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)