ELVIS%20PRESLEY

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• ELVIS PRESLEY

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• MISS
• AMERICA
• 1998

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• ELIZABETH
• TAYLOR

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• What can they possibly have in common???

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• Diabetes Mellitus

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Endogenous Toxins Formed By Diabetes

• Cecilia Liu cecilia_city_at_yahoo.ca
• Kathy Xie k.xie_at_utoronto.ca
• Rosanna Yan rosannayan_at_gmail.com
• PHM226
• Wednesday February 15th, 2006

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Diabetes Mellitus

• Diabetes Mellitus
• -occurs in 6 of all population
• -is a disease that affects people chronically

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Diabetes

• Diabetes is a condition in which an excessive
  amount of glucose circulates in the blood plasma.
• All forms of diabetes are characterized by
  hyperglycemia
• Type 1 and Type 2 Diabetes

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Diabetes

• Type 1 Diabetes
• -Child-onset diabetes
• -also termed Juvenile diabetes
• -immune-induced
• -defects in beta cells
• -an inability to produce insulin (or decreased
  production)

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Diabetes

• Diabetes Type 2
• -Non-insulin dependent Diabetes
• - Adult-onset diabetes
• -genetic environmental factor - a major player
• -caused by a defect in target-response to take up
  insulin when present

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Diabetes Complications

• In diabetic patient, endothelial dysfunction
  result from
• hyperglycemia our focus today
• Hyperglycemia increases oxidative stress and
  carbonyl stress result diabetes complications

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FOUR MAIN HYPOTHESES

• Four main hypotheses for mechanisms of
  hyperglycemia induced damage
• 1) increased polyol pathway flux
• 2) increased advanced glycation end product (AGE)
  
• 3) activation of protein kinase C (PKC) isoforms
• 4) increased hexosamine pathway flux

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AGE hypothesis

• AGE is produced from reactive carbonyls such as
  glyoxal and methylglyoxal.
• AGE precursors damage cells
• 1) modified proteins - show altered functions
• 2) modified extracellular matrix component -
  show abnormal interactions
• 3) modified plasma proteins -gtproducing ROS
  (reactive oxygen species) -gt undesirable changes
  in gene expression

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Link between Four Hypotheses

• Overproduction of superoxide by the mitochondrial
  electron-transport chain

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Oxidative Stress in Diabetes Reactive Oxygen
Species (ROS) -O2 superoxide -OH hydroxyl -RO2
peroxyl -HRO2 hydroperoxyl -H2O2 hydrogen
peroxide -HOCl hypochlorite Reactive Nitrogen
Species (RNS) -NO nitric oxide -ONOO-
peroxynitrite -NO2 nitrogen dioxide -HNO2
nitrous oxide -RONOO alkyl peroxynitrates
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Free radical formation by the body
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Increase in superoxide radical
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How does carbonyl stress fit into the picture?
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Increase in superoxide radical
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Endogenous Toxins

• Elevated glucose/carbohydrates result in
  increased production of glyoxal and methylglyoxal
• Glyoxal and methylglyoxal produce advanced
  glycation end-products (AGE)
• Increased levels of AGE correlate with
  pathogenesis of diabetes mellitus

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Reactive Carbonyl - Glyoxal

• Formed by the autoxidation of ene-diol tautomer
  of glycoaldehyde by ROS (reaction is catalyzed by
  transition metals)
• The most reactive carbonyls even at low
  concentration because they cross-link
  proteins,glycate proteins, form AGE, and
  inactivate enzymes

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Reactive Carbonyl - Methylglyoxal

• Formed from xylitol, ribose, and deoxyribose by
  the pentose phosphate pathway
• Fragmentation of triose phosphates result in
  methylglyoxal-derived AGE
• Triose phosphate levels increase because of the
  inhibition of GAPDH (glyceraldehyde-3-phosphate
  dehydrogenase) by mitochondrial over production
  of reactive oxygen species (ROS).

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• Increased reactive carbonyl from oxidative stress
  and carbonyl stress eventually lead to tissue
  damage

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Reactive carbonyls
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Summary

• Hyperglycemia leads to increased oxidative and
  carbonyl stress (endogenous toxins).
• Increased oxidative stress is due to increased
  production of ROS.
• Increased carbonyl stress is due to increased
  glyoxyl and methylglyoxyl.
• Increased endogenous toxins lead to pathogenesis
  of diabetes.

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References
Special thanks to Nandita Shangari- PhD student
Faculty of Pharmacy-Toronto

• Baynes JW, Thorpe SR Role of Oxidative Stress
  in Diabetic Complications- A new perspective in
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• Bralley JA, Lord RS Organic Acids in Urine.
  Laboratory Evaluations in Molecular medicine.
  www.metametrix.com
• Brownlee M Biochemistry and Molecular Cell
  Biology of diabetic complications. Nature 414
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• Johansen JS, Harris AK, Rychly DJ, Ergul A
  Oxidative Stress and the use of antioxidants in
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  practice. Cardiovascular Diabetology 4 1-11,
  2005
• Gonelle-Gispert C, Halban PA, Neimann H, Palmer
  M, Catsicas S, Sadoul K SNAP-25a and -25b
  isoforms are both expressed in insulin-secreting
  cells and can function in insulin secretion.
  Biochem J 339 159-165, 1999.
• OBrien PJ, Siraki AG, Shangari N Aldehyde
  sources, metabolism, molecular toxicity
  mechanisms, and possible effects on human health.
  Critical Reviews in Toxicology 35 609-662, 2005.
• Yu, PH Semicarbazide-sensitive amine oxidase and
  mortality in chronic heart failure. European
  Heart Journal 211812-1814, 2000