Supplementary Information to Chapter 24

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METABOLIC SYNDROME (METS)

What is metabolic syndrome?
A syndrome of insulin resistance
Metabolic consequences of obesity
Risk factor for CVD
A lifestyle disease
Ameliorated by adopting a healthy lifestyle
The term was coined by Gerald Reaven in 1988.
Initially named as Syndrome X and then renamed as metabolic syndrome.
Obesity was not included in Reavens definition. He included the following criteria:
Impaired glucose tolerance
Hyperinsulinemia
Hypertriglyceridemia
Decreased HDL-C
Coronary vascular disease (CVD)
Diabetes mellitus Type 2 (DMT2)
Hypertension
Based on epidemiologic studies, WHO described it as a measure of insulin resistance (IR) characterized by
Impaired fasting glucose (IFG)/Impaired glucose tolerance (IGT) (There was controversy regarding the yardstick
used to assess IR)
Obesity (BMI >30 kg/m2)
Hypertension (140/90 mms of Hg or more)
Microalbuminuria
It was suggested that waist/hip ratio and waist circumference (WC) are better markers and are to be included in the
criteria. In 1999, European Group renamed syndrome X as insulin resistance syndrome and excluded patients with DM
T2. They gave a new definition including WC and plasma lipid levels.

EGIR Criteria for IR Syndrome

A fasting glucose level above the 75th percentile for the population
Obesity based on a WC of 94 cms (37) for men and 80 cms (32) for women
Hypertension 140/90 or more
Dyslipidemia; TAG 180 mg/dl or more (2 mmol/L)
HDL-C <39 mg/dl (1 mmol/L)

In 2001, NCEP-ATPIII reassigned the title of Metabolic Syndrome (MetS) and prescribed the diagnosis of the condition,
when any three of the following criteria are combined in an individual:
Obesity -WC >102 cms for males and > 88 cm for females
Hypertension-130/85 or more
FPG->110 mg/dl
TAG-> 150 mg/dl
HDL-C <40 mg/dl for men and < 50mg/dl for women
Waist circumference as a measure of obesity and not as an element of Met-S
In 2003, American Association of clinical endocrinologists (AACE) renamed the disorder insulin resistance syndrome.
According to them the syndrome included a group of abnormalities associated with

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Insulin resistance, IGT but not frank DM
Abnormal uric acid metabolism
Dyslipidemia
Hemodynamic changes (BP)
Prothrombotic and inflammatory markers leading to endothelial dysfunction

Persons at risk were defined as those with

BMI >25 kg/m2
WC >40 in males and 35 in females
Known CVD, Hypertension, PCOS, NAFLD
Family history of Type2 DM and hypertension, CVD and GDM
Sedentary lifestyle in those aged >40 years
New criteria were introduced in 2005 by International Diabetes Federation
BMI > 30 kg/m2
If less than 30, ethnic specific WC >90 for males and >80 for females of South Asian origin
FPG >100 mg/dl
TAG >150 mg/dl
HDLC <40 in males and <50 in females
Systolic BP 130 or more and Diastolic 85 or more

Present Harmonized Criteria

Elevated WC (population and country specific)
Elevated TAG > or = 150 mg/dl (1.7 mmol/L)
Low HDL-C for Men < 40 mg/dl (1mmol/L) and Women < 50 mg/dl (1.3 mmol/L)
Hypertension; Systolic BP >130 and Diastolic > 85 mm of Hg
Elevated FPG >100 mg/dl
The Present Criteria is that a combination of any three of the following as per harmonised criteria is taken as metabolic
syndrome
Increased WC
Increased TAG and decreased HDL-C
Increased blood pressure
Increased fasting plasma glucose
WC is a crucial component of MetS
Metabolic syndrome begins with central obesity
While the prevalence was about 35% in US, it is 20% in urban India
As age advances, prevalence increases
World wide highest in white males and lowest in African American males
Western diet increases the risk in Asians. Arabs living in West have higher prevalence than those living in Middle East

Insulin Resistance is a Link between other Components of the Disease

Contributing factors for MetS -Well defined
Lifestyle
Obesity
Disorders of adipose tissue
Physical inactivity
Diet

Supplementary Information to Chapter 24

Contributing factors- Not so well connected; but have a role
Insulin receptor signaling abnormalities
Inflammatory cascades
Mitochondrial dysfunction
Adipose tissue derived hormones
Endocannabinoid receptors

Pathogenesis of IR
Well-known fact -1:
Pancreatic beta cells release insulin in response to glucose stimulation.
Increased uptake and metabolism of glucose by insulin dependent tissues (Muscle and adipose tissue)
Suppression of gluconeogenesis, decreased hepatic glucose output
Well-known fact -2:
GLUT4 is regulated by insulin
Insulin mobilizes GLUT4 from intracellular storage vesicles
GLUT4 fuses with membrane and entraps glucose within cells
Major regulatory step in insulin dependent glucose uptake and synthesis of glycogen in muscle
GLUT4 decreases in adipocytes in old age, obesity and Type 2 DM
In skeletal muscle GLUT4 is not decreased, but found to be dysfunctional
Exercise and adiponectin increases expression of GLUT4
Increases insulin sensitivity
Well-known fact -3:
Manifestations of insulin resistance
Initial loss of immediate postprandial response to insulin
Postprandial hyperglycemia results
Exaggerated second phase response over a period of time
Chronic hyperinsulinemia
Resistance to action of insulin
Well-known fact -4:
Visceral adiposity is independently associated with IR
Classic dyslipidemia seen in IR
Lower HDL-C levels
Higher apolipoprotein B
Increase in TAG and small dense LDL

Cellular Level Signaling by Insulin

Insulin binds to alpha subunit of its receptor

Tyrosine kinase pathway is activated
Receptor substrates and adaptor proteins are phosphorylated on tyrosine residues
Form docking sites for down stream effectors

Which are the downstream effector pathways?

Two major pathways
PI3 Kinase pathway is responsible for metabolic effects
MAP kinase pathway is responsible for growth and mitogenesis

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In PI3 kinase pathway, phosphorylated IRS substrates interact with a regulatory subunit of PI3K
This leads to increased synthesis of PI3 (Inositol-3,4,5-phosphate)
Downstream kinases (Akt) binds to PIP3 and gets activated
Akt (Protein Kinase B) mediates the effects of insulin on glucose transport, storage, protein synthesis and inhibition
of lipolysis
Some metabolic effects of insulin are exerted through phosphorylation of transcription factors (TF) by Akt.
Phosphorylation leads to sequestration of these TF in cytoplasm. Nonactivation of gluconeogenic genes.
Gluconeogenesis suppressed.

Role of AMP Kinase

AMP kinase acts as a metabolic master switch that responds to cellular energy level.
AMPK activates catabolic processes that produce energy like fatty acid oxidation and inhibits lipogenesis and TAG
synthesis.
Promotes muscular glucose uptake.
Modulates insulin secretion by beta cells.

Role of AMPK in IR
Defects or disuse of AMPK signaling system in DMT2
Sedentary lifestyle contributes to these defects
Regular exercise is known to recruit AMPK which may be able to correct the metabolic perturbations resulting from
defective insulin signaling
Provides a therapeutic target
Metformin stimulates AMPK
Decreases hepatic glucose output
Inhibits lipogenic genes
Glucose uptake by skeletal muscle is increased

Adipose Tissue derived Hormones (Leptin, Adiponectin and Resistin)

Leptin secretion depends on the energy stores

Leptin talks to the hypothalamus and acts as a satiety signal
Adiponectin increases insulin sensitivity
Resistin produces more IR
PPAR Gamma (Glitazone receptor) is found in insulin responsive tissues
PPARG stimulates fatty acid storage, adipocyte differentiation and glucose metabolism
PPARG activates PON1 gene and increases paraoxonase activity (antiatherogenic)
Increases adiponectin secretion
Transcription of PPAR gamma promoter gene is repressed. Insulin mediated effects on glucose and lipid metabolism
are affected
PPARG agonists enhance insulin sensitivity causing derepression of GLUT4 genes

Abnormal Metabolic Effects of IR

1. Hyperinsulinemia leads to serine phosphorylation of IRS and prevention of tyrosine phosphorylation
2. TNF alpha increases and decreases PI3K activity
3. Genetic defects in Akt has been shown to induce IR

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4.
5.
6.
7.
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Increased activation of some transcription factors by defective phosphorylation

Increased expression of gluconeogenic genes
Induction of expression of lipogenic TFs (SREBP1)
Increased expression of lipogenic genes
Increase in VLDL secretion

Effects of NEFA (Non Esterified Fatty Acids)

Major source of energy under conditions of fasting
Obesity increases NEFA in spite of high insulin levels
FFA interferes with insulin signaling cascade leading to IR. Negative downstream effects lead to dyslipidemia (High
TAG pool)
Excess FFA in skeletal muscle and liver contributes to IR. The resultant metabolic effects are:
Increase in diacylglycerol (DAG)
Serine phosphorylation of IRS
Defective insulin signaling
Increased gluconeogenesis and accentuation of hyperglycemia
Increase in hepatic glucose output- NAFLD

Effects of NEFA on other Plasma Lipids

VLDL production increased

Increase in TAG pool
Increase in apolipoprotein B
Formation of small dense LDL
HDL-C is decreased
NEFA increases the exchange of VLDL for HDL and increase in hepatic lipase activity causing increased degradation
of HDL

Other Effects of FFA

Endothelial dysfunction
Beta cell apoptosis
Increased production of inflammatory CKs like TNF alpha and IL-1B by macrophages in adipose tissue
Increased oxidative stress
Activation of proinflammatory genes

Role of Anxiety and Stress

Endocannabinoid system (ECS) regulates appetite, energy homeostasis, emotions like anxiety and fear and eating
behavior
Endocannabinoids bind to cannabinoid receptor (CB1)
ECS is overactivated in presence of abdominal obesity or DM
Rimonabant, a CB1 antagonist was used as an anti-obesity drug based on this principle
Chronic stress leads to co-elevation of insulin and cortisol, which leads to metabolic stress and abdominal obesity

Molecular Defects
Increase in TNF alpha and inhibition of NFkB
Decreased expression of endothelial NOS

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Decreased expression of OXPHOS genes

Increased production of ROS, ER stress and decreased half-life of NO
Decreased expression of PPAR gamma coactivator complexes
Decreased mitochondrial biogenesis
Increased response to cellular stress
Central appetite stimulation
Decreased exercise capacity
Low hepatic ATP due to impaired mitochondrial function
Increased fatigability
All the above factors contribute to activation of proinflammatory genes by the various dysregulated transcription
factors leading to a self-perpetuating cycle of upregulation of inflammatory cytokines and inadequate utilization of
energy.

Recent WHO report states that

MetS should not be a clinical diagnosis
It is a pre-morbid condition
Should exclude individuals with established DMT2 and CVD

Metabolically Healthy Obesity (MHO)

Insulin resistance is the fundamental characteristic of obesity
But there are insulin sensitive obese individuals; they are designated as MHO
Metabolically normal and abnormal is assessed, based on SSPG (Steady state plasma glucose during insulin
suppression test)

SSPG Criteria of IR
Most insulin sensitive 61 + or- 2 mg/dl
Intermediate - 114 + or- 2 mg/dl
Most insulin resistant-214+or- 2 mg/dl

SSPG Concentration Varies Widely at any given BMI and WC

Higher the BMI, increase in TAG and decrease in HDL-C
IR group had higher TAG and lower HDL-C at any given BMI

Inter-relation of MetS with MI and Stroke

IR and other components (except WC) of MetS are independent risk factors for or predictors of MI
High WC may have an indirect effect through other components
Regional distribution of fat; abdominal obesity is more dangerous
Good correlation between BMI and WC regardless of age and sex

The Clinical Perspective

Individuals with MetS to be identified so that their risk factors can be modified
Individuals with DMT2 with any major CVD risk factor are to be treated
MetS has a positive correlation with both CVD and DMT2

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MetS confers a higher risk to CVD and DMT2, with or without obesity
BMI and WC were both strongly linked to CVD and DMT2-A world wide study in 63 countries
Any combination of IFG with any 2 of the other criteria for MetS increases the relative risk (RR) from 8.2 to 10.7
A modest degree of risk clustering reflects an underlying IR
Lifestyle modifications should be attempted immediately

MetS A Pediatric Perspective

Few age specific studies are available; but there is a high prevalence
MetS is a progressively developing entity
Full fledged MetS cannot be diagnosed in childhood
Tendency for obesity and MetS in childhood is related to MetS in adulthood
Met S should not be diagnosed in children below 10 yrs

IDF Definition of Pediatric MetS

1016 yrs Abdominal adiposity (WC) and any two of the adult criteria
WC -90th percentile of adult cut off value
Ethnic and country specific values are to be obtained

Adolescent MetS
Pubertal children had a higher prevalence of MetS than prepubertal population
Children and adolescents with MetS have a higher risk of developing MetS, DMT2 and subclinical atherosclerosis
in adult life
BMI alone is a reliable measure of identifying youth at risk
Hyperinsulinemia and insulin resistance are seen
Increased transcription of lipogenic genes in liver
Increased VLDL production
Hypertriglyceridemia
Intrahepatic fat accumulation, leading to nonalcoholic fatty liver disease (NAFLD)
NASH is increasingly recognized in obese children

Two Hit Hypothesis

First hit
IR Abnormal lipid storage Increased flux of FFA from adipose tissue NAFLD
Second hit
Oxidative stress Activates inflammatory cytokines like TNF alpha Generates more ROS
NAFLD in obese youth is an important CVD risk factor

Conclusion and Summary

Understanding of MetS is essential because of
1. Significant impact on health in young adults
2. High financial implications
3. Novel therapeutic strategies may be derived
4. Constant review to develop uniform clinical criteria

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5. More epidemiological studies in different populations may be helpful

6. The present harmonized criteria is most suited for clinical use
7. More validation required in pediatric population.
Emphasis on a healthy lifestyle and weight maintenance are more effective.
A healthy lifestyle focusing on established risk factors.

BIBLIOGRAPHY
Medical clinics of North America Obesity
Pediatric Clinics of North Ameria Endcorinology
Reagen s Review of Metabolic Syndrome in Journal of Internal Meidicine-2011