Title: ELVIS%20PRESLEY
1 2 3 4- What can they possibly have in common???
5 6Endogenous 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
7Diabetes Mellitus
- Diabetes Mellitus
- -occurs in 6 of all population
- -is a disease that affects people chronically
8Diabetes
- 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
-
9Diabetes
- Type 1 Diabetes
- -Child-onset diabetes
- -also termed Juvenile diabetes
- -immune-induced
- -defects in beta cells
- -an inability to produce insulin (or decreased
production)
10Diabetes
- 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
11Diabetes Complications
- In diabetic patient, endothelial dysfunction
result from - hyperglycemia our focus today
- Hyperglycemia increases oxidative stress and
carbonyl stress result diabetes complications
12FOUR 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
13AGE 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
14Link between Four Hypotheses
- Overproduction of superoxide by the mitochondrial
electron-transport chain
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16Oxidative 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
17Free radical formation by the body
18Increase in superoxide radical
19How does carbonyl stress fit into the picture?
20Increase in superoxide radical
21Endogenous 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
22Reactive 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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24Reactive 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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26- Increased reactive carbonyl from oxidative stress
and carbonyl stress eventually lead to tissue
damage
27Reactive carbonyls
28Summary
- 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.
29References
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