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ELVIS PRESLEY MISS AMERICA 1998 ELIZABETH TAYLOR What can they possibly have in common??? Diabetes Mellitus Endogenous Toxins Formed By Diabetes Cecilia Liu: cecilia_city@yahoo.ca Kathy Xie: k.xie@utoronto.ca Rosanna Yan: rosannayan@gmail.com PHM226

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Presentation Transcript
slide2
MISS

AMERICA

1998

endogenous toxins formed by diabetes

Endogenous Toxins Formed By Diabetes

Cecilia Liu: cecilia_city@yahoo.ca

Kathy Xie: k.xie@utoronto.ca

Rosanna Yan: rosannayan@gmail.com

PHM226

Wednesday February 15th, 2006

diabetes mellitus
Diabetes Mellitus
  • Diabetes Mellitus

-occurs in 6% of all population

-is a disease that affects people chronically

diabetes
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
diabetes9
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)

diabetes10
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

diabetes complications
Diabetes – Complications
  • In diabetic patient, endothelial dysfunction result from:

hyperglycemia –our focus today

  • Hyperglycemia increases oxidative stress and carbonyl stress – result: diabetes complications
four main hypotheses

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

age hypothesis
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 ->producing ROS (reactive oxygen species) -> undesirable changes in gene expression

link between four hypotheses
Link between Four Hypotheses
  • Overproduction of superoxide by the mitochondrial electron-transport chain
slide16

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 toxins
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
reactive carbonyl glyoxal
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
reactive carbonyl methylglyoxal
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).
slide26
Increased reactive carbonyl from oxidative stress and carbonyl stress eventually lead to tissue damage
summary
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.
references
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.
  • 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.
  • Yu, PH: Semicarbazide-sensitive amine oxidase and mortality in chronic heart failure. European Heart Journal 21:1812-1814, 2000