Pathogenesis, Diagnosis, and Management of Metabolic Syndrome: A Comprehensive Review
1Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidyapeeth, Puducherry, India
2Department of Pharmacology, JIPMER Karaikal, Puducherry, India
3Department of Pharmacology, Sri Venketeshwaraa Medical College Hospital and Research Centre, Puducherry, India
Corresponding Author: Vimala Ananthy, Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidyapeeth, Puducherry, India, Phone: +91 9585787226, e-mail: email@example.com
How to cite this article: Ananthy V, Priyadharsini RP, Subramanian U. Pathogenesis, Diagnosis, and Management of Metabolic Syndrome: A Comprehensive Review. J Basic Clin Appl Health Sci 2021;4(2):39–45.
Source of support: Nil
Conflict of interest: None
Metabolic syndrome is a constellation of abnormalities, such as insulin resistance, central obesity, dyslipidemia, and high blood pressure. The definition and criteria for diagnosing metabolic syndrome keep changing and are a topic of debate. Regardless of the true criteria, the collection of these metabolic abnormalities increases the risk of developing type II diabetes mellitus and cardiovascular disease. The pathogenesis of metabolic syndrome involves the deregulation of various metabolic pathways involved in fatty acid metabolism, mitochondrial function, and glucose utilization. Metabolic syndrome is associated with an increased risk of other disorders, like nonalcoholic fatty liver, polycystic ovarian disease current terminology (PCOS), Alzheimer’s disease, lipodystrophy, and Cushing’s syndrome. The management of metabolic syndrome begins with lifestyle modification followed by pharmacotherapy of the individual component of metabolic syndrome. Weight reduction and lifestyle modification remains the mainstay of therapy of metabolic syndrome. Since insulin resistance is the major pathology behind the disease, insulin sensitizers, such as metformin and thiazolidinedione, are of great use. Hypolipidemic and antihypertensive drugs are used for treating other components of this syndrome. With the development in the field of molecular biology, the therapeutic targets for treating the individual components of the syndrome have been refined. This review focuses on the etiopathogenesis of metabolic syndrome and highlights the current and future therapeutic targets.
Keywords: Criteria, Hyperlipidemia, Insulin resistance, Metabolic syndrome, Polycystic ovarian syndrome.
The history of metabolic syndrome dates back to 1988 when Gerald Reaven introduced the concept of “syndrome X” which is an aggregation of cardiovascular risk factors in the same individual. It was then given different names by different scientists, such as “the deadly quartet” by Kaplan and “a secret killer” by Foster. As insulin resistance was the underlying factor, Haffner et al. coined the term “insulin resistance syndrome,” which is still being used by some individuals. But at present “metabolic syndrome” is the most widely used term for the aggregation of metabolic abnormalities, which leads to increased cardiovascular risk. An observation by Dr. Vague showed that upper body adiposity as the obesity phenotype was associated with more metabolic abnormalities. These metabolic abnormalities were found to play an important role in the genesis of type II diabetes mellitus and cardiovascular disease.1
The metabolic abnormalities include insulin resistance, glucose intolerance, central obesity, dyslipidemia, and increased blood pressure, all of which are well-documented risk factors for cardiovascular mortality. There is a striking increase in the incidence of metabolic syndrome in the past two decades. This increase is due to the global epidemic of diabetes and obesity. One of the estimations shows that around 20–25% of the world’s population is suffering from metabolic syndrome.2 These people are two times more at risk to die and three times more at risk to suffer from a heart attack or stroke. For treating metabolic syndrome, it has to be first diagnosed by the physicians. There are many diagnosing criteria, which are being revised frequently, that help in the management of metabolic syndrome.
DEFINITION AND CRITERIA FOR DIAGNOSIS
There was a lot of confusion and controversies in defining the criteria for the diagnosis of metabolic syndrome. The World Health Organization (WHO) took the initiative to provide a tool for researchers and clinicians and formulated a set of criteria, following which the National Cholesterol Education Program’s Adult Treatment Panel III (NCEP: ATP III) proposed a separate definition. There were also other organizations, like the European Group for the Study of Insulin Resistance, which came forward with similar criteria. The basic structure in all definitions included parameters to assess insulin resistance, hyperglycemia, dyslipidemia, and central obesity.
Among all, NCEP: ATP III was found to be more user-friendly for clinicians for assessing metabolic syndrome. WHO criteria included a glucose tolerance test and test for albuminuria that were not practical for most of the clinicians when compared to NCEP: ATP III, which requires only fasting glucose level. The New International Diabetes Federation definition included waist circumference with ethnicity-specific values, which is more reliable but not commonly used (Tables 1 to 3).3
|According to the new IDF definition, for a person to be defined as having the metabolic syndrome they must have:
Central obesity (defined as waist circumference* with ethnicity-specific values)
Plus any two of the following four factors:
|Raised triglycerides||>150 mg/dL (1.7 mmol/L)
or specific treatment for lipid abnormality
|Reduced HDL cholesterol||<40 mg/dL (1.03 mmol/L) in males
<50 mg/dL (1.29 mmol/L) in females
or specific treatment for lipid abnormality
|Raised blood pressure||Systolic blood pressure ≥130 mm Hg and diastolic blood pressure ≥85 mm Hg
or treatment of previously diagnosed hypertension
|Raised fasting plasma glucose||≥100 mg/dL
or treatment of previously diagnosed diabetes
|Risk factor||Defining level|
|Abdominal obesity (waist circumference)|
|Blood pressure||>130/80 mm Hg|
|Fasting glucose||>110 mg/dL|
|One of these:
POLYCYSTIC OVARIAN SYNDROME
Polycystic ovarian syndrome (PCOS) is characterized by increased ovarian androgen production and deregulated gonadotropin secretion. A study conducted to obtain the prevalence of metabolic syndrome in women with PCOS showed that about 37.5% had metabolic syndrome. This constituted about one-third of the women attending the infertility clinic. The study also showed that women who were more than 25 years and with a waist: hip ratio of more than 0.85 were the risk factors for metabolic syndrome.7 It was found that 93% of the women had dyslipidemia, which stresses the need for screening these patients for such abnormalities to prevent the genesis of metabolic syndrome.
Carcinogenesis is individually linked to various components of metabolic syndrome, such as obesity, dyslipidemia, and type II diabetes mellitus. Excess weight and adiposity increase the levels of free fatty acid, TNF-α, resistin, and decreased levels of adiponectin. This results in insulin resistance and hyperinsulinemia that in turn leads to the reduced liver synthesis of insulin-like growth factor–binding protein (IGFBP-1).8 Thus, there is a raised level of free IGF in the circulation that acts on the insulin receptor and is responsible for the proliferation of cell and inhibition of apoptosis. Decreased level of adiponectin leads to an increase in IGF and vascular endothelial growth factor, resulting in angiogenesis and tumor growth. A meta-analysis shows the highest risk of sex-specific cancers like endometrial cancer and breast cancer in postmenopausal women. Other cancers that have a higher magnitude of risk are colorectal cancer, pancreatic cancer and prostate cancer.9
DISTAL SYMMETRIC POLYNEUROPATHY
Distal symmetric polyneuropathy (DSP) is defined as neuropathic symptoms with at least one confirmatory test (peroneal conduction velocity, heavy monofilament, and vibration threshold). The mechanism involved in the development of neuropathy can be explained by vascular dysfunction as a result of altered mitochondrial function, dyslipidemia, and hyperglycemia. This leads to microangiopathy and endoneurial hypoxia, resulting in the accumulation of reactive oxygen species and neuropathy.
In a study conducted in patients with neuropathy symptoms with prediabetes, there was 5.6% DSP rate among those without any additional component of metabolic syndrome when compared to a rate of 10.6% DSP rate in participants with additional metabolic syndrome components.10
The pathology behind Alzheimer’s disease is a deposition of amyloid Aβ peptide and tau proteins in the cerebral cortex. Insulin has been seen to affect Aβ peptide metabolism and is found to increase its secretion. Insulin also increases the extracellular level of Aβ peptide level by inhibiting its degradation by insulin-degrading enzyme. Insulin resistance and hyperinsulinemia, which are the major components of metabolic syndrome, lead to increased levels of amyloid protein and facilitate their deposition in the brain. Another study revealed microstructural damage in white and gray matter in patients with metabolic syndrome, leading to a spectrum of cognitive disorders.11
Erectile dysfunction is interrelated to the cardiovascular risk factors involved in the metabolic syndrome. A study conducted in patients with metabolic syndrome shows that 79 to 96% of patients develop erectile dysfunction and 29 to 66% of patients with erectile dysfunction have metabolic syndrome.12 Visceral obesity and insulin resistance decrease androgen and increase oxidative stress. This leads to endothelial dysfunction and impairment of cavernosal arteries, leading to erectile dysfunction.
Cushing’s syndrome is characterized by central obesity, visceral adiposity, impaired glucose tolerance, hypertension, and raised triglyceride levels. Nearly two-thirds of patients with Cushing’s syndrome satisfy at least three criteria of metabolic syndrome. High levels of glucocorticoids result in insulin resistance in muscle, adipocyte, and liver. Efficient treatment of hypercortisolism helps to improve all the components of metabolic syndrome.13
Other important disorders associated with metabolic syndrome are gout, sleep apnea, gallstones, and chronic kidney disease. The increased uric acid level in gout is associated with insulin resistance by causing an increase in the inflammatory response and oxidative stress. Uric acid also decreases adiponectin level, which is involved in the pathogenesis of insulin resistance. The presence of gout in patients with metabolic syndrome has been shown to increase cardiovascular mortality. Clinicians must be conscious about metabolic syndrome while treating patients with gout, which can reduce the cardiovascular mortality. Sleep apnea is associated with metabolic syndrome, and the combination is termed as “syndrome Z”. Adipokines, such as adiponectin, ghrelin, and leptin, seem to be deregulated in sleep apnea, which are common abnormalities seen in metabolic syndrome patients.14
Current Treatment Strategies
The management of metabolic syndrome consists of two main therapeutic goals.
- Treatment of the underlying cause ( central obesity, sedentary lifestyle)
- Treatment of the cardiovascular risk factors, which persist despite lifestyle modification
The dietary advice mainly concentrates on the amount of carbohydrates, fat, and sodium.
Hypocaloric diet: The most commonly recommended dietary strategy is an energy-restricted diet. A hypocaloric diet produces less energy than the body’s demand, resulting in a negative energy balance. Weight loss causes improvement of all the components of metabolic syndrome. As inflammation is strongly associated with obesity and metabolic syndrome, reduction in weight can bring down the inflammatory markers in plasma, such as IL-6. Restriction of calorie has improved the proinflammatory state of the whole body, insulin signal transduction, and insulin sensitivity.
Omega-3 fatty acid: Essential fatty acids constitute omega-3 polyunsaturated fatty acids namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). A diet rich in these fatty acids has been found to decrease the cardiovascular mortality. Different studies have shown that following a diet rich in omega-3 fatty acid, there was a fall in plasma proinflammatory cytokines, such as IL-6, C-reactive protein, and TNF-α. A daily intake of 250 mg of EPA + DHA is recommended for the prevention of cardiovascular mortality. A diet rich in omega-3 fatty acids includes fatty fish, fish oil, walnuts, spinach, and flaxseed oil.15
Glycemic index: The quality of carbohydrate is measured by glycemic index. Diet with a high glycemic index tends to increase blood glucose level more promptly and a rapid insulin response, resulting in hypoglycemia. This is associated with a feeling of hunger and increased intake of calorie. A high glycemic index is found in sweetened beverages, juice drinks, soft drinks, cakes, cookies, and candy.
Moderate–high protein diet: Usual recommendation of a normal diet constitutes 55% of carbohydrate, 15% of protein, and 30% of fat. In obese individuals in order to bring down the carbohydrate content, a moderate–high protein diet of >20% of protein is recommended. The mechanisms involved are increased thermogenesis and increased satiety. Whenever a hypocaloric diet is advised, it is better to increase the protein content in order to reach the protein energy requirements.16
Other recommendations: Other dietary recommendations are high meal frequency, a diet with high total antioxidant capacity, and a Mediterranean diet. Increasing the frequency of meals in small quantities is found to have less fluctuation of glucose level and stable insulin secretion with better appetite control. A diet with high antioxidant content helps in free radical scavenging. WHO recommends fruits and vegetables consumption up to 400 g/day. Other sources of antioxidant are spices and herbs. A Mediterranean diet was so named because it was observed that countries around the Mediterranean Sea had less incidence of coronary heart disease. Their diet comprised of more plant food, olive oil, and less amount of red meat and sweets.
A meta-analysis described that moderate and high levels of physical activity had 11% and 42% reduced risk of metabolic syndrome. Another study reported that there were significantly lower levels of risk components (in terms of fasting blood glucose, triglyceride levels, and waist circumference) in participants who had one or more per week of physical activity compared to participants who had no physical activity. The beneficial effect of exercise on metabolic syndrome varies with respect to the frequency and intensity of physical activity. The effect was similar in both men and women in improving the components of metabolic syndrome except for triglyceride levels.17
It was seen in a similar study that the reduction of triglyceride level following physical activity was 30% in men in comparison to 2% in women. In a study conducted in overweight postmenopausal women, interruption of prolonged sitting with 5 minutes of standing or walking significantly reduced postprandial glucose levels, but did not have any effect on triglyceride levels. In a randomized control study, the effect of lifestyle modification, which included a 30-minute exercise daily, reported that there was a significant reduction of the prevalence of metabolic syndrome by 47%. This result was sustained even after a median follow-up period of 4.3 years.18 In the Finnish Diabetes Prevention trial, there was a reduction of diabetes by 52% at a median follow-up of 3.2 years in the intervention group who received individual counseling about weight reduction, physical activity, and intake of saturated fat and fiber diet.19
Controversies still remain regarding the concept of metabolic syndrome, but the aggregation of metabolic abnormalities in the same patient warrants meticulous treatment in order to prevent complications. Multiple pathways and molecular mechanism are involved in the pathogenesis of metabolic syndrome. Since early treatment prevents major complications and mortality, it is the clinician’s responsibility to rule out metabolic syndrome when there is a grouping of symptoms. Each component must be treated individually and monitored for complications. Lifestyle modification, dietary change, and physical activities are the mainstay of therapy without which other therapies will be unsuccessful. Hence, the management of metabolic syndrome requires proper counseling by a physician and high compliance from patients.
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