elvis presley. missamerica1998 elizabethtaylor what can they possibly have in common???
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Endogenous Toxins Endogenous Toxins Formed By DiabetesFormed By Diabetes
Cecilia Liu: Cecilia Liu: [email protected][email protected]
Kathy Xie: Kathy Xie: [email protected]@utoronto.ca
Rosanna Yan: Rosanna Yan: [email protected]@gmail.com
PHM226PHM226
Wednesday February 15Wednesday February 15thth, 2006, 2006
Diabetes MellitusDiabetes Mellitus
►Diabetes MellitusDiabetes Mellitus
-occurs in 6% of all population-occurs in 6% of all population
-is a disease that affects people -is a disease that affects people chronicallychronically
DiabetesDiabetes
► DiabetesDiabetes is a condition in which an excessive is a condition in which an excessive amount of amount of glucoseglucose circulates in the circulates in the blood plasmablood plasma..
► All forms of diabetes are characterized by All forms of diabetes are characterized by hyperglycemiahyperglycemia
► Type 1 and Type 2 DiabetesType 1 and Type 2 Diabetes
DiabetesDiabetes
Type 1 Diabetes:Type 1 Diabetes:
-Child-onset diabetes-Child-onset diabetes
-also termed Juvenile diabetes-also termed Juvenile diabetes
-immune-induced -immune-induced
-defects in beta cells-defects in beta cells
-an inability to produce insulin (or -an inability to produce insulin (or decreased production)decreased production)
DiabetesDiabetes
►Diabetes Type 2Diabetes Type 2
-Non-insulin dependent Diabetes-Non-insulin dependent Diabetes
- “Adult-onset diabetes”- “Adult-onset diabetes”
-genetic + environmental factor - a -genetic + environmental factor - a major playermajor player
-caused by a defect in target-response -caused by a defect in target-response to take up insulin when presentto take up insulin when present
Diabetes – ComplicationsDiabetes – Complications
► In diabetic patient, endothelial In diabetic patient, endothelial dysfunction result from:dysfunction result from:
hyperglycemia hyperglycemia –our focus today–our focus today►Hyperglycemia increases oxidative Hyperglycemia increases oxidative
stress and carbonyl stress – result: stress and carbonyl stress – result: diabetes complicationsdiabetes complications
FOUR MAIN FOUR MAIN HYPOTHESES HYPOTHESES
Four main hypotheses for Four main hypotheses for mechanisms of hyperglycemia mechanisms of hyperglycemia induced damage:induced damage:
1) increased polyol pathway flux 1) increased polyol pathway flux 2) 2) increased advanced glycation increased advanced glycation
end product (AGE)end product (AGE) 3) activation of protein kinase C (PKC) 3) activation of protein kinase C (PKC)
isoformsisoforms4) increased hexosamine pathway flux 4) increased hexosamine pathway flux
AGE hypothesisAGE hypothesis► AGE is produced from reactive carbonyls AGE is produced from reactive carbonyls
such as glyoxal and methylglyoxal.such as glyoxal and methylglyoxal.
► AGE precursors damage cells:AGE precursors damage cells:1) modified proteins - show altered functions1) modified proteins - show altered functions2) modified extracellular matrix component - 2) modified extracellular matrix component - show abnormal interactionsshow abnormal interactions3) modified plasma proteins ->producing 3) modified plasma proteins ->producing ROS (reactive oxygen species) -> ROS (reactive oxygen species) -> undesirable changes in gene expressionundesirable changes in gene expression
Link between Four Link between Four HypothesesHypotheses
►Overproduction of superoxide by the Overproduction of superoxide by the mitochondrial electron-transport chainmitochondrial electron-transport chain
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
Endogenous ToxinsEndogenous Toxins
►Elevated glucose/carbohydrates result Elevated glucose/carbohydrates result in increased production of glyoxal and in increased production of glyoxal and methylglyoxalmethylglyoxal
►Glyoxal and methylglyoxal produce Glyoxal and methylglyoxal produce advanced glycation end-products advanced glycation end-products (AGE)(AGE)
► Increased levels of AGE correlate with Increased levels of AGE correlate with pathogenesis of diabetes mellituspathogenesis of diabetes mellitus
Reactive Carbonyl - GlyoxalReactive Carbonyl - Glyoxal
►Formed by the autoxidation of ene-diol Formed by the autoxidation of ene-diol tautomer of glycoaldehyde by ROS tautomer of glycoaldehyde by ROS (reaction is catalyzed by transition (reaction is catalyzed by transition metals)metals)
►The most reactive carbonyls even at The most reactive carbonyls even at low concentration because they cross-low concentration because they cross-link proteins,glycate proteins, form link proteins,glycate proteins, form AGE, and inactivate enzymesAGE, and inactivate enzymes
Reactive Carbonyl - Reactive Carbonyl - MethylglyoxalMethylglyoxal
► Formed from xylitol, ribose, and deoxyribose Formed from xylitol, ribose, and deoxyribose by the pentose phosphate pathwayby the pentose phosphate pathway
► Fragmentation of triose phosphates result in Fragmentation of triose phosphates result in methylglyoxal-derived AGEmethylglyoxal-derived AGE
► Triose phosphate levels increase because of Triose phosphate levels increase because of the inhibition of GAPDH (glyceraldehyde-3-the inhibition of GAPDH (glyceraldehyde-3-phosphate dehydrogenase) by mitochondrial phosphate dehydrogenase) by mitochondrial over production of reactive oxygen species over production of reactive oxygen species (ROS).(ROS).
► Increased reactive carbonyl from Increased reactive carbonyl from oxidative stress and carbonyl stress oxidative stress and carbonyl stress eventually lead to tissue damageeventually lead to tissue damage
SummarySummary
►Hyperglycemia leads to increased Hyperglycemia leads to increased oxidative and carbonyl stress oxidative and carbonyl stress (endogenous toxins).(endogenous toxins).
► Increased oxidative stress is due to Increased oxidative stress is due to increased production of ROS.increased production of ROS.
► Increased carbonyl stress is due to Increased carbonyl stress is due to increased glyoxyl and methylglyoxyl.increased glyoxyl and methylglyoxyl.
► Increased endogenous toxins lead to Increased endogenous toxins lead to pathogenesis of diabetes.pathogenesis of diabetes.
ReferencesReferences
- Baynes JW, Thorpe SR: Role of Oxidative Stress in Diabetic Complications- A new perspective in an Old Baynes JW, Thorpe SR: Role of Oxidative Stress in Diabetic Complications- A new perspective in an Old Paradigm. Diabetes 48: 1-7, 1999.Paradigm. Diabetes 48: 1-7, 1999.
- Bralley JA, Lord RS: Organic Acids in Urine. Laboratory Evaluations in Molecular medicine. Bralley JA, Lord RS: Organic Acids in Urine. Laboratory Evaluations in Molecular medicine. www.metametrix.com www.metametrix.com
- Brownlee M: Biochemistry and Molecular Cell Biology of diabetic complications. Nature 414: 813-820, Brownlee M: Biochemistry and Molecular Cell Biology of diabetic complications. Nature 414: 813-820, 2001.2001.
- Johansen JS, Harris AK, Rychly DJ, Ergul A: Oxidative Stress and the use of antioxidants in diabetes: 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, 2005Linking 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 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-are both expressed in insulin-secreting cells and can function in insulin secretion. Biochem J 339: 159-165, 1999. 165, 1999.
- O’Brien PJ, Siraki AG, Shangari N: Aldehyde sources, metabolism, molecular toxicity mechanisms, and O’Brien 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.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 Yu, PH: Semicarbazide-sensitive amine oxidase and mortality in chronic heart failure. European Heart Journal 21:1812-1814, 2000Journal 21:1812-1814, 2000
Special thanks to Nandita Shangari- PhD student –Faculty of Pharmacy-Toronto