INAMSC 2014– Paper Number (The committee will replace this section with paper registration number if the

manuscript is accepted)

Enhanced External Counterpulsation for Glycemic

Control and Anti-obesity Effect
David Christorei Tooy (davidtooy@gmail.com)*, Adelia Suryani Ekwendi
(adeliaekwendi12224@gmail.com)* and Ameliya Secil Japanto (amelsecil@yahoo.com) *

Abstract

Obesity threatens pubic health and quality of life globally. The mortality rate is
assosiated with cardiovascular disease and type 2 diabetes mellitus. Recently, we
found an nonivasive cardiovascular disease therapy , enhanced external
counterpulsation (EECP), that reduce 2 hour-plasma glucose level similliar by physical
exercise. We hypothesize that EECP may have glycemic control and anti-obesity effect.
EECP is affect glucose uptake in skeletal muscle and improve vascular function by
increasing bioavailability of nitric oxide and vascular endothelial growth factor. EECP
also reduce inflammatory cytokines, especially tumor necrosis factor-α which is release
by adipose tissue. Nevertheless, we haven’t found studies that observe BMI nor fat
mass by EECP. The current regiment also ajusted to treat cardiovascular disease and
never intended to control glucose level or obesity. In conclusion, EECP has proven its
benficiality as an exercise mimetic therapy, thus may have a role in glycemic control
and anti-obesity effect.

Keywords: EECP, Obesity, gycemic control, anti-obesity.

Introduction
Obesity is a global burden that threatens
pubic health and quality of life1-3. Obesity
is an excess of body fat which portrait in
Body Mass Index (BMI) value more than
30 kg/m24. WHO shows that at least 2.8
million people die each year as a result of
being overweight or obese5. This mortality
account is supported by the fact that
obesity is a major risk factor of various
chronic disease such as Type 2 Diabetes
Mellitus (T2DM) and coronary artery
disease. More over, when T2DM have
developed in obese patient, it increases the
risk of cardiovascular disease6,7.
Obesity is often assosiated with metabolic
syndrome, insulin resistance, impaired
glucose tolerance (IGT) and impaired
6-8
fasting glucose (IFG) . IGT is marked by
2-hour plasma glucose (2-PG) of 140-199
mg/dl after a 75-g glucose load on the oral
glucose tolerance test (OGTT) while IFG is
marked by fasting plasma glucose (FPG)
level 100-125 mg/dl. These conditions
often called prediabetic state because most
people with these conditions are more
likely to develop T2DM9. Physician often
suggested prevention by physical activity
and balanced diet to reduce weight by 5-
10% or pharmacological approachment
such as thiazolidinediones and metformin
to reduce level of plasma glucose7.
Nevertheless, perhaps 70% individuals
with IGT would develop T2DM8.
Recently, we found a study that utilizes
enhanced external counterpulsation
(EECP), class IIb of recommendation for
stable ischemic heart disease in ACC/AHA
2012 guideline10, for patient with IGT11.
EECP is a non-invasive Food and Drug
INAMSC 2014– Paper Number (The committee will replace this section with paper registration number if the
manuscript is accepted)

Administration (FDA) approved therapy pathway is activated by muscle contraction

for patient with coronary artery disease12-17, or exercise mimetic drug due to indresing
heart failure10,20 and hypertension18,19. The energy demand23. Beside glycemic control,
device involves sequential inflation and this acton plays role of lipolytic of adipose
deflation during cardiac diastole by tissue. Since NO acts the same way to
compression cuff applied on the calves to induce AMPK mediated pathway as
buttocks while monitored by muscle contraction and AMP analog, 5-
electrocardiogram. The pneumatic aminoimidazole-4-carboxamide 1-β-d-
compression (300 mmHg) by EECP ribofuranoside 5-aminoimidazole-4-
created a blood flow pattern on femoral carboxamide riboside (AICAR), there a
and brachial arteries, retrograd and possiblity of anti-obesity effect by
antegrad respectively21 (figure 1). This EECP11,22,23.
blood flow acutely increase shear rate thus
upregulated nitric oxide (NO) that Through this writing, we presented an
improves dilatation of arteries and alternative approachment utilizing EECP
angiogenesis10. for obese patient to control his/her
glycemic level and prove its anti-obesity
Study by Martin et al show nearly 17 mg/dl effect. We shown the basic biomolecular
decline of FPG and 28 mg/dl of 2h-PG science that supports glycemic control and
from baseline, suggested a direct antiobesity effect by EECP.
involvement of EECP in glycemic
control11. One of the theory that could
answer this phenomenon is glucose uptake
in skeletal muscle cells. Skeletal muscle
accounts for 65-90% clearance of oral or
intravenous glucose intake mainly by
regulating the expression of glucose
transporter 4 (GLUT4)22. GLUT4
expression is regulate by insulin,
contraction of muscle and recently NO-
mediated pathway23. Since EECP increase
NO bioavailability, FPG decline might be
resulted by GLUT4 expression by NO
mediated pathway11. In addition, increased
marker of angiogenesis such as vascular Fig. 1. Three pneumatic cuffs were set
endothelial growth factor (VEGF) and from calves to bottocks. Vascular
capillary density in skeletal muscle may pressure from lower extremities
improved insulin recruitment to interstitial increasing diastolik pressure and venous
skeletal muscle24. return. This pressure can be monitored
by electrocardiogram during EECP
Such control of glycemic level by EECP is treatment.19
similliar to the result achieved by routine
exercise11. These NO action is mediated by
5’AMP activated protein kinase (AMPK)
Material and Methods
pathway that related with mitochondrial
biogenesis and adenosin triphosphate We did a computerized search of studies
(ATP) depletion25,26. Normally, this that related to utilization of EECP from
INAMSC 2014– Paper Number (The committee will replace this section with paper registration number if the
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january 2007 to February 2014. Some pathway23 (Figure 2). Interestingly,

clinical research about EECP and its increasing NO bioavailability promotes
possibility to improve participant metabolic GLUT4 similiar to the AMPK pathway by
were found in PubMed search library. We muscle contraction 22(Figure 3).
observed the prevalence of patients who
attend EECP with BMI more than 30
kg/mm2 or have cormobid condition that
related to obesity complication. The search
extended used key word for the state of
interest (obesity), overview by its
epidemiology (prevalence, incidence,
mortality), comorbiditiies of interest
(prediabetic, type 2 diabetes mellitus,
impaired glucose tolerance, impaired
fasting glucose, cardiovascular risk) and
basic science that supports the hypothesis
about EECP for glycemic control and anti-
obesity effect (glucose uptake, NO, VEGF,
GLUT4, AMPK). We found 21 research
studies, 8 literature review, one medical
book and one website related to the
objective of our writing

Fig. 2. This is the main mechanism of

Main Parts of the Review Article (Result NO to control glucose level by
and Discussion) promoting GLUT4 in skeletal muscle.22
These are the main mechanism that involve
in glycemic control and obesity effect of
EECP.

Glucose uptake by skeletal muscle

In skeletal muscle cell, GLUT4 is highly

expressed to regulate the level of plasma
glucose. Physiologically, GLUT4
expression is promoted by insulin and
physical exercise for muscle contraction
mediated pathway22-25. Insulin promotes
GLUT4 by trigerring insulin receptor (IR)
tyrosine kinase and activated series of
protein kinases, such as
phosphatidylinositol 3-kinase (PI3K) and
Akt 24,27. Mean while, GLUT4 promotion
by muscle contraction is run by 5-
AMPactivated protein kinase (AMPK)
which is differ from insulin mediated-
INAMSC 2014– Paper Number (The committee will replace this section with paper registration number if the
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Fig. 3. The biomolecular pathway of
NO compared with muscle contraction
to control glucose level via promotion
GLUT4. 23
NO is produce by converting l-arginin to l-
citruline by NO-synthase (NOS). NO
bioavailabillity is decrease in obese patient
often with comorbidities of hypertension
and T2DM. There are many form of NOS
such as inducible NOS (iNOS) ,
endothelial NOS (eNOS) and neuronal
NOS (NOS). Normally, insulin activate
PI3K, leading to phosphorylation of eNOS
or by muscle contraction which also
phosphorilated both eNOS and nNOS.
eNOS can also be activated by pulsatile
blood flow through vessels27, support the
finding of increasing NO level during
EECP.
The main action of NO to promote GLUT4
is increasing AMP-to-ATP ratio with in a
cell by bind and inhibit cytochrome
synthase and creatine kinase activity22.
AMP-to-ATP ratio is crucial to
mitochondrial energy usage by AMPK thus
NO may have lipolytic effect. Exercise
increase ATM-to-ATP ratio by NO-
mediated pathway or by more direct
muscle contraction mechanism. Usually
AICAR has been use as an exercise
mimetic drug to increase the ratio23,26.
Since secrection of NO is rising during
EECP treatment, there have been found an
improvement on 2-hPG level similliar to
exercise11.
Improve vascular function
EECP improve vascular function mainly by
inducing secretion of two substances, NO
and vascular endothelial growth factor
(VEGF)19. NO acts as a vasodilator, beside
its, antiinflammatory, and antioxidant
properties. When NO is produce, especially
by eNOS, it diffuses in into vascular
smooth muscle cell (VSMC) and activate
guanylate cyclase to increase cyclic
guanylate monophosphate (cGMP) therby,
inducing relaxation of VSMC27. VEGF
plays important role of angiogenesis. Level
of VEGF assosiated with metabolic
syndrome feature such as BMI, waist
circumfence, fat mass, blood pressure,
insulin sensitivity28. This is probably due
to decrease level of VEGF and NO in
obese patient. Increasing NO and VEGF
resulted a better blood perfusion from
decrease vessels resistance and growth of
new arteries11,12.
Reduce inflammatory cytokines
Adipocyte tissue is capable of realeasing
oxidative species like free fatty acid and
powerful inflammatory cytokines tumor
necrosis factor α (TNF-α)10,12. TNF α
regulates the immune response,
inflammation, and apoptosis. TNF- α is
produce by adipocyte and capable of
INAMSC 2014– Paper Number (The committee will replace this section with paper registration number if the
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inducing others inflammatory cytokines
such as interleukin-6 (IL-6), which in turn
regulates the expression of C-reactive
protein (CRP). CRP then increases the
expression of endothelial intercellular
adhesion molecule-1 (ICAM-1), vascular
cell adhesion molecule-1 (VCAM-1), E-
selectin, monocytes chemoattractant
protein-1 (MCP-1) and increases the
secretion of endothelin-1 (ET1. Increasing
level of TNF-α plays impotant role in
insulin resitance by impairing tirosine
kinase of IR and insulin receptor substrate-
1 (IRS-1) )27. These cytokines worsen
metabolic status of obese patient leading
the patient to bear more comorbid
conditions such as insulin resistance, IGT,
IFG, endothelial dysfunction and
6
dylipidemia .
Study by Casey et al show reduction in
TNF-α (29%) observed after EECP is
similar to what has been previously
reported with interventions such as
exercise in patients with cardiovascular
disease (CVD). TNF-α reduction may be
mediated by EECP-induced shear stress
since arterial region of low shear stress is
lack of NO and excess of inflammatory
markers12. In, addition Thus, EECP may
avoid development of disease that
associated with obesity complication.
Utilization EECP for glycemic control and
anti-obesity
EECP has proven its beneficiality in heart
failure, Ischemic Heart Disease and
Refractory Angina. However, ECCP also
can be a potential control and anti-obesity
therapy mediated by the same
biomolecular machanism used to treat
those diseases. Until now, we haven’t
found studies that observed the utilization
of EECP and participant ‘s BMI or fat
mass. Many of EECP studies is conduct to
see improvement in CVD. Nevertheless,
EECP has a real action to control glucose
level, improve vascular function and
reduce inflammatory cytokines, suggested
its exercise mimetic effect.
The current regiment of EECP itself only
ajust for the conventional EECP indication
for CVD. The regiment of one hour session
in 35 times therapy is not suitable to
achieved the maximun anti-obesity.
Despite of that, that regiment is still
beneficial to reduce the burden of
metabolical syndrome decribe by Martin et
al and Casey et al. We suggest clinician to
conduct research that observed EECP
effect on obese patient metabolical status.
Conclusion
EECP is a potential exercise mimetic
therapy that improves glucose level and
may have anti-obesity effect. This
improvement is induce due the increasing
bioavailabiliy of NO and VEGF which in
turn affect peripheral arterial function and
glucose control by skeletal muscle. EECP
is also reduce inflammatory cytokines
release by adipose tissue. Nevertheless, the
current regiment of EECP is ajusted to treat
CVD and not to control glucose level or
obesity. Despite of that, EECP is beneficial
to reduce the burden of metabolic
syndrome due to complication of obesity
Acknowledgementar
The authors thank Almighty God because
His blessing for the endurance to write this
article. We also thank dr. Meilany Durry,
Mkes, SpPA, Hermanto Quedarusman,
Daniel A. Lallo for reviewing our ideas and
manuscript, and the whole Medical Science
Community members of Universitas Sam
Ratulangi for the feed back of this article
Conflict of Interest
INAMSC 2014– Paper Number (The committee will replace this section with paper registration number if the
manuscript is accepted)

Our colleges gave us a feedback wheater America: The McGraw-Hill

this therapy is related to prevention of
diabetes mellitus. Thus, we change our
subject and ajust the objective towards
obesity.
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Appendices

No appendices are added in this paper

David Tooy, Adelia Ekwendi, Ameliya Japanto Universitas Sam Ratulangi

LETTER OF ORIGINALITY
To Comittees of INAMSC 2014,

Hereby, we, undersigned,

first author : David Christorei Tooy, Medical Faculty- Universitas Sam Ratulangi

second author : Adelia Suryani Ekwendi, Medical Faculty – Universitas Sam Ratulangi

third author : Ameliya Secil Japanto, Medical Faculty – Universitas Sam Ratulangi

state that the review we made, entitled:

“Enhanced External Counterpulsation for Glycemic Control and Anti-obesity Effect”

is the purely made by us. This paper has not been published in any competition, congress or
any other events out of Indonesia International (bio)Medical Students’ Congress (INAMSC)
2014.

If there is any violation related to this paper, we are ready to be disqualified from this
competition due to the consequences.

Manado, 02-11-2014

David Christorei Tooy

©INAMSC 2014