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.
• Regardless of the relative contributions of visceral fat and abdominal subcutaneous fat to insulin resistance, a pattern of abdominal (or upper body) obesity correlates more strongly with the insulin resistance and the MetS than does lower body obesity.
• 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