1. ELVIS PRESLEY

2. MISSAMERICA1998

3. ELIZABETHTAYLOR

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

5. Diabetes Mellitus

6. Endogenous Toxins Formed By Diabetes Cecilia Liu: cecilia_city@yahoo.ca cecilia_city@yahoo.ca Kathy Xie: k.xie@utoronto.ca k.xie@utoronto.ca Rosanna Yan: rosannayan@gmail.com rosannayan@gmail.com PHM226 Wednesday February 15 th, 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. glucoseblood plasmaglucoseblood 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 ->producing ROS (reactive oxygen species) -> undesirable changes in gene expression

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

16. Oxidative Stress in Diabetes Reactive Oxygen Species (ROS) - O 2 * superoxide -OH* hydroxyl -RO 2 peroxyl -HRO 2 hydroperoxyl -H 2 O 2 hydrogen peroxide -HOCl hypochlorite Reactive Nitrogen Species (RNS) - NO* nitric oxide -ONOO- peroxynitrite -NO 2 * nitrogen dioxide -HNO 2 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

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).

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