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ELVIS%20PRESLEY

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Endogenous Toxins ... leads to increased oxidative and carbonyl stress (endogenous toxins) ... Increased endogenous toxins lead to pathogenesis of diabetes. References ... – PowerPoint PPT presentation

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Title: ELVIS%20PRESLEY


1
  • ELVIS PRESLEY

2
  • MISS
  • AMERICA
  • 1998

3
  • ELIZABETH
  • TAYLOR

4
  • What can they possibly have in common???

5
  • Diabetes Mellitus

6
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

7
Diabetes Mellitus
  • Diabetes Mellitus
  • -occurs in 6 of all population
  • -is a disease that affects people chronically

8
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

9
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)

10
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

11
Diabetes Complications
  • In diabetic patient, endothelial dysfunction
    result from
  • hyperglycemia our focus today
  • Hyperglycemia increases oxidative stress and
    carbonyl stress result diabetes complications

12
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

13
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

14
Link between Four Hypotheses
  • Overproduction of superoxide by the mitochondrial
    electron-transport chain

15
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16
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
17
Free radical formation by the body
18
Increase in superoxide radical
19
How does carbonyl stress fit into the picture?
20
Increase in superoxide radical
21
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

22
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

23
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24
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).

25
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26
  • Increased reactive carbonyl from oxidative stress
    and carbonyl stress eventually lead to tissue
    damage

27
Reactive carbonyls
28
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.

29
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
    an Old Paradigm. Diabetes 48 1-7, 1999.
  • 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
    813-820, 2001.
  • Johansen JS, Harris AK, Rychly DJ, Ergul A
    Oxidative Stress and the use of antioxidants in
    diabetes Linking basic science to clinical
    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
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