ELVIS ELVIS PRESLEYPRESLEY

MISS MISS

AMERICA AMERICA

19981998

ELIZABETH ELIZABETH

TAYLORTAYLOR

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

Diabetes Diabetes MellitusMellitus

Endogenous Toxins Endogenous Toxins Formed By DiabetesFormed By Diabetes

Cecilia Liu: Cecilia Liu: cecilia_city@yahoo.cacecilia_city@yahoo.ca

Kathy Xie: Kathy Xie: k.xie@utoronto.cak.xie@utoronto.ca

Rosanna Yan: Rosanna Yan: rosannayan@gmail.comrosannayan@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

Free radical formation by the body

Increase in superoxide radical

How does carbonyl stress fit into the picture?

Increase in superoxide radical

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

Reactive carbonyls

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