Metabolic Syndrome (MS) is a metabolic disorder often presented as a cardiovascular risk factor, with central fat accumulation resulting in insulin resistance (IR). MS represents a cluster of metabolically related symptoms such as obesity, hypertension, dyslipidemia, and carbohydrate intolerance, significantly increasing the risk of Type II diabetes mellitus (T2DM). Insulin resistance and hyperinsulinemia are consistent characteristics of MS, but which of these features constitutes the initiating insult is still widely debated. This study aims to understand the biochemical changes in patients with metabolic syndrome. After analyzing data from different studies, it is concluded that the biochemical changes in metabolic syndrome are complex, multi-system changes which include IR, dyslipidemia, inflammation, hypercoagulable state or thrombosis, oxidative damage, adipokine dysregulation, and hormonal impairment. This syndrome can be managed through behavioral therapy (diet & exercise, lifestyle modification, and proper training), medical therapy (pharmacotherapy), and surgical procedures (metabolic surgery/bariatric surgery (BS)).

Type-II diabetes mellitus, Metabolic syndrome, Dyslipidemia, Hyperinsulinemia, Insulin resistance, Obesity.

MS is a complex metabolic disorder characterized by insulin resistance, abdominal obesity, hypertension, and hyperlipidemia. MS mainly causes three disturbances: lipid metabolism, carbohydrate metabolism, and hemodynamic disturbance, resulting in obesity & dyslipidemia, glucose intolerance & diabetes, and arterial hypertension, respectively.[1-8] There are different standard definitions of metabolic syndrome according to various expert groups such as World Health Organization (WHO), National cholesterol education program adult treatment panel III (NCEP ATP III), European group for the study of insulin resistance (EGIR), American association of clinical endocrinologists (AACE), and the International diabetes federation (IDF). For instance, central obesity is necessary for the IDF criteria but not for the EGIR, NCEP ATP III, and WHO criteria.[1,3,5] It is estimated that 16% of people worldwide suffer from MS who are over 20 years old.[2] The prevalence of metabolic syndrome has increased in developing Western and Asian countries.[1,3] The prevalence of metabolic syndrome in China rose from 24.2% in 2015 to 31.1% in 2017.[4,7] It is found that MS patients have mortality rates twice as high, suffer from heart attacks/strokes three times more, and suffer from T2DM five times more compared to the normal population.[6,8,10] MS increases the risk of developing T2DM and cardiovascular diseases; it is a strong predictor for the development of cardiovascular diseases and T2DM.[1,3,8,9] Both T2DM and MS are metabolic disorders due to IR.[1,11,12]. The degree of β-cell dysfunction is associated with the severity of MS.[13] The pathogenesis of MS includes both genetic and acquired factors, which ultimately result in an inflammatory process.[14]

Disease
MS is a metabolic disorder often presented as a cardiovascular risk factor, with central accumulation of fat resulting in IR.[15] It is a multifactorial disease defined as a cluster of mainly these four conditions: obesity (which may be central or visceral), having IR with hyperinsulinemia, hyperamylasemia, and hyperleptinemia due to leptin resistance; hyperlipidemia with atherogenic dyslipidemia, which is characterized by a high level of very low-density lipoproteins (VLDL) or triglycerides (TGs), a high level of low-density lipoprotein (LDL) cholesterol (LDL-C), and a low level of high-density lipoprotein (HDL) cholesterol (HDL-C); essential hypertension (HTN); and glucose intolerance with or without T2DM. That is, MS is a collection of unhealthy body parameters with laboratory abnormalities such as atherogenic dyslipidemia, hypertension, glucose intolerance, a pro-inflammatory condition, and a pro-thrombotic condition.[16-21]. Clinical picture and biochemical changes with complications are explained in Figure 1.

Figure 1: Photogenic diagram shows the clinical presentation and biochemical changes with its complications

Abbreviations: Interleukine-6(IL-6), tumor necrotic factor-𝛼 (TNF-𝛼), C-reactive proteins (CRP), free fatty acid (FFA), plasminogen activator inhibitor-1(PAI-1), interferon-Y (IFN-Y), metabolic dysfunction -assocaited fatty liver disease (MAFLD), chronic kidney disease (CKD), polycystic ovarian syndrome (PCOS)

Pathophysiology and mechanism
The pathophysiological mechanism of MS illustrates a metabolic disorder resulting from obesity with IR secondary to a chronic inflammatory condition.[22,23] Changes in visceral vascular and lymphatic secondary to high visceral adipose tissue caused hypoxia and lipotoxicity of adipocytes, which are accompanied by the release of fatty acids and other substances, which activate the pro-inflammatory pathways of the parenchymal cells of the tissues.[24] This inflammatory process occurred at multiple sites of adipose tissue, causing the systemic spread of inflammatory cytokines to visceral organs, especially which is sensitive to insulin, resulting in the accumulation of lipids in the muscles and liver that predispose to IR and play an important role in the progression and transition of MS to cardiovascular diseases (CVD) and T2DM.[25,26] It was found that high levels of glucose due to IR caused high insulin levels (Hyperinsulinemia) by stimulating pancreatic β cells, and this compensatory effect in multifactorial and initial to maintained euglycemic state, but if continuous hyperglycemic and hyperlipidemic condition persist then leads to β cells dysfunction and/or death which leads to diabetes.[13,19,27] IR due to abnormal adipocyte cells causes inhibition of insulin-mediated lipolysis and leads to increases in FFA, which further inhibits the anti-lipolytic effect of insulin and can inhibit the insulin-dependent glucose uptake.[19,28] Visual of the pathophysiological mechanism as shown in Figure 2.

Figure 2: Visual diagram of the pathophysiological mechanism of metabolic syndrome with common complications

Abbreviations: Plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen Activator (tPA), reactive oxygen species (ROS), renin angiotensin system (RAS), angiotensinogen-II (Ang-II)

Diagnostic criteria
MS has been defined a bit differently by different expert groups like WHO, IDF, EGIR & NCEP ATP, and hence there was a difficulty in diagnosing. Then, the joint statement approved a consensus definition to help diagnose if three of the following criteria are present.[5,19]

• High waist circumference (WC): Definition depends upon country& population ( ≥ 102cm and ≥88cm in European male and female respectively)
• Blood triglyceride (TG): ≥ 150mg/dL
• Blood HDL-cholesterol: < 40mg/dL in male & < 50mg/dL in female
• High blood pressure (BP): ≥ 130/85mmHg
• Fasting blood glucose (FBG): ≥ 100mg/dL

Biochemical changes
Biochemical changes that occur in MS are complex, and a few important ones are explained below.

IR: During pathophysiological conditions, normal insulin levels don’t adequately respond to peripheral target tissues such as adipose tissues, muscle, and liver, where pancreatic β cells produce more insulin to overcome hyperglycemia.[22] Compensatory hyperinsulinemia due to IR results from multiple impairement occurs in MS, which may occur due to impaired insulin signaling of the phosphoinositide 3-kinase/ Protein kinase B (PI3kinase/AKT) pathways which is associated with serine hyperphosphorylation of the insulin receptor substrate 2 (IRS2) signaling pathway where low insulin level stimulated no production with decreased vasodilation and pro constrictive, prothrombotic along with pro-atherosclerotic effect on vessels resulting in atherosclerosis.[9,29,30] Hormone leptin and Adipocyte-derived peptide adipokine play an important role in adiposity. IR and leptin also play an important role in insulin-mediated glucose uptake.[9,31,32] Leptin plays a role in volume and BP regulation under normal physiological conditions, while leptin resistance (LR) and hyperleptinemia occur in obese patients with MS, which, along with adipokines, play an important role in the development of HTN and cerebro-cardiovascular disease  (CCVD).[33] High compensatory insulin and amylin may increase the risk of islet amyloid deposition secondary to amyloidogenic hyperamylasemia and hyperinsulinemia, where these two conditions are common to IR with MS. The study showed that obese mice developed IR in fat and muscle due to blockage of NF-kB and Jun N-terminal kinase (JNK) pathway, which play an important role in the suppression of inflammatory signals.[34]

Dyslipidemia: Dyslipidemia is defined as quantitative lipid abnormalities that cause structure, metabolism, and biological activities of both atherogenic lipoproteins and antiatherogenic HDL-C, which includes high levels of lipoproteins containing apolipoprotein B (ApoB), high levels of TGs, high levels of small particles of LDL, and Low levels of HDL-C.[22] Oxidative LDL (Ox-LDL) plays an important role in the atherosclerosis process by expressing adhesive molecules, cytokines, and growth factors along with changes in the function of vasoactive molecules such as NO, AngII, or endothelin 1 (ET1).[34,35] High cholesterol level promotes oxidative stress in endothelial cells.[35,36] In the mice model, it was found that FFA can activate the RAS in mice adipocytes (3T3L1) by TLR4/NF-kB pathway.[36,37] Insulin is the regulator of lipoprotein lipase, which is the mediator of VLDL clearance; therefore, there is hypertriglyceridemia in IR conditions due to high VLDL production and low clearance.[22] TGs of VLDL transform into HDL in the presence of cholesterol ester transport protein (CETP) in exchange for cholesteryl esters, which finally transform into TG-enriched HDL and cholesteryl ester-enriched VLDL.[22]

Inflammation: The immune system and metabolic system play an important role in metabolic homeostasis, while an imbalance between these two systems causes mild chronic systemic inflammation, which leads to MS.[38,39] Chronic inflammation is characterized by the abnormal presence of abnormal cytokines, which causes an increase in the acute reactant and another medium which is closely associated with various chronic diseases such as obesity, T2DM, atherosclerosis, non-alcoholic fatty liver disease, gout, and so on.[38-40] Several scholars suggested that inflammatory response plays a role in IR and glucose intolerance, which may induce β cell dysfunction and promote tissue remodeling.[40,41] T-cells play an important role in inflammation and are directly involved in the development of metabolic diseases such as chronic inflammation due to the balance of T17/Treg is closely related to metabolic disease, T-cell phenotype stratifies the obese and /or T2DM, which exhibits positive therapeutic and prognostic implications and also T cell senescence plays a role in hepatic glucose homeostasis.[38,42-44] TNF-𝛼 induces adipocyte apoptosis and promotes IR by inhibiting insulin receptor substrate, one signaling pathway whose value increases with an increase in body weight, WC, and TGs while value decreases with increased HDL-C level.[45] High CRP is associated with increased WC, IR, high body mass index (BMI), hyperglycemia, and increased metabolic components where, whereas CRP is also an independent predictor of the occurrence of CVD, regardless of MS.[46] Both Adipose tissue and skeletal muscle in human are responsible for the release of IL-6, which has both inflammatory and anti-inflammatory actions.[22] IL-6 receptors are also present in different régions of brain, such as in the hypothalamus, where it controls an appetite and energy intake.[22] IL-6 is a systemic adipokine that impairs insulin sensitivity and is a determinant of the production of CRP by hepatic tissue, where its value increases with an increase in BMI, high fasting insulin, and T2DM while a decrease in an increased level of HDL-C level.[22]

Hypercoagulable state or thrombosis: A prothrombotic state is characterized by impairment of pro-coagulation factors such as an increase in fibrinogen, factor VII, and factor VIII, as well as the PAI-1, platelet abrasions, and endothelial dysfunctions.[22] A Grundy study found that fibrinogen and an acute-phase reactant have a positive association with a high-cytokine state.[47] PAI-1 is a serine protease inhibitor that is secreted from intra-abdominal adipocytes, platelets, and the vascular endothelium, which exerts an effect on inhibition of tPA and is hence considered a marker of dysfunctional fibrinolysis and atherothrombosis, where it depends on abdominal obesity and inflammatory conditions, and hence predicts the risk of thrombosis and adverse cardiovascular outcomes.[22,48] Adiponectin plays a role in multifactorial anti-atherogenic action that includes inhibition of endothelial activation, reduction in conversion of microphage to foam cells, and inhibition of smooth cell proliferation and arterial remodeling, which implies the development of mature atherosclerotic plaque.[22] Adiponectin is inversely related to CVD risk factors such as blood pressure, LDL-C, and TGs.[49]

Oxidative damage: Oxidative stress (OxS) is the cause and consequence of MS, which triggers the signaling pathways dysregulation associated with metabolism and epigenetics, including micro ribonucleic acid  (microRNA), which are biomarkers of metabolic disorders.[35] OxS is a prolonged condition of impairment between the oxidative and anti-oxidative systems of cells caused by the overproduction of free radicals and ROS, resulting in cellular and tissue damage.[35,50] The peptide exerts its pathogenic effect by activating nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase, which increases the production of ROS.[51] Mitochondria are a great source of ROS generation from the electron transport chain (ETC) due to the leak of a few high-energy electrons and their direct reaction with oxygen.[52] Mitochondria play an important role in effective antioxidant mechanisms, which activate superoxide dismutase and other enzymes to kill ROS produced either locally or with the help of other organelles, such as peroxisomes.[53] The abnormal mitochondrial function may lead to the overproduction of ROS, causing cell injury, i.e., Oxidative stress, which may contribute to many metabolic disorders, including MS.[54] Mitochondrial function declined due to Insulin IR may exhibit susceptibility to oxidative stress and reduced oxidative phosphorylation and energy production (EP).[55] ROS has several pleiotropic effects, including endothelial injury, NF-kB expression, aggregation of platelets, LDL oxidation, and expression of lipoprotein receptor-1(LOX-1) on vascular smooth muscle cells (VSMCs) and endothelium. RAS, LOX-1, and ROS together give a positive feedback loop that induces a variety of cycles of endothelial dysfunction, inflammation, and fibroblast proliferation, resulting in the progression of dyslipidemia, T2DM, hypertension, vasculopathy, and CVDs.[51]

Adipokine dysregulation: White adipose tissue (WAT) is composed of Adipose-derived stem cells (ASCs), preadipocytes, adipocytes, and immune cells that are responsible for fat storage and deposit an excess of energy in mobilized FA or TGs according to metabolic needs.[35] WAT works as an immunological organ that releases peptides (Adipo-/cytokines) metabolites capable of producing systemic actions, including body weight /energy balance, appetite regulation, glucose homeostasis, insulin signaling, and blood pressure control. Hypoxia has an inciting etiology of necrosis and macrophage infiltration into adipose tissue, which leads to an overproduction of biologically active metabolites called adipocytokines that include glycerol, FFA, pro-inflammatory mediators (TNF-𝛼, IL-6, PAI-1, CRP).[56-58] Leptin is the first known adipocyte hormone whose genetic absence causes massive obesity and suppresses appetites, while other hormones like adiponectin have negative effects [59,60]. Adipocytokines transmit endocrine, autocrine, and paracrine signals to proceed with multiple processes, including insulin sensitivity, oxidant stress, energy metabolism, blood coagulation, and inflammatory responses that are thought to accelerate cardiovascular disorders such as atherosclerosis, plaque rupture, and atherothrombosis.[22]

Hormonal impairment: Chronic hypersecretion of stress hormones like cortisol when exposed to a permissive environment in individuals with genetic predisposition, which may lead to visceral fat accumulation due to chronic hypercortisolism, low growth hormone secretion, and hypogonadism.[61] Cortisol increases the activities of fatty acid synthesis and promotes the secretion of lipoproteins, induces the hepatic gluconeogenesis pathway, promotes the differentiation of pre-adipocytes to adipocytes that increase body fat mass, inhibits insulin-stimulated amino acid uptake by adipocytes, and causes high lipolysis or oxidation of lipid, which causes peripheral IR. Cortisol secretion and clearance have a positive relation with fasting glucose, blood pressure, and insulin.[62] These hormonal abnormalities may lead to hypersecretion of reactive insulin, visceral obesity increases, and sarcopenia, which leads to dyslipidemia, hypertension, and T2DM.[22,63]

Comorbidities and complications
MS increases the risk of CVDs due to the presence of pro-inflammatory conditions, which may result from high plasma glucose levels.[64] Diabetes is a serious health threat and the leading cause of CVDs, end-stage renal disease (ESRD), and blindness, which often arises in the background of MS.[65] Pre-diabetic has clinically asymptomatic conditions but increase the risk of T2DM and CVDs, which can be limited by lifestyle modification and correction of other risks associated with cardio-metabolic disease.[66]. Obesity is one of the risk factors for MS, including HTN, T2DM, dyslipidemia, and non-alcoholic fatty liver disease (NAFLD) that may lead to many complications such as obstructive sleep apnea (OSA), which contributes to low-quality of life and high cardiovascular disorders and also associated with osteoarthritis, increased risk of cancer and cancer-related mortality that may attributable to chronic hyperinsulinemia.[67-70]. Intra-vascular and extra-vascular fatty deposition increases the risk of CVDs and other morbid conditions, while subcutaneous fat deposition in the lower body is seen to be metabolically healthy and less prone to developing metabolic comorbidities.[71,72]. HTN is a critical risk factor for CVDs, which is one of the factors of MS that occurs five times more commonly with visceral obesity than with normal body weight, and HTN represents the leading cause of worldwide premature death.[73,74]. Dyslipidemia is one of the factors of MS that is responsible for significant morbidity and mortality, and that can be limited by lowering LDL-C with therapy.[75,76]. MS may also be complicated as NAFLD, major depressive disorder (MDD), male infertility may be due to oxidative stress on sperm quality, polycystic ovarian syndrome (PCOS), cognitive impairment (Alzheimer’s disease and vascular dementia).[77,78]

MS can be treated by behavioral therapy, pharmacotherapy, and surgical therapy, which are as follows:

Behavioral therapy: Behavior therapy includes a set of principles and techniques that modify eating and physical activity.[79] Lifestyle modification, low-calorie with low-fat diet (Mediterranean diet), and increased physical activity play important roles in the prevention and limiting the progression of the disease, with risk reduction.[22,51]

Pharmacotherapy: The national institutes of health guidelines for the management of obesity and comorbidities associated with it, which include appetite suppression and nutrition absorption inhibitors.[80] Statins therapy for the management of dyslipidemia.[51] Anti-hypertensive therapy like beta-blockers (β-blockers), calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), anti-hyperglycemic agents like metformin, dipeptidyl peptidase-4 (DPP-4), Glucagon-like peptide-1 GLP-1), and anti-platelet therapy to reduce comorbidities associated with hypercoagulable state.[22,51]

Surgical therapy: BS is a metabolic surgery that is indicated to reduce comorbidities. It is indicated in patients with extreme obesity (high BMI >40 kg/m2) or if they have a BMI >35 to 40 kg/m2 with one or more comorbidities.[80] BS can be divided into three types according to their mechanism of action. They are restrictive types (adjustable gastric banding, vertical banded gastroplasty, and sleeve gastrectomy), malabsorptive types (biliopancreatic diversion and biliopancreatic diversion with duodenal switch), and a combination of both (Roux-en-Y gastric bypass).[81]

MS is a complex metabolic disorder that can be characterized by insulin resistance, abdominal obesity, hypertension, and hyperlipidemia. Biochemical changes that occur in metabolic syndrome are very complex and include IR (not adequate response to insulin secondary to change in adipose tissues and compensatory hyperinsulinism), dyslipidemia (high LDL, TGs & ApoB and low HDL-C), chronic inflammation (high CRP, IL-6 & TNF-𝛼), Hypercoagulable state or thrombosis (high PAI-1, fibrinogen, factor-VII, factor-VIII, and low tPA), Oxidative damage (prolong oxidative and anti-oxidative impairment, high ROS, NADPH oxidase, and free radicals), adipokines dysregulation (abnormal secretion of adipokines like as glycerol, FFA and pro-inflammatory mediators) and hormonal impairment (hypercortisolism, low growth hormone secretion and hypogonadism). MS can be limited by behavior therapy (diet & exercise, lifestyle modification, and proper training), medical therapy (pharmacotherapy), and surgical procedure (BS).

The author acknowledges the endocrinology department, The First Bethune Hospital of Jilin University, Changchun, China, for the infrastructure needed to prepare this review and apologizes to researchers whose work was not cited due to space limitations.

Not reported

Corresponding Author:
Rajiv Kumar Yadav
Department of Endocrinology and Metabolism
First Affiliated Hospital of Jilin University, China
Email: rajivakumar1@yahoo.com

Co-Authors:
Zhang Jizhou
Department of Biochemistry
College of Basic Medical Sciences, Jilin University, China

Xiaokun Gang
Department of Endocrinology and Metabolism
First Affiliated Hospital of Jilin University, China

All authors contributed to the conceptualization, investigation, and data curation by acquiring and critically reviewing the selected articles. They were collectively involved in the writing – original draft preparation, and writing – review & editing to refine the manuscript. Additionally, all authors participated in the supervision of the work, ensuring accuracy and completeness. The final manuscript was approved by all named authors for submission to the journal.

Not applicable

Not reported

None

https://doi.org/10.63096/medtigo30622446

Rajiv KY, Zhang J, Xiaokun G. Biochemical Changes in Metabolic Syndrome. medtigo J Med. 2024;2(4):e30622446. doi:10.63096/medtigo30622446 Crossref