Sandbox 2

Historical Perspective

• The term "metabolic syndrome" dates back to at least the late 1950s, but came into common usage in the late 1970s to describe various associations of risk factors with diabetes.
• In 1947, Dr. Jean Vague proposed a theory that upper body obesity predisposed to diabetes, atherosclerosis, gout, and calculi.
• In 1967, Avogaro, Crepaldi and co-workers discovered obese patients with diabetes, hypercholesterolemia, and marked hypertriglyceridemia improved when they were put on a hypocaloric, low carbohydrate diet.
• In 1977, Haller coined the term "metabolic syndrome" for the first time when describing the additive effects of risk factors on atherosclerosis.
• In 1977, Singer coined the term hyperlipoproteinemia to describe the associations of obesity, gout, diabetes mellitus, and hypertension with metabolic syndrome.
• In 1977 and 1978, Gerald B. Phillips developed the concept that risk factors for myocardial infarction are not only associated with heart disease, but also with aging, obesity and other clinical states.
• In 1988, Gerald M. Reaven proposed insulin resistance as the underlying factor and named the constellation of abnormalities as Syndrome X.

Screening

According to the Endocrine Society clinical guidelines, screening for metabolic syndrome is recommended every 3 years among patients with one or more risk factors (type 2 DM or with a family history of dyslipidemia, CVD, or hereditary conditions associated with cardiovascular mortality such as polycystic ovary syndrome, and in cases of childhood obesity). Screening assessment includes measurement of:

• Blood pressure
• Waist circumference
• Fasting lipid profile, and fasting glucose.

Natural History

• If left untreated, consistently high levels of insulin in metabolic syndrome usually leads to type 2 diabetes. Insulin resistance is also associated with many changes in the body prior to its manifesting as disease including chronic inflammation and damage to arterial walls, decreased excretion by the kidneys, and coagulopathies.

Complications

Common complications of metabolic syndrome include:

• Cardiovascular disease
• Type 2 DM
• Nonalcoholic fatty liver disease
• Infertility
• Osteoarthritis
• Gout
• Cancer

Prognosis

Prognosis is generally good with appropriate treatment and life style modifications.

Pathophysiology

Adipose tissue and inflammatory process play an important role in the pathogenesis of metabolic syndrome.

Role of adipose tissue

• Adipose tissue has two major functions
  • Storage and release of energy-rich fatty acids
  • Secretion of proteins required for endocrine and autocrine regulation of energy metabolism.
• Adipocytes exert their metabolic effects by the release of free fatty acids, enhanced by the secretion of
  • Catecholamines
  • Glucocorticoids
  • Increased β-receptor agonist activity
  • Reduction of lipid storage mediated by insulin
• Visceral adipose tissue has been identified as an important source of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), as well as anti-inflammatory cytokines such as adiponectin.
• Increased levels of proinflammatory cytokines likely contribute to the etiology of insulin resistance primarily by obstructing insulin signaling and contributing to down-regulation of peroxisomal proliferator-activated receptor-γ, processes that are fundamentally important regulators of adipocyte differentiation and control.
• Additionally, insulin resistance may promote inflammation through the diminution of insulin’s anti-inflammatory effects.
• Finally, oxidative stress is increased in obesity, primarily as a result of excessive intake of macronutrients and a concomitant increase in metabolic rate. These factors also contribute to the inflammatory response.
• Proteins such as leptin and adiponectin, are produced primarily by adipocytes, are classified as adipokines. Although leptin is primarily involved in appetite control, its immunologic effects include protection of T lymphocytes from apoptosis and regulation of T-cell activation and proliferation.
• Other cytokines (primarily IL-6 and TNF-α) and adipokines (leptin, adiponectin, and adipose-derived resistin) are two additional major groups of inflammatory proteins produced and released by adipose and adipose-associated tissue.
• Reduced leptin levels may increase appetite and slow metabolism, but they may also increase susceptibility to the toxicity of proinflammatory stimuli, such as endotoxin and TNF-α.
• Elevated leptin levels are proinflammatory, and this feature likely plays an important role in the progression of heart disease and diabetes, especially in obese patients. *Serum levels of adiponectin correlate with insulin sensitivity and do not rise in obesity. Significantly reduced adiponectin levels are found in patients with type 2 diabetes.
• Adiponectin reduces both TNF-α production and activity. It also inhibits IL-6 production.
• Resistin, an adipokine that induces insulin resistance, is induced by endotoxin and cytokines.

Immune response

• Native immune responses act aberrantly in obese individuals.
• Natural killer (NK) cell cytotoxic activity is depressed in obesity, as well as plasma levels of cytokines such as IL-12, IL-18 and interferon-γ known to regulate NK cell function.
• Resistin, an adipokine that induces insulin resistance, is induced by endotoxin and cytokines.
• Resistin acts at the cellular level to up-regulate production of proinflammatory cytokines, most likely through the nuclear factor κB (NFκB) pathway.
• Resistin appears to present a molecular link among metabolic signaling, inflammatory processes, and the development of cardiovascular disease.
• Resistin levels have been associated with inflammatory markers apparently independently of BMI in humans.
• Both free fatty acids and TNF-α act through intracellular inflammatory cascade pathways to arrest insulin signaling. This process is mediated by activation of transcription factors present within the cell cytoplasm, which, following their translocation to the nucleus, eventually bind to transcription factors regulating the inflammatory process. *The cytoplasm also contains NFκB, another transcription factor whose activation is implicated in a number of diseases, including diabetes.
• NFκB is also induced by hypoxia, and it increases production of proinflammatory cytokines TNF-α and IL-6, both of which are frequently increased in patients with OSA syndrome. Therefore, inflammation provides the common linkage underlying the association of obesity, metabolic syndrome, and OSA.

Associated Conditions

The metabolic syndrome has been associated with several obesity-related disorders including:

• Fatty liver disease with steatosis, fibrosis, and cirrhosis
• Hepatocellular and intrahepatic cholangiocarcinoma
• Chronic kidney disease (CKD)
• Polycystic ovary syndrome
• Obstructive sleep apnea
• Hyperuricemia and gout

Pathophysiology

Physical inactivity Smoking Energy dense food Stress

Positive energy balance resulting in Adipose tissue hyperplasia and hypertrophy

Altered FFA metabolism

Altered release of adipokines

↑ Portal FFA

Insulin resistance hyperinsulinemia

↑Leptin ↑AT-II ↑Aldosterone

↑ Factor VII ↑ Factor V ↑ PAI-I

↑ Lipoprotein synthesis ↑ Gluconeogenesis

Impairs 𝛽-cell function of pancreas

Activate RAAS and SNS

Oxidative stress endothelial dysfunction

Dyslipidemia

Hyperglycemia

↑ Sodium reabsorption Vasoconstriction

Proinflammatory state prothrombotic state

Hypertension

Hypercoagulable state

Metabolic syndrome

Insulin resistance

• Insulin resistance is defined as a condition in which the peripheral target tissues such as adipose, muscle, and liver fail to respond to normal levels of insulin levels in response normal blood glucose.
• Free fatty acids inhibit insulin-mediated glucose uptake in the muscles by downregulating signaling pathways.
• As a result, pancreatic beta cells of pancreas secretes more insulin (i.e., hyperinsulinemia) to overcome the hyperglycemia among insulin-resistant individuals.
• These responses by pancreas may cause an overexpression of insulin activity in some normal tissues.
• Imbalance between normal and resistant tissue responses to insulin is believed to be responsible for an abnormal fat distribution that is characterized by a predominantly upper body fat.
• Insulin acts by binding of insulin receptor, a ligand-activated tyrosine kinase.
• Binding of insulin results in a tyrosine phosphorylation of downstream substrates and activation of two parallel pathways
  • The phosphoinositide 3-kinase (PI3K) pathway
  • The mitogen-activated protein (MAP) kinase pathway.

	PI3K pathway	(MAP) kinase pathway
Effected by Insulin resistance	Yes	No
Results in	Reduction in endothelial NO production resulting in an endothelial dysfunction Reduction in GLUT4 translocation	Continued endothelin-1 (ET-1) production Mitogenic stimulus to vascular smooth muscle cells
Decreased glucose intake by	Decreased skeletal muscle and fat glucose uptake

Adipose tissue

• Adipose tissue is a collection of adipocytes, stromal pre-adipocytes, immune cells, and endothelium.
• Adipocytes are dynamic in nature and respond to alterations in calorie intake through hypertrophy and hyperplasia.
• Obesity occurs when there is increased consumption of calorie dense food with reduced physical activity.
• Combined with obesity and adipocyte hypertrophy results in decreased blood supply to adipocytes and subsequently hypoxia.
• Decreased blood supply along with hypoxia leads to necrosis and macrophage infiltration into adipose tissue.
• Infiltration by macrophages also attracts various inflammatory cells such as glycerol, free fatty acids (FFA), proinflammatory mediators (tumor necrosis factor alpha (TNF𝛼) and interleukin-6 (IL-6)), plasminogen activator inhibitor-1 (PAI-1), and C-reactive protein (CRP).

Free Fatty Acids (FFA)	Produced by upper body subcutaneous adipocytes.	Acute exposure results in decreased glucose intake by smooth muscles Chronic exposure results in impairment of pancreatic 𝛽-cell function
Tumor necrosis factor alpha (TNF𝛼)	Paracrine mediator in adipocytes	Reduce the insulin sensitivity of adipocytes Induces adipocytes apoptosis Inhibits insulin receptor substrate 1 signalling pathway
Interleukin-6 (IL-6)	Released by both adipose tissue and skeletal muscle	Systemic adipokine impairs insulin sensitivity by suppressing lipoprotein lipase activity. Major determinant of the hepatic production of CRP
CRP	Produced majorly by liver	Elevated levels of CRP are associated with an increased WC, insulin resistance, BMI, and hyperglycemia.
Adiponectin	Adiponectin is inversely associated with CVD risk factors.	Increases glucose transport in muscles and enhances fatty acid oxidation. It inhibits hepatic gluconeogenic enzymes and the rate of an endogenous glucose production in the liver.
Leptin.	Adipokine involved in the regulation of satiety and energy intake. Leptin receptors are located mostly in the hypothalamus and the brain stem Controls satiety, energy expenditure	Levels increase during the development of obesity and decline during the weight loss. Leptin resistance sets in obesity(no control over eating)

Dyslipidemia

• Dyslipidemia is characterized by a spectrum of qualitative lipid abnormalities reflecting perturbations in the structure, metabolism, and biological activities of both atherogenic lipoproteins and antiatherogenic HDL-C which includes an elevation of lipoproteins containing apolipoprotein B (apoB), elevated TGs, increased levels of small particles of LDL, and low levels of HDLC.
• Insulin resistance leads to an atherogenic dyslipidemia in several ways.
• First, insulin normally suppresses lipolysis in adipocytes, so an impaired insulin signalling increases lipolysis, resulting in increased FFA levels.
• In the liver, FFAs serve as a substrate for the synthesis of TGs.
• FFAs also stabilize the production of apoB, themajor lipoprotein of very low density lipoprotein (VLDL) particles, resulting in a more VLDL production. Second, insulin normally degrades apoB through PI3K-dependent pathways, so an insulin resistance directly increases VLDL production.
• Third, insulin regulates the activity of lipoprotein lipase, the rate-limiting and major mediator of VLDL clearance.
• Thus, hypertriglyceridemia in insulin resistance is the result of both an increase in VLDL production and a decrease in VLDL clearance.
• VLDL is metabolized to remnant lipoproteins and small dense LDL, both of which can promote an atheroma formation.
• The TGs in VLDL are transferred to HDL by the cholesterol ester transport protein (CETP) in exchange for cholesteryl esters, resulting in the TG-enriched HDL and cholesteryl esterenriched VLDL particles.
• Further, the TG-enriched HDL is a better substrate for hepatic lipase, so it is cleared rapidly from the circulation, leaving a fewer HDL particles to participate in a reverse cholesterol transport from the vasculature.
• Thus, in the liver of insulin-resistant patients, FFA flux is high, TGs synthesis and storage are increased, and excess TG is secreted as VLDL.
• For the most part, it is believed that the dyslipidemia associated with insulin resistance is a direct consequence of increased VLDL secretion by the liver
• These anomalies are closely associatedwith an increased oxidative stress and an endothelial dysfunction, thereby reinforcing the proinflammatory nature of macrovascular atherosclerotic disease.

===Hypertension===.

• Insulin is a vasodilator under normal physiologic conditions with secondary effects on sodium reabsorption.
• In hyperinsulinemia and insulin resistance this vasodilatory effect of insulin is lost but the sodium reabsorption effect on the kidney is preserved.
• Hyperglycemia and hyperinsulinemia also activates the renin-angiotensin system (RAS) by increasing the expression of angiotensin receptors.
• There is also evidence that insulin resistance and hyperinsulinemia lead to sympathetic nervous system activation.
• As a result, the kidneys increase sodium reabsorption, the heart increases cardiac output, and arteries respond with vasoconstriction resulting in hypertension.

Endothelial Function

• It is characterized by an impaired endothelium-dependent vasodilatation, a reduced arterial compliance, and an accelerated process of atherosclerosis.
• Various factors like oxidative stress, hyperglycemia, advanced glycation products, FFAs, inflammatory cytokines, or adipokines cause an inability of endothelium to serve its normal physiological and protective mechanisms.
• Hansson has shown that immune cells play an important role in all the stages of the atherosclerotic process; in addition, a reduction in NO, a key regulator of endothelial homeostasis, and an increase in reactive oxygen species result in an endothelial dysfunction and a proatherogenic vascular bed.

Hypercoagulable State

• A proinflammatory state is characterized by elevated circulating cytokines and acute-phase reactants (e.g., CRP).
• Further, a prothrombotic state signifies anomalies in the procoagulant factors, that is, an increase in fibrinogen, factor VII and factor VIII as well as the antifibrinolytic factor (PAI-1), platelet abrasions, and endothelial dysfunctions.
• Grundy has shown that a fibrinogen, an acute-phase reactant protein like CRP, rises in response to a high-cytokine state.
• This shows that the prothrombotic and proinflammatory states may bemetabolically interconnected

Diet

• High dietary fat intake is associated with an oxidative stress and an activation of the proinflammatory transcription factor, that is, nuclear factor kappa-beta (NF𝜅B).
• In contrast, a diet rich in fruits and fibres has no inflammation-inducing capacity compared with a high-fat diet even if it has the same calories content.

Chronic Stress and Glucocorticoids

• Chronic hypersecretion of stress mediators, such as cortisol, in individuals with a genetic predisposition exposed to a permissive environment, may lead to the visceral fat accumulation as a result of chronic hypercortisolism, low growth hormone secretion, and hypogonadism.
• GCs increase the activities of enzymes involved in fatty acid synthesis and promote the secretion of lipoproteins; induce the hepatic gluconeogenic pathway; promote the differentiation of preadipocytes to adipocytes,which could lead to an increased body fat mass; inhibit an insulin-stimulated amino acid uptake by adipocytes and increase lipolysis or lipid oxidation which leads to the peripheral insulin resistance.
• A good correlation was observed between plasma cortisol levels, total urinary GC metabolites, and the number of features of the MetS among these patients.
• Both the secretion rate and the peripheral clearance of cortisol in these patients were positively correlated with the systolic blood pressure, and fasting glucose and insulin.
• These hormonal alterations may lead to a reactive insulin hypersecretion, an increasing visceral obesity, and sarcopenia, resulting in dyslipidemia, hypertension, and T2DM.