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THE ROLE OF SUPPLEMENT THERAPY FOR

TYPE 2 DIABETES PATIENTS

Focus on antioxidant

Makbul Aman Mansyur


Division of Endocrine and Metabolism Department of
Internal Medicine Faculty of Medicine Hasanuddin
University / RS. Dr. Wahidin Sudirohusodo Makassar

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

1. Wild. Diabetes Care. 2004. 27:1047-1053.


2. International Diabetes Federation. IDF Diabetes Atlas. Fifth Edition. 2011

Diabetes is one of the major healthcare


burden in Indonesia
Country/
Territory

2013 Country/
Millions Territory

2035
Millions

China

98.4 China

142.7

India

65.1 India

109.0

United States of America

24.4 United States of America

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

DF Diabetes Atlas 6th edition. @International Diabetes Federation

YEARS

14.1
13.1
12.8
11.8
11.2

Type 2 Diabetes is Associated With


Serious Complications
Stroke

Diabetic
Retinopathy

2- to 4-fold increase in
cardiovascular mortality
and stroke

Leading cause
of blindness
in adults

Every 6 seconds a person dies from Cardiovascular


diabetes
Disease
individuals with
related complications 8/10
diabetes die from CV
events

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

How do complications occur?


Hyperglycemia in diabetic patients lead, via several
mechanisms (glucose autooxidation, stimulation of the
polyol pathway, imbalance in amounts and ratios of reduced
to oxidized forms of redox coenzymes, and formation of
advanced glycation end products) to multiple biochemical
sequalae aimed to an increase production of reactive oxygen
species (ROS).
Diabeticsincreased metabolic processes that
produce reactive oxygen species (ROS)
ROS serve as signaling mechanisms mediate
many of the functional & structural vascular
abnormalities observed in diabetics

Hyperglycemia, Mitochondrial Dysfunction and


Diabetic Complication
mitochondria
Euglycemia

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

Carbohydrates, lipids, and


proteins are sources of
energy for the body
Energy is stored in the
electrons associated with
C-H bonds
Lipids contain the most of
these bonds per gram and
so have the highest
number of Calories
A food Calorie contains
sufficient energy to
elevate 1 liter of water by
1 degree Celsius
Energy from foods is
converted to ATP: Cell Chapter Twenty One
energy

Role of mitochondria
produce ATP

Energy
generating
metabolism
in
mitochondria

5 respiration enzyme complexes


1. Complex I: NADH dehydrogenase
Transfers e- from NADH to quinone pool & pumps H+.
2. Complex II: succinate dehydrogenase
Transfers e- from succinate to quinone pool
3. Complex III: cytochrome reductase
Transfers e- from quinol to cytochrome c & pumps H+.
4. Complex IV: cytochrome oxidase
Accepts e- from cytochrome c, reduces O2 to H2O & pumps H+.

5. Complex V: (ATP synthase)


Harvests H+ gradient & regenerates ATP.

UNCOUPLED Electron Transport and


OXPHOS in Diabetes
(ROS generation and Reduce ATP)
In Diabetes
2H+

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+

ROS e + O` O2 H2O2 (OH) and ONOO

ADP + P1

ATP + H2O
3H+

Hyperglycemia-induced production of superoxide


by the mitochondrial electron transport chain.

(Miller
(Miller 1998)
1998)

Hyperglycemia

Mitochondrial Dysfunction : Excessive ROS Production


Polyol pathway

Activation
PKC

AGES

Hexosamine
pathway

Free radicals (reactive


oxygen
e
species) are known to fuel diabetic
vascular complications
Protein Modification
Matrix Modification

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

Diabetic Vascular injury

Physiopathology of diabetic complications

Fructose
-6- Phosphate

TGF-
PAI-1

Excess Free Radicals Are


the Enemies of Human Health
Excess free radicals can cause oxidative damages to:

- Lipid peroxidation membrane


damage
- Protein damage inactivation of
enzimes
- DNA damage block DNA
transcription and cause mutations.

Excess Free radicals can contribute to diseases:


Aging, Heart disease, Cancer,
Inflammatory-immune injuries, Rheumatoid Arthritis, Diabetes, AIDS,
Lupus, Alzheimers disease,
Adult Respiratory Distress Syndrome and more

Oxidative Stress
What Should You Know?
Oxygen

is critical for life: respiration and energy


Oxygen is also implicated in many disease
processes.
The

dangerous form of oxygen is from the formation


of free radicals or reactive oxygen species, or prooxidants (superoxide anion, hydroxyl radical,
hydrogen peroxide)

If excess free radicals exist in the human body,


oxidative damage occurs
Oxidative Stress = Imbalance between prooxidants (free radicals, reactive oxygen species)
and anti-oxidants

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

even optimal control of blood glucose


could not prevent complications suggesting that
alternative treatment strategies are needed.
The Diabetes Control and Complications trial N Engl J Med 1993,
329(14):977-986.

A NEW THERAPEUTIC APPROACH:


THE CAUSAL ANTIOXIDANT THERAPY
Interrupting the overproduction
of O2 - by the mitochondrial electron-transport
chain would normalize the pathways involved
in the development of diabetic complications.

Antioxidants in the
Management of Diabetes.
Exogenous
Endogenous
Antioxidants Antioxidants

(from food)

(made in

Coenzyme Q10: Ubiquinone

is an essential cofactor (an endogenously synthesized compound)


that acts as an electron carrier in the mitochondrial electron
transport chain and is necessary for ATP production.
Brownlee et al reported that this is the site of O2- generation under
hyperglycemic condition.
CoQ10 is a fat-soluble compound synthesized by the body and also
consumed in the diet
Endogenous synthesis decreases after age 20. Believed to fall off
rapidly in middle age, accelerating the aging process
CoQ10 is required for energy production and as antioxidant
Exercise increases catabolism of and need for CoQ10
Disease or other stress impairs intake and absorption of the
substrate

Functions of Coenzyme Q10:


Antioxidant
50 times
more antioxidant power than Vitamin E

neutralize free-radical
an effective lipid-soluble antioxidant
continuously go through an oxidation-reduction state
hold electrons loosely in its reduced form
regenerate

-tocopherol from the -tocopheroxyl radical.

interact with dihydrolipoic acid.


Dihydrolipoic acid reduces ubiquinone to ubiquinol
inhibit

lipid peroxidation

occurs when cell membranes and low-density lipoproteins (LDL) are


oxidized ex vivo
May prevent signs of skin aging

CoQ10 and Type 2 Diabetes and Insulin


Resistance
Singh et al, 1999.
oral treatment with
coenzyme Q10 60
mg twice daily 8
weeks

The patients receiving coenzyme Q10 had


reduced plasma levels of insulin and glucose.

Hodgson et al. Coenzyme Q10 improves blood


pressure and glycaemic control: a controlled trial
in subjects with type 2 DM (Eur J Clin Nutr. 2002). oral dose
of 100mg CoQ twice daily for 12 weeks.

CoQ10 is a lipid soluble antioxidant


In higher concentrations, it scavenges O2Improves endothelial dysfunction in diabetes.
1.

Hodgson et al. Coenzyme Q10


improves blood pressure and
glycaemic control: a controlled
trial in subjects with type 2 DM

1.

(Eur J Clin Nutr. 2002). oral dose of 100mg CoQ


twice daily for 12 weeks.

2.

Watts et al. Coenzyme Q10


improves endothelial dysfunction
of the brachial artery in Type2

Thromb Vasc Biol. 1996).

(Diabetologia 2002).

3.

Singh et al. Effect of hydrosoluble


coenzyme Q10 on blood
pressures and insulin resistance
in hypertensive patients with
coronary artery disease (J Hum
Hypertens. 1999 ) the oral treatment with Q10 (60
mg twice d) for 8 weeks

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.

Burke et al. Randomized,


double-blind, placebocontrolled trial of coenzyme
Q10 in isolated systolic
hypertension (South Med. J 2001)
12-week with twice daily 60 mg of oral

-lipoic acid

A Dietary Factor that Potentially Improves Antioxidant Defenses

ROS

ROS Scavenger

Safe
Compound

an essential cofactor for several mitochondrial enzyme complexes (PDH)


that catalyze critical reactions related to energy production
Human body, only produce small amount of ALA
Source from the diet also limited. Consumption of ALA from food
has not yet been found in detectable increase in ALA human
plasma
Powerful antioxidant In lipid and water phase and may cycle GSH
Clinically effective in hyperglycemia

-lipoic acid

1.
2.
3.

Alpha Lipoic Acid - An anti-oxidant 400 times


stronger than Vitamin "C" or "E".
Considered the universal anti-oxidant because
it is both fat and water-soluble
Strong antioxidant protection and enhanced
antioxidant recycling
Enhanced biological energy production also an
effective anti-inflammatory.
Protects against CVD
Clinically effective in hyperglycemia
Claims that lipoic acid slows aging of the brain and
The anti-aging
defence against
oxidative
stresstobybe
increasing
of
has
benefits
seem
relatedthe
to synthesis
is
anti-oxidants
like glutathione.
potent
antioxidant
properties
Directly scavenge ROS and RNS.
With Dihydrolipoic acid (DHLA), 23regenerate endogenous
antioxidants: glutathione, coenzyme Q10, vitC, vitE

ROLE IN SIGNAL
TRANSDUCTION

-lipoic acid
1.

2.

3.

Activates insulin receptors,


leads to a cascade of
substrate phosphorylation
that causes the translocation
of glucose transporters.
Involved in the regulation
of the NF-kB and Akt
signaling pathways.
Rudich et
al. Diabetologia 1999.
.

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

Carnitine transports FA inside the


mitochondria where they are burnt to
produce energy (-oxidation)
Carnitine-deficiency hypoglycemia due to
reduced gluconeogenesis resulting from impaired
fatty acid oxidation, resulting in muscle weakness

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

Carnitine may improve insulin sensitivity in


diabetic resistant insulin
Mingron, J Am Coll Nutri. 1999

TREATMENT OF DIABETIC
NEUROPATHY

L-Carnitine in the treatment of painful diabetic


neuropathy and its effect on plasma -endorphin
levels. Cakir et al. Current Therapeutic Research. 2000.

Acetyl-L-carnitine improves pain, nerve regeneration, and


vibratory perception in patients with chronic diabetic
neuropathy: an analysis of two randomized placebocontrolled trials. 52-week ALC: 500 and 1,000 mg/day t.i.d. Sima
et al. Diabetes Care, 2005.

Effect of L-carnitine on diabetic neuropathy and ventricular


dispersion in patients with diabetes mellitus. LC 2 g/day for 10
months. Hizir et al. Turk J Med Sci 2010.

decrease
oxidative
stress and
improve
endothelial
cell
functioning

improves
insulin
sensitivity in
insulin
resistant
diabetic
patients

Effects of L-carnitine treatment on


oxidant/antioxidant state and vascular
reactivity of streptozotocin-diabetic rat
aorta.Irat et al.J Pharm Pharmacol 2003.

Effects of carnitine supplementation on flowmediated dilation and vascular inflammatory


responses to a high-fat meal in healthy young
adults. 3 weeks 2 g/day Volek et al. Am J Cardiol. 2008.

Effect of oral acetyl L-carnitine arginate on


resting and postprandial blood biomarkers in prediabetics. 3g/d 8 weeks. Bloomer et al., Nutrition & Metabolism

2009.
L-Carnitine

Improves Glucose Disposal in Type 2


Diabetic Patients. infusion of L-carnitine (0.28 mmole/kg bw/mnt
2 hr. Mingrone etal., Journal of the American College of Nutrition,
1999

Ameliorating Hypertension and Insulin Resistance in


Subjects at Increased Cardiovascular Risk Effects of
Acetyl-L-Carnitine Therapy. Ruggenenti etal,. Hypertension.
2009.

The Three Musketeers


Alpha Lipoid Acid Functions as a coenzyme in carbohydrate metabolism,
Increases number or activation of GLUTs and
Slows the development of diabetic neuropathy
and recycling an antioxidant
Ubiquinone Boost energy, enhances
immune system and an anti oxidant,
serves as a coenzyme for several of the
key enzymatic steps in production of
energy, lower blood pressure, prevent
atherosclerosis
L- Carnitine: Helps in oxidation of fatty
acids, role in oxidative phosphorylation.
Carnitine may improve insulin sensitivity
in diabetic resistant insulin, body weight
loss
Working
together
to fight
and
and
It may improve
diabetic
neuropathy.

improve diabetes symptoms and


prevent complications

30

Take Home Message

Hyperglycemia induce Diabetic


Complication through excessive ROS
generation (Mitochondrial dysfunction)
Modifying Diabetes should be done for
Hba1c treatment and endothelial
monitoring to reduce risk of CVD
Causal antioxidant therapy, Coenzim
Q10, L-carnitine and -lipoic acid,
which work as intracellular superoxide
scavengers, improving mitochondrial
function and reducing DNA damage,
may be good for such a strategy.

Thank you so much