennett PH, Knowler WC. Components of the “Metabolic Syndrome” and Incidence of Type 2 Diabetes. Diabetes. 2002 Oct 1;51(10):3120–7.

13.       Hu G. Prevalence of the Metabolic Syndrome and Its Relation to All-Cause and Cardiovascular Mortality in Nondiabetic European Men and Women. Arch Intern Med. 2004 May 24;164(10):1066.

14.       Lakka H-M. The Metabolic Syndrome and Total and Cardiovascular Disease Mortality in Middle-aged Men. JAMA. 2002 Dec 4;288(21):2709.

15.       Isomaa B, Almgren P, Tuomi T, Forsén B, Lahti K, Nissén M, et al. Cardiovascular Morbidity and Mortality Associated With the Metabolic Syndrome. Diabetes Care. 2001 Apr 1;24(4):683–9.

16.       Shin J-A, Lee J-H, Lim S-Y, Ha H-S, Kwon H-S, Park Y-M, et al. Metabolic syndrome as a predictor of type 2 diabetes, and its clinical interpretations and usefulness. J Diabetes Investig. 2013 Jul;4(4):334–43.

17.       Bonomini F, Rodella LF, Rezzani R. Metabolic Syndrome, Aging and Involvement of Oxidative Stress. Aging Dis. 2015;6(2):109.

18.       Guicciardi M, Crisafulli A, Doneddu A, Fadda D, Lecis R. Effects of Metabolic Syndrome on Cognitive Performance of Adults During Exercise. Front Psychol. 2019 Aug 8;10:1845.

19.       Ford ES, Giles WH, Mokdad AH. Increasing Prevalence of the Metabolic Syndrome Among U.S. Adults. Diabetes Care. 2004 Oct 1;27(10):2444–9.

20.       De Ferranti SD, Osganian SK. Epidemiology of paediatric metabolic syndrome and type 2 diabetes mellitus. Diab Vasc Dis Res. 2007 Dec;4(4):285–96.

21.       Nunn AV, Bell JD, Guy GW. Lifestyle-induced metabolic inflexibility and accelerated ageing syndrome: insulin resistance, friend or foe? Nutr Metab. 2009;6(1):16.

22.       Fadini GP, Ceolotto G, Pagnin E, de Kreutzenberg S, Avogaro A. At the crossroads of longevity and metabolism: the metabolic syndrome and lifespan determinant pathways: Longevity pathways and metabolic syndrome. Aging Cell. 2011 Feb;10(1):10–7.

23.       Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, et al. Mitochondrial Dysfunction in the Elderly: Possible Role in Insulin Resistance. Science. 2003 May 16;300(5622):1140–2.

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25.       Tjønna AE, Lee SJ, Rognmo Ø, Stølen TO, Bye A, Haram PM, et al. Aerobic Interval Training Versus Continuous Moderate Exercise as a Treatment for the Metabolic Syndrome: A Pilot Study. Circulation. 2008 Jul 22;118(4):346–54.

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