Syndrome X in Type2 Diabetes

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Syndrome - Xin Type-2 Diabetes

• Dr. K.A.SUDHARSHANA MURTHY
• and
• Dr. RAVISHANKAR SARGUR .B

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Definition
SYNDROME - X

• Refers to a complex interrelationship of
  metabolic abnormalities namely,

HYPERINSULINAEMIA
HYPERTENSION
GLUCOSE INTOLERANCE
DYSLIPIDAEMIA
CENTRAL OBESITY
that are associated with an increased risk of
coronary artery disease in type 2 DM.
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History
SYNDROME - X

• Concept of insulin resistance is more than 50 yrs
  old.
• Himsworth (in 1936 Lancet) wrote about
  subdivision of DM into Insulin sensitive and
  Insulin Insensitive.
• In 1960 RIA measured Insulin levels proved this
• Raevan ( Banting Oration, 1988) introduced the
  concept of IR

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SYNDROME - X
Synonyms

• Insulin Resistance Syndrome
• Reavens Syndrome
• Metabolic Syndrome
• Deadly Quartet
• CHAOS
• New World Syndrome
• Civilization Syndrome

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Prevalence
SYNDROME - X

• IRS is a common disorder
• 50 of Hypertensive patients are IR
• IR is common in elderly (25 in men at 75 yrs
  were IR)
• IR may also occur in childhood,
• low birth weight thinness at birth

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METABOLIC SEQUELAE OF EARLY NUTRITIONAL
DEPRIVATION
Maternal/Placental Abnormalities
Maternal malnutrition
Reduced placental blood flow
Reduced protein intake

• Fetal Malnutrition
• supply of aminoacids

Endocrinal Changes
Endocrinal Changes
Reduced Beta cell mass/function
Reduced fetal growth
SNS Catecholamines
Cortisol GH IGF
Postnatal malnutrition
Reduced adult beta cell mass or function
Food Abundance
Continuing protein deprivation in early infancy
MRDM
INSULIN RESISTANCE
HYPERTENSION
DYSLIPEDEMIA
NIDDM
SYNDROME X
Underlying hypothesis MRDM NIDDM Syndrome X
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INSULIN RESISTANCE - MECHANISMS
SYNDROME - X

• Pre receptor ( abnormal insulin or insulin
• antibodies)
• Receptor ( decreased receptor number or
  affinity)
• Postreceptor (abnormal signal transduction and
  phosphorylation)
• Glucose transporter ( decreased GLUT 4 molecule)

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IR Signaling defects
SYNDROME - X

• Elevated TNF alpha
• Elevated NEFA
• Reduced physical activity, aging
• Smoking
• Drug Therapy Cs Nico. A ?-B Th. Diu.
• Central Obesity
• Hyper-insulinemia

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OBESITY
SYNDROME - X

• Frequently associated with IR
• Wt. more than 35 - 40 of IBW declines Insulin
  sensitivity by 40

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OBESITY
SYNDROME - X

• IR is due to various factors
• ? Down-regulation of Insulin receptors
• ? Reduction in Glucose transporters (GLUT 4)
• ? Reduced sensitivity of insulin dependent
  enzymes like lipoprotein lipase
• ? Glycosylation of various proteins including
  receptors and enzymes

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OBESITY - PATIENT ASSESSMENT
SYNDROME - X

• It can be clinically suspected in
• - individuals who have abdominal obesity
• - a family history of type 2 DM
• - History of GDM
• - Hypertension with Dyslipidemia
• - Women with PCOS

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OBESITY Patient Assessment -Diagnosis Grading
SYNDROME - X

• For clinical purposes, three diagnostic
• methods are used
• BODY MASS INDEX - BMI
• SKIN FOLD THICKNESS
• BIO - IMPEDANCE ANALYSIS

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OBESITY - ASSESSMENT
SYNDROME - X
Modified WHO classification of overweight
Obesity

• CLASS BMI
• Normal range 18.50 - 24.99
• Grade 1 Overweight 25 - 29.99
• Grade 2a Overweight 30 - 34.99
• Grade 2b Overweight 35 - 39.99
• Grade 3 Overweight 40.00
• BMI wt (kg)/ height in meters.

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OBESITY - ASSESSMENT
SYNDROME - X

• SKIN FOLD THICKNESS
• 4 sites are used
• 2 sites for trunk - subscapsular supra-iliac
• 2 sites for periphery - Triceps Thigh
• INSTRUMENT USED HARPENDEN CALIPERS
• PERCENT OF BODY FAT IS CALCULATED AS DESCRIBED BY
  DUMIN WOMERSLE

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OBESITY - ASSESSMENT
SYNDROME - X

• Bio - Impedance Analysis
• Measures the electrical impedance of the body
  and computes total body water based on an
  in-built program. Further derivation of percent
  body fat and lean body mass is made from total
  body water.

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OBESITY - ASSESSMENT
SYNDROME - X

• Percent body fat
• Body fat ()
• Males Females
• Normal 12 - 20 20 - 30
• Borderline 21 - 25 31 - 33
• Obese gt 25 gt 33

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OBESITY - Body fat distribution
SYNDROME - X

• Distribution of body fat has great prognostic
• significance.
• Gynecoid pattern Fat accumulates in the
  lower body
• Android pattern Fat accumulates in the
• abdomen

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OBESITY - Body fat distribution
SYNDROME - X

• ABDOMINAL OBESITYis a better predictor of IR,
  DM, IGT
• Waist-to-Hip Ratio gt 1.0 for males gt 0.8 for
  females
• suggest abdominal obesity

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OBESITY - ASSESSMENT
SYNDROME - X

• Accurate measurement for research purpose
• - measurement of body density by under -
• water weighing
• - total body water by isotopic dilution
• techniques
• FOR ACCURATE EVALUATION OF VISCERAL FAT, a CT or
  MRI OF ABDOMEN IS REQUIRED

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SYNDROME - X

• ACANTHOSIS NIGRICANS ( AN ) IS A
• CLINICAL MARKER OF IR
• Velvety, mossy, verrucous, hyperpigmented
• skin change often found over the nape of the
• neck, in the axillae or beneath the breasts.
• IR is present in more than 90 of patients
• with AN

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EVALUATION OF INSULIN RESISTANCE (IR)
SYNDROME - X

• Hyperinsulinemic Euglycemic Clamp Study
• Excellent method of assessing IR but it is
• labor intensive and technically demanding.
• Fasting insulin concentrations more than 15
• micro U/ml. suggest IR

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CLINICAL CONSEQUENCES OF HYPERINSULINEMIA
SYNDROME - X

• HYPERTENSION
• DYSLIPEDIMIA
• OBESITY
• CORONARY ARTERY DISEASE(CAD)
• IMPAIRED GLUCOSE TOLERANCE DM 2

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INSULIN RESISTANCE HYPERTENSION
SYNDROME - X

• More than 50 of hypertensives are found to
• be Insulin Resistant and Hyper-insulinemic.
• IR and Hyperinsulinemia have been
• documented to be present even in lean
• Hypertensives who are not Diabetic

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Insulin Resistance and Hypertension Mechanisms
SYNDROME - X

• Hyperinsulinemia
• Produces renal sodium retention.
• Stimulates Sympathetic Nervous activity
• Vascular smooth muscle hypertrophy
  (mitogenic action of insulin)
• Endothelial dysfunction and decreased
  production of NO

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Insulin Resistance and Hypertension Mechanisms
SYNDROME - X
Hyperinsulinemia

• Modification of ion transport across the cell
  membrane - membrane defect hypothesis - increase
  in cytosolic calcium
• Augmentation of the pressor and aldosterone
  response to angiotensin II

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INSULIN RESISTANCE -DYSLIPIDEMIA
SYNDROME - X

• Characteristic pattern of lipid abnormality is
• Elevated Triglycerides
• Reduced HDL -C
• Normal or Slightly elevated LDL - C

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INSULIN RESISTANCE - DYSLIPIDEMIA
SYNDROME - X

• IR impairs the normal suppression of FFA
• release from adipose tissue in the post-prandial
• state. Increased FFA released from abdominal
• adipose tissue and delivered to the liver by
• portal circulation offers a substrate for
• increased synthesis of TG, a rate limiting step
• in the production of VLDL -C

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INSULIN RESISTANCE - DYSLIPIDEMIA
SYNDROME - X

• Hyperinsulinemia downregulates the activity of
• Lipoprotein lipase, an enzyme important for
• VLDL - C metabolism.

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IR DYSLIPIDEMIA LDL-C
SYNDROME - X
Characteristic Features

• Atherogenic Dyslipidemia- Pattern B
• Increased oxidation of LDL - C
• Glycated apolipoproteins are more susceptible
• to oxidation, thus increasing atherogencity
• Oxidised LDL - C
• causes endothelial dysfunction increase
• smooth muscle cell growth

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INSULIN RESISTANCE PCOS
SYNDROME - X

• Unique combination
• Chronic anovulation, hyperandrogenism,
• polycystic ovaries
• Affects 5 to 10 of premenopausal females
• Magnitude of IR is similar to type 2 DM
• May or may not be associated with central
• obesity
• Decreasing IR may induce ovulation

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INSULIN RESISTANCE CORONARY ARTEY DISEASE
SYNDROME - X

• - Helsinki policemen study
• - Quebec cardiovascular study

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HYPERINSULINEMIA CAD
SYNDROME - X

• Biological effects of insulin on arterial tissue
• Proliferation of smooth muscle cells
• Stimulation of growth factors
• Stimulation of connective tissue
• production

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HYPERINSULINEMIA CAD
SYNDROME - X

• Biological effects of insulin on arterial tissue
• Enhanced LDL receptor activity and
• cholesterol synthesis
• Increased formation and decreased
• regression of Lipid plaques

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HYPERINSULINEMIA CORONARY ARTERY DISEASE
SYNDROME - X

• IS IT
• INSULIN
• OR
• PROINSULIN SPLIT PRODUCTS ?

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HYPERINSULINEMIA CAD
SYNDROME - X
Conventional RIA overestimates Insulin due to
Insulin like molecule, namely Pro-insulin
32-33 split pro-insulin

• Newer technique - two site monoclonal
• antibody based assay have shown Proinsulin
• Split insulin comprise of major components
• of the circulating insulin in DM 2

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SYNDROME - X
HYPERINSULINEMIA CAD
The focus of attention has now shifted
from HYPER INSULINEMIA TO HYPER PRO
INSULINEMIA
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HYPERINSULINEMIA CAD
SYNDROME - X

• Nagi has shown a
• POSITIVE Correlation of concentrations of 32 -
  33 split proinsulin with triglycerides, total
  cholesterols, plasminogen activator inhibitor and
  with diastolic BP
• NEGATIVE Correlation with HDL - C

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INSULIN RESISTANCE CAD
SYNDROME - X

• OTHER MECHANISMS
• ENDOTHELIAL DYSFUNCTION
• Reduced Nitric oxide
• ATTENUATION OF NORMAL FIBRINOLYSIS
• Elevated Plasminogen activator Inhibitor-1
• Elevated Fibrinogen
• Von Willebrand factor
• Factor X

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IR HYPERINSULINEMIA IGT DM 2
SYNDROME - X

• INSULIN RESISTANCE
• BETA CELL HYPER FUNCTION
• HYPER INSULINEMIA NORMAL BLOOD
  GLUCOSE
• BETA CELL FAILURE
• INSULOPENIA
• IGT DIABETES MELLITUS 2

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MANAGEMENT STRATEGIES
SYNDROME - X

• Need for screening
• Holistic, Individualized treatment
• Life style modifications
• Drug therapy
• To improve Insulin sensitivity
• Metformin, Troglitazone

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VASCULAR ENDOTHELIUM
SYNDROME - X

• They generate Angiotensin II and NO, balance of
  which maintain vessel function and structure.
  Imbalance results in atherosclerosis, cardiac
  failure and hypertension

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VASCULAR ENDOTHELIUM
SYNDROME - X

• NITRIC OXIDE ANGIOTENSIN II
• Vasodilator - Vasoconstriction
• Anti-thrombotic - Pro-thrombotic
• Anti-inflammatory - Pro-inflammatory
• Growth-Inhibitor - Growth-Promotor
• Anti-Oxidant - Pro-Oxidant
• Anti-Atherogenic - Pro-Atherogenic

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SYNDROME - X PLUS
SYNDROME - X

• Micro - Vascular Angina
• Glaucoma,
• Central vein thrombosis,
• Hyperuricemia,
• Microalbuminuria