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DIABETES DEFINITION
Diabetes mellitus is a group of
metabolic diseases characterized
by chronic hyperglycemia
resulting from defects in insulin
secretion, insulin action, or both
(Expert Committee on the Diagnosis and
Classification of Diabetes Mellitus 2012)
Long-term
Long-term damage,
damage, dysfunction, and
and failure
failure
of
of various
various organs especially the
the eyes,
eyes,
kidneys,
kidneys, nerves, heart, and blood vessels
171 million1
366 million2
552 million2
2000
2011
2035
2013 Country/
Millions Territory
2035
Millions
China
98.4 China
142.7
India
65.1 India
109.0
29.7
Brazil
11.9 Brazil
19.2
Russian Federation
10.9 Mexico
15.7
65
%
Mexico
8.7 Indonesia
Indonesia
8.5 Egypt
Germany
7.6 Pakistan
Egypt
7.5 Turkey
Japan
IN JUST 22
7.2 Russian Federation
YEARS
14.1
13.1
12.8
11.8
11.2
Diabetic
Retinopathy
2- to 4-fold increase in
cardiovascular mortality
and stroke
Leading cause
of blindness
in adults
Diabetic
Nephropathy
Diabetic
Neuropathy
Leading cause of
end-stage renal disease
Leading cause of
non-traumatic lower
extremity amputations
5
UK Prospective Diabetes Study Group. Diab Res 1990; 13: 111.
Fong DS, et al. Diab Care 2003; 26 (Suppl. 1): S99S102.
Molitch ME, et al. Diab Care 2003; 26 (Suppl. 1): S94S98.
13
ATP
Mitochondrial dysfunction
Hyperglycemia
ROS (superoxide)
Diabetic
Vascular
Complication
Polyol
pathway
AGE
pathway
Hexosamine
pathway
Protein kinase
C pathway
Mitochondrial Function :
Generating ATP in normal Condition
H+
Intermembrane space
F0
CoQ10
Complex I
Complex II Complex III Complex IV
NADH
cytochrome
dehydrogenase succinate cytochrome
oxidase
dehydrogenase reductase
Inner
mitochondrial
membrane
F1
UCP
Complex V
(ATP synthase)
ADP
Matrix
ATP
Sources of
energy
Role of mitochondria
produce ATP
Energy
generating
metabolism
in
mitochondria
4H+
e
Complex
I
NADH
CoQ
Complex
II
Complex
III
H+
Cyt
C
3H+
Intermembrane
Space
Complex
IV
Complex Mitochondrial
Complex
inner
V
membrane
Matrix
O2
NAD+
e
Succinate Fumazate
2H+
2H+
H2O
ATP
Synthase
2H+
ADP + P1
ATP + H2O
3H+
(Miller
(Miller 1998)
1998)
Hyperglycemia
Activation
PKC
AGES
Hexosamine
pathway
NADPH
GSH
ROS
Cytokines & Growth Factor
C IL-1, IGF-1, TNF-, MCSF,
TGF-, VICAM-1, VEGF
NOS
Endotheli-1
VEGF, TGF-, PAI-1
NFB
NADPH Oxidase
Cell injury
Fructose
-6- Phosphate
TGF-
PAI-1
Oxidative Stress
What Should You Know?
Oxygen
Antioxidant:
An Agent that prevents or inhibits oxidation.
Antioxidants are substances or nutrients in our
foods which can slow or prevent the damaging
effects of oxygen radicals, highly reactive
chemicals that play a part in atherosclerosis,
some forms of cancer, and reperfusion injuries
Antioxidants in the
Management of Diabetes.
Exogenous
Endogenous
Antioxidants Antioxidants
(from food)
(made in
neutralize free-radical
an effective lipid-soluble antioxidant
continuously go through an oxidation-reduction state
hold electrons loosely in its reduced form
regenerate
lipid peroxidation
1.
2.
(Diabetologia 2002).
3.
Thomas et al.
Cosupplementation With
Coenzyme Q Prevents the
Prooxidant Effect of Tocopherol and Increases the
Resistance of LDL to
Transition MetalDependent
Oxidation Initiation . (Arterioscler
2.
-lipoic acid
ROS
ROS Scavenger
Safe
Compound
-lipoic acid
1.
2.
3.
ROLE IN SIGNAL
TRANSDUCTION
-lipoic acid
1.
2.
3.
TREATMENT OF DIABETIC
NEUROPATHY
Several studies have demonstrated the benefits of
ALA in symptomatic polyneuropathy and improve
neuropathic deficits.
Ziegler, et al1995; Ziegler, et al1999, Reljanovic et al, 1999; Ruhnau et al, 1999;
Ametov et al, 2003; Ziegler, et al 2006.
TREATMENT OF INSULIN
RESISTANCE
ALA has shown therapeutic potential in the area of
insulin resistance.
Jacob et al,1995; Jacob et al,1999; Kamenova, 2006; Midaoui and Jacques de Champlain,
2002; Karen and William, 2002; Timmers et al; 2010.
Carnitin: Fatty
acid trasporter to
mitochondria
L-Carnitine
Carnitine is known as a
vitamin like and amino acid like substance
facilitate transport of long-chain fatty acids
across the inner mitochondrial membrane for oxidation, promoting energy availability and
preventing toxic accumulation of long-chain fatty
acids.
Mingrone,1999
L-CARNITINE
Intracellular superoxide scavenger, which is associated
with a reduction in xanthine oxidase activity and known
to possess free radical scavenging activity, improving
mitochondrial function reducing DNA damage.
Di Giacomo
etal. Neurochem
Res 1993; Vanella
Cell Bil Toxicol,2000 .
Acetyl-L-carnitine
(ALC)
is deficient
inet al.DM.
Scarpini et al. , J Peripher Nerv Syst 1:157163,
1996
Ido et al. Diabetes 43:14691477, 1994
TREATMENT OF DIABETIC
NEUROPATHY
decrease
oxidative
stress and
improve
endothelial
cell
functioning
improves
insulin
sensitivity in
insulin
resistant
diabetic
patients
2009.
L-Carnitine
30