«Oxidative stress: the commonpathogenetic factor between insulin

resistance, diabetes mellitus andcardiovascular disease»

Antonio Ceriello

Chair of Internal MedicineUniversity of UdineUdine, Italy

EASD 2004

From Insulin Resistance to Diabetes350300250200150100

50

ReducedInsulinSecretion

250200150100

500ß-

cell

Func

tion

(%)

FastingGlucose

Post-MealGlucose

Gly

cem

ia(m

g/dL

)

Cardiovascular Disease

Ins Res IGT Diabetes

Years -10 -5 0 5 10 15 20 25 30

Microvascular Disease

Impaired1st phaseinsulinsecretion

Food

Glucose Fats

Acetyl-CoAAcetyl-CoA

glycolysis

Beta-oxidation

III

Q+ III Cyt C

IV ATP syntasee-

e-

e-e-

NADH

NAD+

FADH2FADH2O

O2

ATP ADP+Pi

O•-2 O2

Dm H+H+

Acetyl-CoA

III

Q+ III Cyt C

IV ATP syntasee-

e-

e-e-

NADH

NAD+

FADH2FADH2O

O2

ATP ADP+Pi

O•-2 O2

Dm H+H+

Acetyl-CoA Overload

High glucose level and free fatty acidstimulate reactive oxygen species

production through protein kinase C-dependent activation of NAD(P)H oxidase

in cultured vascular cells.Inoguchi T et al.

0

2

4

6

8

10

Control High glucose Control Palmitate

Diabetes 2000

Smooth muscle cells

Protection Against Oxidative Stress-Induced Insulin Resistance in Rat L6

Muscle Cells and Humans by a-Lipoic Acid

0

10

20

30

40

50

60

2-D

G U

pta

ke

(pm

ol/

min

/mg)

Basal

Insulin (1

microM)

Evans JL et al. Diabetes 2003Maddux B et al. Diabetes 2001

0

10

20

30

40

50

60

delt

a m

eta

bo

lic c

lea

ra

nce r

ate

(%

)

Glu Ox - + +LA - - +

Oral IV IV (600-1800 mg) (500 mg) (1000 mg)

High glucose level and free fatty acidstimulate reactive oxygen species

production through protein kinase C-dependent activation of NAD(P)H oxidase

in cultured vascular cells.Inoguchi T et al.

0

2

4

6

8

10

Control High glucose Control Palmitate

Diabetes 2000

Smooth muscle cells

0

2

4

6

8

10

Control High glucose Control Palmitate

Endothelial cells

Free radicals induced by elevatedglucose mediate endothelial cell

dysfunction

Acetylcholine-induced relaxation of rabbit aortic rings. The aortic rings wereincubated in control glucose (5.5 mM) or elevated glucose (44 mM) for 6 hours.

0

20

40

60

80

1008 7 6 5

Rel

axat

ion

(%)

Acetylcholine, -Log M

44 mM glucose5.5 mM glucose

Tesfamariam B et al. Am J Physiol 1996

FFA-induced endothelial dysfunctioncan be corrected by vitamin C.

Pleiner J et al.

50

100

150

200

250

300

350

Baseline 25 50 100

nmol/min

FB

F R

ati

o (

%)

J Clin Endocrinol Metab 2002

50

100

150

200

250

300

350

Baseline 25 50 100 nmol/min

FB

F R

ati

o (

%)

Baseline Intralipid/Heparin

0

5

10

15

20

25

30

0 3 6 24 48 72 96

RO

S

co

ncen

tra

tio

n

(mic

ro

M)

5 mM

glucose

30 mM

glucose

Mitochondrialreactive oxygenspecies reduce

insulin secretion bypancreatic beta-cells.

Sakai K et al

BBRC 2003

0

5

10

15

20

25

30

5mM

G (-

)

30m

M G

(-)

30m

M G

+rote

none

30m

M G

+ T

TFA

30m

M G

+ C

CC

P

RO

S c

on

cen

trati

on

(m

icro

M)

5 mM

glucose

30 mM

glucose

OxidativeStress

Glucose

FFA

Cellular Overload

b cells

AlteredInsulin

Secretion

Overnutrition

Decreased Physical Activity

CVDMetabolicSyndrome

Diabetes (ChronicHyperglycemia)

IGT (Post PrandialHyperglycemia)

Endothelial cells

EndothelialDysfunction

Gen

etic

Pred

ispo

sitio

n Muscle Adipocyte

Insulin Resistance

Ceriello A, ATVB 2004