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ÂŤOxidative stress: the common pathogenetic factor between insulin resistance, diabetes mellitus and cardiovascular diseaseÂť

Antonio Ceriello EASD 2004

Chair of Internal Medicine University of Udine Udine, Italy


Ă&#x;-cell Function (%)

Glycemia (mg/dL)

From Insulin Resistance to Diabetes 350 300 250 200 150 100 50

Post-Meal Glucose Fasting Glucose

Impaired 1st phase insulin secretion

250 200 150 100 50 0

Ins Res

IGT

Reduced Insulin Secretion

Diabetes

Cardiovascular Disease Microvascular Disease Years

-10

-5

0

5

10

15

20

25

30


Food Fats

Acetyl-CoA

Beta-oxidation

Acetyl-CoA

glycolysis

Glucose


DmH+

e-

IV

III

Q+

Cyt C

e-

II

ATP syntase

I

H+

e-

eNADH

FAD

FADH2

O2•-

O2

NAD+

Acetyl-CoA

H2O

O2 ATP

ADP+Pi


DmH+

e-

Q+

IV

III

Cyt C

e-

II

ATP syntase

I

H+

e-

eNADH

FAD

FADH2

O2•-

O2

H2O

NAD+

Acetyl-CoA Overload

O2 ATP

ADP+Pi


High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase Cdependent activation of NAD(P)H oxidase in cultured vascular cells. Inoguchi T et al. Smooth muscle cells

10 8 6 4 2 0 Control

High glucose

Control

Palmitate

Diabetes 2000


Protection Against Oxidative StressInduced Insulin Resistance in Rat L6 Muscle Cells and Humans by aLipoic Acid

50

Basal

40 30

Insulin (1 microM)

20 10

delta metabolic clearance rate (%)

2-DG Uptake (pmol/min/mg)

60

60 50 40 30 20 10 0

0

Glu Ox LA

-

+ -

+ +

Maddux B et al. Diabetes 2001

Oral (600-1800 mg)

IV

IV

(500 mg)

(1000 mg)

Evans JL et al. Diabetes 2003


High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase Cdependent activation of NAD(P)H oxidase in cultured vascular cells. Inoguchi T et al. Smooth muscle cells

10

Endothelial cells

10

8

8

6

6

4

4

2

2

0 Control

High glucose

Control

Palmitate

0 Control

High glucose

Control

Palmitate

Diabetes 2000


Free radicals induced by elevated glucose mediate endothelial cell dysfunction Relaxation (%)

0 20

44 mM glucose 5.5 mM glucose

40 60 80 100 8

7 6 Acetylcholine, -Log M

5

Acetylcholine-induced relaxation of rabbit aortic rings. The aortic rings were incubated in control glucose (5.5 mM) or elevated glucose (44 mM) for 6 hours. Tesfamariam B et al. Am J Physiol 1996


FFA-induced endothelial dysfunction can be corrected by vitamin C.

350

350

300

300

FBF Ratio (%)

FBF Ratio (%)

Pleiner J et al.

250 200 150

250 200 150

100

100

50

50

Baseline

Baseline

25

50

100 nmol/min

Baseline

25

50

100 nmol/min

Intralipid/Heparin

J Clin Endocrinol Metab 2002


5 mM glucose

20 15

30 mM glucose

25 20

5 mM glucose

15 10

30 mM glucose

5 0

0

3

6

24

48

72

96

30 m M

0

30 m M

5m M

G

5

G

(-)

10

30

(-) G +r ot en on 30 e m M G + TT 30 FA m M G + C C C P

25

ROS concentration (microM)

ROS concentration (microM)

30

Mitochondrial reactive oxygen species reduce insulin secretion by pancreatic beta-cells. Sakai K et al BBRC 2003


Overnutrition

Glucose

Decreased Physical Activity

FFA

Genetic Predisposition

Cellular Overload

Oxidative Stress

Endothelial cells

Muscle Adipocyte

b cells

Endothelial Dysfunction

Insulin Resistance

Altered Insulin Secretion

CVD

Metabolic Syndrome

Ceriello A, ATVB 2004

IGT (Post Prandial Hyperglycemia)

Diabetes (Chronic Hyperglycemia)


Ceriello