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Pathophysiology of the metabolic syndrome
Pathophysiology of the metabolic syndrome Emma McCracken, Monica Monaghan, Shiva Sreenivasan PII: DOI: Reference:
S0738-081X(17)30158-X doi: 10.1016/j.clindermatol.2017.09.004 CID 7182
To appear in:
Clinics in Dermatology
Please cite this article as: McCracken Emma, Monaghan Monica, Sreenivasan Shiva, Pathophysiology of the metabolic syndrome, Clinics in Dermatology (2017), doi: 10.1016/j.clindermatol.2017.09.004
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ACCEPTED MANUSCRIPT Pathophysiology of the metabolic syndrome
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Emma McCracken MRCP(UK) Consultant in Diabetes and Endocrinology, Department of Medicine, South West Acute Hospital, Enniskillen, County Fermanagh BT74 6DN, United
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Kingdom.
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Monica Monaghan MBBCh BAO BSc PhD MRCP
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Consultant Cardiologist, Division of Cardiology, South West Acute Hospital,
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Enniskillen, County Fermanagh BT74 6DN, United Kingdom.
Shiva Sreenivasan FRCP Edin FRCP Consultant in Acute and General Medicine, Department of Medicine, South
Kingdom
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West Acute Hospital, Enniskillen, County Fermanagh BT74 6DN, United
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Honorary Lecturer, School of Medicine, Dentistry, and Biomedical Sciences, Queen’s University, Belfast BT7 1NN, United Kingdom.
Corresponding author Name:
Shiva Sreenivasan
Address:
Department of Medicine, South West Acute Hospital, Enniskillen, County Fermanagh BT 74 6DN, United Kingdom
Email:
[email protected]
ACCEPTED MANUSCRIPT Abstract
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The metabolic syndrome (MetS) – otherwise called Syndrome X, Insulin Resistance Syndrome, Reaven’s Syndrome, and “the deadly quartet” – is the name given to the aggregate of clinical conditions
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comprising central/abdominal obesity, systemic hypertension, insulin resistance (or type 2 diabetes mellitus), and atherogenic dyslipidemia.
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It is a prothrombotic and proinflammatory state characterized by
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increased inflammatory cytokine activity. In addition to inflammatory dermatoses, such as psoriasis, lichen planus, and hidradenitis
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suppurativa, MetS is also commonly associated with accelerated atherosclerotic cardiovascular disease, hyperuricemia/gout, chronic kidney disease, and obstructive sleep apnea. Current therapeutic options for MetS are limited to individual treatments for hypertension,
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hyperglycemia, and hypertriglyceridemia, as well as dietary control
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measures and regular exercise.
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Introduction
The metabolic syndrome (MetS) – also called Syndrome X, Reaven’s Syndrome, “the deadly quartet”, and Insulin Resistance Syndrome – was
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originally described by Reaven in 1988 [1], and refers to the commonlyoccurring disorder comprising central obesity, systemic hypertension, insulin
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resistance, atherogenic dyslipidemia (specifically hypertriglyceridemia and
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reduced levels of high-density lipoprotein [HDL] cholesterol). It is associated with accelerated atherosclerosis in response to chronic inflammation and
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vascular endothelial dysfunction and confers significantly increased cardiovascular risk. MetS is implicated in both dermatologic, as well as nondermatologic pathologic conditions. We have reviewed the definition, epidemiology, and commonly-attributed postulated pathophysiologic
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mechanisms of MetS.
Definition
MetS has been subjected to numerous definitions since its original description. This makes comparisons difficult between separate studies that use different criteria, especially when comparing populations with varying definitions of abdominal obesity. Diagnostic criteria have been sequentially developed by the World Health Organization (WHO), the European Group for Study of Insulin Resistance (EGIR), and the National Cholesterol Education
ACCEPTED MANUSCRIPT Program (NCEP) Adult Treatment Panel III (ATP III). [2] [3] [4] These were subsequently modified by the American Association of Clinical
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Endocrinologists (AACE), the International Diabetes Federation (IDF) Task Force on Epidemiology and Prevention, and the American Heart Association (AHA) in collaboration with the National Heart, Lung, and Blood Institute
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(NHLBI). [5] [6] [7] In 2009, a harmonized consensus definition was agreed upon by the IDF, NHLBI, AHA, World Heart Federation, International
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Atherosclerosis Society, and the International Association for the Study of
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Obesity. [8] The previous various historic, as well as the more recent
Epidemiology
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diagnostic MetS criteria, are listed in Table 1.
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The global prevalence of MetS differs depending on geographic and socio-
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demographic factors, as well as the diagnostic criteria used. National Health and Nutrition Examination Survey (NHANES) data estimate that 35% of adults in the United States, and as much as 50% of the over-60 population, carry a diagnosis of MetS (30.3% in men and 35.6% in women), based on the NCEP ATP III criteria, with recent trends suggesting a stable overall prevalence, and a reduced prevalence in women. [9] Mexican-American women have been reported as having the highest MetS prevalence. [10] European MetS prevalence, using IDF diagnostic criteria, has been estimated as 41% in men, and 38% in women. [11] A systematic review of epidemiologic data from the Middle East reports a prevalence of MetS in men of 20.7 - 37.2%, and 32.1 -
ACCEPTED MANUSCRIPT 42.7% in women (using ATP III criteria). [12] Data from China suggest a 58.1% prevalence in the 60 and over age group. [13]
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The conditions listed below have all been described as risk factors for the development of MetS: ● Positive family history [14]
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● Smoking [15]
● Obesity [16]
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● Low socioeconomic status [16]
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● Increasing age [16]
● Mexican-American ethnicity [16] ● Postmenopausal status [16]
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● Physical inactivity [17]
● Sugary drink and soft-drink consumption [18] [19] ● Excessive alcohol consumption [20]
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● Western dietary patterns [21]
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● Low cardiorespiratory fitness [22] ● Excessive television-watching [23] ● Use of antiretroviral drugs in human immunodeficiency virus (HIV) infection [24] ● Atypical antipsychotic drug use (e.g., clozapine) [25]
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Proposed pathophysiologic mechanisms of the metabolic syndrome.
There are several hypothesized mechanisms for the underlying
pathophysiology of MetS, and the most widely accepted of these is insulin
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resistance with fatty acid flux. Other potential mechanisms include low-grade
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chronic inflammation and oxidative stress. [1] [26] [27]
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Insulin
The polypeptide hormone insulin is secreted by the beta cells of the
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pancreatic islet of Langerhans and acts via glycoprotein receptors located in the main target tissues of the liver, skeletal muscle, and adipocytes. The insulin receptor is a dimer of two alpha-subunits which host the binding sites for insulin, and two beta-subunits, which traverse the cell membrane. Insulin
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binds to the extracellular alpha-subunit of the insulin receptor, transmitting a
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signal across the plasma membrane and activating the tyrosine kinase domain of the intracellular beta-subunit, resulting in intermolecular autophosphorylation reactions of tyrosine residues on the receptor substrate, allowing progression to full kinase activity. The catalytic subunit of one such lipid kinase, namely PI3-kinase, triggers a sequence of further phosphorylation reactions.
A key downstream effector of this process is protein kinase B, also known as Akt. Akt is activated by protein kinase 3-phosphoinositide dependent protein kinase-1 (PDK1), in combination with another currently unidentified kinase,
ACCEPTED MANUSCRIPT provisionally named PKD2. Activated Akt will ultimately phosphorylate and inactivate glycogen synthase kinase 3, allowing glycogen synthesis and
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promoting glucose storage as glycogen. [27] [28] [29] This is not the only role of Akt. Protein kinase A (PKA) is the main effector of lipolysis in adipose tissue. Activation of Akt also results in inhibition of PKA, and thus lipolysis
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suppression. [30]
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Figure 1
Insulin-dependent glucose cellular uptake is stimulated by inducing migration
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of the glucose transporter protein GLUT4 to the cell surface, promoting glucose transport into the cell. Glucose is then phosphorylated to be either stored as glycogen or metabolized to produce adenosine triphosphate (ATP). GLUT4 is highly expressed in skeletal muscle and adipose tissue. In
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the fasting state, when insulin levels are reduced, GLUT4 is reduced at the
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plasma membrane and is instead relocated to intracellular membrane storage compartments. Overexpression of active mutants of PI3-kinase and AKT can promote expression of GLUT4 on the cell surface in the absence of insulin. [27] [28] [29] [30] [31]
Insulin inhibits gluconeogenesis and glycogenolysis, together with promoting glucose storage, and it also stimulates genetic transcription of enzymes involved in glycolytic and fatty acid synthetic pathways. It directly inhibits transcription and activity of hepatic gluconeogenic enzymes, achieving this through Akt-mediated phosphorylation of the forkhead box class O-1 (FOXO1)
ACCEPTED MANUSCRIPT transcription factor. Other transcriptional regulators have also been associated with inhibition of gluconeogenesis; these include cAMP response
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element-binding protein (CREB)-regulated transcription coactivator 2, peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and
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FOXO6. [32] [33] [34] [35]
Insulin resistance
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As previously stated, the most widely accepted hypothesis for the underlying
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pathophysiology of the metabolic syndrome is that of insulin resistance, driven to a degree by fatty acid excess as a consequence of inappropriate lipolysis.
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Reduced responsiveness to normal insulin levels is an obvious precursor to the development of type 2 diabetes. Early in the process, beta cells secrete increased amounts of insulin as a compensatory mechanism to maintain
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euglycemia. Eventually decompensation will occur.
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Considering the main tissues targeted by insulin, insulin resistance in skeletal muscle results in a reduction in glycogen synthesis and glucose transport, while insulin resistance in the liver appears to lead to reduced effectiveness of insulin signalling pathways; however, discordant to this observation is evidence that hepatic lipogenesis continues. Precise mechanisms have not been definitively confirmed, and research in this area continues. [26] [32]
Lipid accumulation in skeletal muscle is associated with reduced tyrosine phosphorylation, inhibiting subsequent activation of PI3 kinase. Again, a specific pathway has not yet been identified; a number of serine kinases and
ACCEPTED MANUSCRIPT inflammatory intermediates could be responsible for this effect. In addition, raised levels of acyl-CoAs or acyl-CoA derivatives can reduce Akt activation.
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Lipid accumulation itself may be a consequence of increased fatty acid delivery to tissues ,where energy intake outstrips storage capacity.
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An alternative hypothesis is that of mitochondrial dysfunction, namely a defect in the process of mitochondrial oxidative phosphorylation. [26] [27] [32]
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In skeletal muscle, free fatty acids can inhibit insulin dependent glucose
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uptake. In the liver, free fatty acids promote increased production of glucose, triglycerides and apo B-containing triglyceride-rich very low-density
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lipoproteins (VLDL), which are atherogenic.
Free fatty acids are mainly derived from triglyceride stores in adipose tissue, released via action of cyclic AMP during lipolysis. During periods of fasting,
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this process is initiated by catecholamines. Post-prandially, this process is
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inhibited by insulin via a proposed mechanism of reducing cAMP activity. In the setting of insulin resistance,where the effects of insulin are reduced, the rate of lipolysis will increase, resulting in increased fatty acid production. This will potentiate the negative cycle of inhibiting the antilipolytic properties of insulin, leading to further lipolysis. [26] [30] [36] [37]
Inflammatory and oxidative mediators The development of MetS is not fully understood, but central obesity and insulin resistance are implicated in its etiology. The condition confers significantly increased risk for type 2 diabetes and atherosclerotic
ACCEPTED MANUSCRIPT cardiovascular disease. [38] MetS is recognized to be a proinflammatory and prothrombotic state [4] [7], with adipose tissue being central to its
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pathophysiology. [39]
Adipose tissue is now considered a biologically active endocrine and
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paracrine organ. [40] Adipocytes undergo hypertrophy and hyperplasia in response to nutritional excess that can lead the cells to outgrow their blood
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supply with induction of a hypoxic state. [41] [42] Hypoxia can lead to cell
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necrosis with macrophage infiltration and the production of adipocytokines, which include the proinflammatory mediators interleukin-6 (IL-6) and tumor
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necrosis factor alpha (TNF-α), as well as the prothrombotic mediator plasminogen activator inhibitor-1 (PAI-1). [40] [43]
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Figure 2
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Interleukin-6 (IL-6) is a potent inflammatory cytokine that plays a vital role in the pathogenesis of insulin resistance and type 2 diabetes. [44] [45] Elevated IL-6 levels have been measured in adipose tissue of patients with diabetes mellitus and obesity, and also notably in patients with features of MetS. Epidemiologic studies have demonstrated increased IL-6 concentrations in association with hypertension, atherosclerosis, and cardiovascular events. [45] [46] In a murine model, chronic IL-6 exposure led to insulin resistance with hyperglycemia. [47] TNF-α, a proinflammatory cytokine named after its antitumor activity, is a significant mediator of numerous cardiovascular pathologies, including
ACCEPTED MANUSCRIPT atherosclerosis and heart failure. [48] It has been reported to act as a paracrine mediator to reduce insulin resistance in adipocytes. [40] [43]
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PAI-1 is a serine protease inhibitor and acts to inhibit tissue plasminogen activator and is prothrombotic. Circulating PAI-1 is increased in obese MetS subjects, as well as in patients with type 2 diabetes, and there is a positive
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correlation between the severity of the MetS and the plasma concentration of PAI-1. [49] The mechanism of PAI-1 overexpression in MetS likely involves
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multiple mediators and the mechanism as yet remains unknown. Interestingly,
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the Alessi group has postulated that in addition to its role in atherothrombosis, PAI-1 is also involved in adipose tissue development and control of insulin
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signaling. [49]
The mechanism by which adipocyte dysregulation occurs is not clearly understood, but a role for obesity induced oxidative stress is postulated. In human and animal studies there has been a positive correlation between fat
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accumulation and oxidative stress, with production of reactive oxygen species
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and increased expression of NADPH oxidase with concomitant decreased expression of antioxidant enzymes. In vitro studies showed that cultured adipocytes with increased levels of fatty acids exhibited increased oxidative stress via the NADPH pathway. [50] In addition, obese mice treated with NADPH oxidase inhibitor showed reduced reactive oxygen species (ROS) production with improvement in the diabetes phenotype. Markers of prooxidant state that include oxidized LDL (OxLDL) and uric acid are elevated in MetS. [51] Expression of the anti-infammatory cytokine adiponectin was shown to be decreased in MetS. Apiponectin is secreted from adipocytes and functions in
ACCEPTED MANUSCRIPT insulin sensitization, anti-atherogenesis and vasodilatation, [51] and levels are negatively correlated with fasting plasma glucose and insulin levels, waist
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circumference and visceral fat. [39] Adiponectin inhibits the pro-atherogenic molecular pathways that include monocyte adhesion to endothelial cells by the expression of adhesion molecules, oxidized LDL uptake of macrophages
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through scavenger receptors, and proliferation of migrated smooth muscle
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cells by the action of platelet-derived growth factors. [52] Studies have indicated a significant elevation in the expression of OxLDL in
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MetS, in insulin resistance and in adiposity. [51] OxLDL is one product of lipid oxidation. Reactive oxygen species (ROS) are also generated. Antioxidant
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cytokines that include Adiponectin are downregulated in MetS allowing OxLDL and ROS to activate an oxidative cascade that leads to apoptosis and cellular damage. [53] When the integrity of the endothelial cell is breached, a cascade
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is initiated that terminates in atherosclerosis.
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While the role of adipose tissue and the molecular pathways involved in MetS pathophysiology remain in the experimental phase, new molecular targets may be uncovered to develop therapeutic strategies to improve cardiovascular outcomes.
Conclusions MetS is an increasingly international common cause of morbidity and mortality, and has been linked with many risk factors as well as numerous postulated pathophysiological mechanisms. The most commonly described
ACCEPTED MANUSCRIPT mechanisms result in insulin resistance, together with a low-grade pro-
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inflammatory, pro-thrombotic, and oxidative physiologic state.
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S0738-081X(17)30158-X doi: 10.1016/j.clindermatol.2017.09.004 CID 7182
To appear in:
Clinics in Dermatology
Please cite this article as: McCracken Emma, Monaghan Monica, Sreenivasan Shiva, Pathophysiology of the metabolic syndrome, Clinics in Dermatology (2017), doi: 10.1016/j.clindermatol.2017.09.004
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Pathophysiology of the metabolic syndrome
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Emma McCracken MRCP(UK) Consultant in Diabetes and Endocrinology, Department of Medicine, South West Acute Hospital, Enniskillen, County Fermanagh BT74 6DN, United
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Kingdom.
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Monica Monaghan MBBCh BAO BSc PhD MRCP
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Consultant Cardiologist, Division of Cardiology, South West Acute Hospital,
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Enniskillen, County Fermanagh BT74 6DN, United Kingdom.
Shiva Sreenivasan FRCP Edin FRCP Consultant in Acute and General Medicine, Department of Medicine, South
Kingdom
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West Acute Hospital, Enniskillen, County Fermanagh BT74 6DN, United
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Honorary Lecturer, School of Medicine, Dentistry, and Biomedical Sciences, Queen’s University, Belfast BT7 1NN, United Kingdom.
Corresponding author Name:
Shiva Sreenivasan
Address:
Department of Medicine, South West Acute Hospital, Enniskillen, County Fermanagh BT 74 6DN, United Kingdom
Email:
[email protected]
ACCEPTED MANUSCRIPT Abstract
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The metabolic syndrome (MetS) – otherwise called Syndrome X, Insulin Resistance Syndrome, Reaven’s Syndrome, and “the deadly quartet” – is the name given to the aggregate of clinical conditions
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comprising central/abdominal obesity, systemic hypertension, insulin resistance (or type 2 diabetes mellitus), and atherogenic dyslipidemia.
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It is a prothrombotic and proinflammatory state characterized by
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increased inflammatory cytokine activity. In addition to inflammatory dermatoses, such as psoriasis, lichen planus, and hidradenitis
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suppurativa, MetS is also commonly associated with accelerated atherosclerotic cardiovascular disease, hyperuricemia/gout, chronic kidney disease, and obstructive sleep apnea. Current therapeutic options for MetS are limited to individual treatments for hypertension,
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hyperglycemia, and hypertriglyceridemia, as well as dietary control
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measures and regular exercise.
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Introduction
The metabolic syndrome (MetS) – also called Syndrome X, Reaven’s Syndrome, “the deadly quartet”, and Insulin Resistance Syndrome – was
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originally described by Reaven in 1988 [1], and refers to the commonlyoccurring disorder comprising central obesity, systemic hypertension, insulin
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resistance, atherogenic dyslipidemia (specifically hypertriglyceridemia and
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reduced levels of high-density lipoprotein [HDL] cholesterol). It is associated with accelerated atherosclerosis in response to chronic inflammation and
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vascular endothelial dysfunction and confers significantly increased cardiovascular risk. MetS is implicated in both dermatologic, as well as nondermatologic pathologic conditions. We have reviewed the definition, epidemiology, and commonly-attributed postulated pathophysiologic
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mechanisms of MetS.
Definition
MetS has been subjected to numerous definitions since its original description. This makes comparisons difficult between separate studies that use different criteria, especially when comparing populations with varying definitions of abdominal obesity. Diagnostic criteria have been sequentially developed by the World Health Organization (WHO), the European Group for Study of Insulin Resistance (EGIR), and the National Cholesterol Education
ACCEPTED MANUSCRIPT Program (NCEP) Adult Treatment Panel III (ATP III). [2] [3] [4] These were subsequently modified by the American Association of Clinical
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Endocrinologists (AACE), the International Diabetes Federation (IDF) Task Force on Epidemiology and Prevention, and the American Heart Association (AHA) in collaboration with the National Heart, Lung, and Blood Institute
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(NHLBI). [5] [6] [7] In 2009, a harmonized consensus definition was agreed upon by the IDF, NHLBI, AHA, World Heart Federation, International
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Atherosclerosis Society, and the International Association for the Study of
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Obesity. [8] The previous various historic, as well as the more recent
Epidemiology
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diagnostic MetS criteria, are listed in Table 1.
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The global prevalence of MetS differs depending on geographic and socio-
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demographic factors, as well as the diagnostic criteria used. National Health and Nutrition Examination Survey (NHANES) data estimate that 35% of adults in the United States, and as much as 50% of the over-60 population, carry a diagnosis of MetS (30.3% in men and 35.6% in women), based on the NCEP ATP III criteria, with recent trends suggesting a stable overall prevalence, and a reduced prevalence in women. [9] Mexican-American women have been reported as having the highest MetS prevalence. [10] European MetS prevalence, using IDF diagnostic criteria, has been estimated as 41% in men, and 38% in women. [11] A systematic review of epidemiologic data from the Middle East reports a prevalence of MetS in men of 20.7 - 37.2%, and 32.1 -
ACCEPTED MANUSCRIPT 42.7% in women (using ATP III criteria). [12] Data from China suggest a 58.1% prevalence in the 60 and over age group. [13]
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The conditions listed below have all been described as risk factors for the development of MetS: ● Positive family history [14]
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● Smoking [15]
● Obesity [16]
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● Low socioeconomic status [16]
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● Increasing age [16]
● Mexican-American ethnicity [16] ● Postmenopausal status [16]
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● Physical inactivity [17]
● Sugary drink and soft-drink consumption [18] [19] ● Excessive alcohol consumption [20]
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● Western dietary patterns [21]
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● Low cardiorespiratory fitness [22] ● Excessive television-watching [23] ● Use of antiretroviral drugs in human immunodeficiency virus (HIV) infection [24] ● Atypical antipsychotic drug use (e.g., clozapine) [25]
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Proposed pathophysiologic mechanisms of the metabolic syndrome.
There are several hypothesized mechanisms for the underlying
pathophysiology of MetS, and the most widely accepted of these is insulin
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resistance with fatty acid flux. Other potential mechanisms include low-grade
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chronic inflammation and oxidative stress. [1] [26] [27]
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Insulin
The polypeptide hormone insulin is secreted by the beta cells of the
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pancreatic islet of Langerhans and acts via glycoprotein receptors located in the main target tissues of the liver, skeletal muscle, and adipocytes. The insulin receptor is a dimer of two alpha-subunits which host the binding sites for insulin, and two beta-subunits, which traverse the cell membrane. Insulin
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binds to the extracellular alpha-subunit of the insulin receptor, transmitting a
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signal across the plasma membrane and activating the tyrosine kinase domain of the intracellular beta-subunit, resulting in intermolecular autophosphorylation reactions of tyrosine residues on the receptor substrate, allowing progression to full kinase activity. The catalytic subunit of one such lipid kinase, namely PI3-kinase, triggers a sequence of further phosphorylation reactions.
A key downstream effector of this process is protein kinase B, also known as Akt. Akt is activated by protein kinase 3-phosphoinositide dependent protein kinase-1 (PDK1), in combination with another currently unidentified kinase,
ACCEPTED MANUSCRIPT provisionally named PKD2. Activated Akt will ultimately phosphorylate and inactivate glycogen synthase kinase 3, allowing glycogen synthesis and
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promoting glucose storage as glycogen. [27] [28] [29] This is not the only role of Akt. Protein kinase A (PKA) is the main effector of lipolysis in adipose tissue. Activation of Akt also results in inhibition of PKA, and thus lipolysis
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suppression. [30]
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Figure 1
Insulin-dependent glucose cellular uptake is stimulated by inducing migration
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of the glucose transporter protein GLUT4 to the cell surface, promoting glucose transport into the cell. Glucose is then phosphorylated to be either stored as glycogen or metabolized to produce adenosine triphosphate (ATP). GLUT4 is highly expressed in skeletal muscle and adipose tissue. In
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the fasting state, when insulin levels are reduced, GLUT4 is reduced at the
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plasma membrane and is instead relocated to intracellular membrane storage compartments. Overexpression of active mutants of PI3-kinase and AKT can promote expression of GLUT4 on the cell surface in the absence of insulin. [27] [28] [29] [30] [31]
Insulin inhibits gluconeogenesis and glycogenolysis, together with promoting glucose storage, and it also stimulates genetic transcription of enzymes involved in glycolytic and fatty acid synthetic pathways. It directly inhibits transcription and activity of hepatic gluconeogenic enzymes, achieving this through Akt-mediated phosphorylation of the forkhead box class O-1 (FOXO1)
ACCEPTED MANUSCRIPT transcription factor. Other transcriptional regulators have also been associated with inhibition of gluconeogenesis; these include cAMP response
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element-binding protein (CREB)-regulated transcription coactivator 2, peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and
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FOXO6. [32] [33] [34] [35]
Insulin resistance
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As previously stated, the most widely accepted hypothesis for the underlying
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pathophysiology of the metabolic syndrome is that of insulin resistance, driven to a degree by fatty acid excess as a consequence of inappropriate lipolysis.
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Reduced responsiveness to normal insulin levels is an obvious precursor to the development of type 2 diabetes. Early in the process, beta cells secrete increased amounts of insulin as a compensatory mechanism to maintain
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euglycemia. Eventually decompensation will occur.
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Considering the main tissues targeted by insulin, insulin resistance in skeletal muscle results in a reduction in glycogen synthesis and glucose transport, while insulin resistance in the liver appears to lead to reduced effectiveness of insulin signalling pathways; however, discordant to this observation is evidence that hepatic lipogenesis continues. Precise mechanisms have not been definitively confirmed, and research in this area continues. [26] [32]
Lipid accumulation in skeletal muscle is associated with reduced tyrosine phosphorylation, inhibiting subsequent activation of PI3 kinase. Again, a specific pathway has not yet been identified; a number of serine kinases and
ACCEPTED MANUSCRIPT inflammatory intermediates could be responsible for this effect. In addition, raised levels of acyl-CoAs or acyl-CoA derivatives can reduce Akt activation.
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Lipid accumulation itself may be a consequence of increased fatty acid delivery to tissues ,where energy intake outstrips storage capacity.
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An alternative hypothesis is that of mitochondrial dysfunction, namely a defect in the process of mitochondrial oxidative phosphorylation. [26] [27] [32]
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In skeletal muscle, free fatty acids can inhibit insulin dependent glucose
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uptake. In the liver, free fatty acids promote increased production of glucose, triglycerides and apo B-containing triglyceride-rich very low-density
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lipoproteins (VLDL), which are atherogenic.
Free fatty acids are mainly derived from triglyceride stores in adipose tissue, released via action of cyclic AMP during lipolysis. During periods of fasting,
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this process is initiated by catecholamines. Post-prandially, this process is
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inhibited by insulin via a proposed mechanism of reducing cAMP activity. In the setting of insulin resistance,where the effects of insulin are reduced, the rate of lipolysis will increase, resulting in increased fatty acid production. This will potentiate the negative cycle of inhibiting the antilipolytic properties of insulin, leading to further lipolysis. [26] [30] [36] [37]
Inflammatory and oxidative mediators The development of MetS is not fully understood, but central obesity and insulin resistance are implicated in its etiology. The condition confers significantly increased risk for type 2 diabetes and atherosclerotic
ACCEPTED MANUSCRIPT cardiovascular disease. [38] MetS is recognized to be a proinflammatory and prothrombotic state [4] [7], with adipose tissue being central to its
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pathophysiology. [39]
Adipose tissue is now considered a biologically active endocrine and
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paracrine organ. [40] Adipocytes undergo hypertrophy and hyperplasia in response to nutritional excess that can lead the cells to outgrow their blood
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supply with induction of a hypoxic state. [41] [42] Hypoxia can lead to cell
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necrosis with macrophage infiltration and the production of adipocytokines, which include the proinflammatory mediators interleukin-6 (IL-6) and tumor
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necrosis factor alpha (TNF-α), as well as the prothrombotic mediator plasminogen activator inhibitor-1 (PAI-1). [40] [43]
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Figure 2
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Interleukin-6 (IL-6) is a potent inflammatory cytokine that plays a vital role in the pathogenesis of insulin resistance and type 2 diabetes. [44] [45] Elevated IL-6 levels have been measured in adipose tissue of patients with diabetes mellitus and obesity, and also notably in patients with features of MetS. Epidemiologic studies have demonstrated increased IL-6 concentrations in association with hypertension, atherosclerosis, and cardiovascular events. [45] [46] In a murine model, chronic IL-6 exposure led to insulin resistance with hyperglycemia. [47] TNF-α, a proinflammatory cytokine named after its antitumor activity, is a significant mediator of numerous cardiovascular pathologies, including
ACCEPTED MANUSCRIPT atherosclerosis and heart failure. [48] It has been reported to act as a paracrine mediator to reduce insulin resistance in adipocytes. [40] [43]
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PAI-1 is a serine protease inhibitor and acts to inhibit tissue plasminogen activator and is prothrombotic. Circulating PAI-1 is increased in obese MetS subjects, as well as in patients with type 2 diabetes, and there is a positive
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correlation between the severity of the MetS and the plasma concentration of PAI-1. [49] The mechanism of PAI-1 overexpression in MetS likely involves
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multiple mediators and the mechanism as yet remains unknown. Interestingly,
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the Alessi group has postulated that in addition to its role in atherothrombosis, PAI-1 is also involved in adipose tissue development and control of insulin
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signaling. [49]
The mechanism by which adipocyte dysregulation occurs is not clearly understood, but a role for obesity induced oxidative stress is postulated. In human and animal studies there has been a positive correlation between fat
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accumulation and oxidative stress, with production of reactive oxygen species
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and increased expression of NADPH oxidase with concomitant decreased expression of antioxidant enzymes. In vitro studies showed that cultured adipocytes with increased levels of fatty acids exhibited increased oxidative stress via the NADPH pathway. [50] In addition, obese mice treated with NADPH oxidase inhibitor showed reduced reactive oxygen species (ROS) production with improvement in the diabetes phenotype. Markers of prooxidant state that include oxidized LDL (OxLDL) and uric acid are elevated in MetS. [51] Expression of the anti-infammatory cytokine adiponectin was shown to be decreased in MetS. Apiponectin is secreted from adipocytes and functions in
ACCEPTED MANUSCRIPT insulin sensitization, anti-atherogenesis and vasodilatation, [51] and levels are negatively correlated with fasting plasma glucose and insulin levels, waist
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circumference and visceral fat. [39] Adiponectin inhibits the pro-atherogenic molecular pathways that include monocyte adhesion to endothelial cells by the expression of adhesion molecules, oxidized LDL uptake of macrophages
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through scavenger receptors, and proliferation of migrated smooth muscle
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cells by the action of platelet-derived growth factors. [52] Studies have indicated a significant elevation in the expression of OxLDL in
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MetS, in insulin resistance and in adiposity. [51] OxLDL is one product of lipid oxidation. Reactive oxygen species (ROS) are also generated. Antioxidant
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cytokines that include Adiponectin are downregulated in MetS allowing OxLDL and ROS to activate an oxidative cascade that leads to apoptosis and cellular damage. [53] When the integrity of the endothelial cell is breached, a cascade
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is initiated that terminates in atherosclerosis.
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While the role of adipose tissue and the molecular pathways involved in MetS pathophysiology remain in the experimental phase, new molecular targets may be uncovered to develop therapeutic strategies to improve cardiovascular outcomes.
Conclusions MetS is an increasingly international common cause of morbidity and mortality, and has been linked with many risk factors as well as numerous postulated pathophysiological mechanisms. The most commonly described
ACCEPTED MANUSCRIPT mechanisms result in insulin resistance, together with a low-grade pro-
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inflammatory, pro-thrombotic, and oxidative physiologic state.
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