Kidapawan City Division

Research Article
The Feasibility Of Unripe Papaya (Carica papaya) Pulp as Hypoglycemic
Agent Used in Hydrochlorothiazide-Induced Hyperglycemic Albino Mice
(Mus musculus)
Kriza Jade P. Ganancial, Hope Gwyneth R. Maldepeña, and Hemo Chem M. Sorupia
Kidapawan City National High School, Science, Technology and Engineering Program, Kidapawan City, Philippines
Abstract
With the aim to search and prove a cure to diabetes, the study on the feasibility of unripe Carica papaya pulp as
hypoglycemic agent in hydrochlorothiazide-induced hyperglycemic albino mice was laid out using 6 treatments with 3
replications, including the negative control. The phytochemical screening of the unripe C. papaya pulp showed the pres-
ence of saponins which is helpful in lowering the blood glucose level by stimulating insulin production in the pancreas.
The induction of hyperglycemia was by the use of Hydrochlorothiazide and the administration of the pure fruit extract
was in increasing dosages computed using the approximate effective dose formula.
The data collected showed a significant difference in the displacement of blood glucose level within the given
time using the Single-factor ANOVA that revealed the result of F value 14.91 greater than the F critical value of 3.31.
Treatment 5 had the highest BGL reduction percentage showing 5.66 mL of the fruit extract as the most effective dose. T
-test also showed that 8 out of 15 treatment comparisons had significant differences in terms of blood glucose level dis-
placement.
The two null hypotheses, stating that there is no significant difference on the level of effectiveness of the unripe
Carica papaya pulp in lowering the blood glucose level upon administration within the given time and there is no signifi-
cant difference among the six treatments in lowering the blood glucose level were rejected. The results revealed that the
unripe C. papaya pulp is capable and is a potential hypoglycemic agent.

Keywords: Carica papaya; hypoglycemic; diabetes;
hydrochlorothiazide; saponins; Blood Glucose Level
(BGL)
Introduction
Diabetes evolved from being a common disease
for the aged to being rampant not only to people aging 30
to 70. Diabetes has paved its way towards juvenile occur-
rences. The baseline of diabetic persons shifted to the
lowest possible age of 20, and even early teens depend-
ing on the health status and lifestyle (International Diabe-
tes Federation Western Pacific, 2015).
The desired blood glucose level of human bodies
should be maintained between 70 mg/dL and 100 mg/dL.
If a person has fasted, BGL of above 140 mg/dL is termed
hyperglycemia. Above 110 mg/dl, after eating is normal
but should not exceed to 180 mg/dl (American Diabetes
Association, 2006). According to the International Diabe-
tes Federation (2012), the Philippines ranked 15th in the
world for the most diabetes prevalence. About 4 million of
the Philippines’ population has been diagnosed with dia-
betes and there must be a larger number of persons who
do not know they have the disease.
On the other hand, Oloyede (2005) conducted a
phytochemical analysis of the unripe Carica papaya
(papaya) where it showed the presence saponins and
cardenolides. Saponins are glycosylated compounds that
stimulate the release of insulin and block the formation of
glucose in the bloodstream (Arif et. al, 2014). The Philip-
pines as a tropical country, has an abundant vegetation of C.
papaya.
Though there are synthetic drugs distributed all
throughout the country, the increasing number of hypergly-
cemic and diabetic persons, especially people who are lack-
ing knowledge in the disease and cannot afford insulin shots,
gives more reason to the one of the purposes of the study
that is to contribute to the rise of alternative medicine.
The objectives of the study are the following:
 Determine the dosages to be used in the test for the
hypoglycemic effect of the Carica papaya pulp.
 Determine if there is a significant difference on the
level of effectiveness of unripe Carica papaya pulp
in reducing the blood sugar level upon administering
the extract to the albino mice within the given time.

Page 1 of 7
 Determination of Baseline
 Determine the most effective dosage of
administration of unripe Carica papaya After twelve (12) hours of fasting, each mouse’s
extract as hypoglycemic agent tail was punctured to get a blood sample to be placed in
the glucometer strip to be analyzed by the glucometer
 Determine if there is a significant differ- (EasyMate). The results were read after 10 seconds
ence among the treatments in lowering (EasyMate Glucometer instruction manual).
blood sugar levels in albino mice.
Preparation and Administration of Hydrochlorothia-
The study aims to find a possible prophylaxis zide
to the said disease using accessible materials, simple
methods, and attaining significant results. With the utili- Using a mortar and a pestle, a 12.5 mg of hydro-
zation of the unripe C. papaya pulp, the study aims to chlorothiazide was powdered and was made into a solu-
present concrete evidences for future researchers to tion and was measured for the approximate effective dose
further study about the problem. The hypotheses of the for each mouse. Thirty minutes after the administration,
study are the following: the tails of the mice were punctured to collect blood sam-
ples for measuring the initial blood glucose level. (Akmad,
 There is no significant difference on the 2014)
level of effectiveness of the unripe Carica
Data Collection and Analysis
papaya pulp in lowering the blood glucose
level upon administration within the given The desired data to be collected and interpreted
time. are the blood glucose levels of the subject mice. Single-
factor Analysis of Variance (ANOVA) was used to deter-
 There is no significant difference among mine if there is a significant difference. Post ANOVA test
the six treatments in lowering the blood was then conducted (t-test). The statistical analysis was
glucose level. done using Microsoft Excel 2013.
Materials and Methods
Results
Study Design and study area
Single-factor ANOVA was employed to determine
The study on the utilization of unripe C. papa- the significant difference of the blood glucose levels and
ya pulp extract was laid out using an experimental re- blood glucose displacements in the treatments and repli-
search design to evaluate the feasibility of the fruit as a cations as evaluated on the subjects. A post analysis was
hypoglycemic agent used in hydrochlorothiazide- done using the t-test in order to determine specifically in
induced hyperglycemic albino mice. The study was which treatment comparisons had significant differences.
conducted in Saguing, Makilala, Cotabato.
Computed Dosage
Collection and Preparation of the Plant
Table 1 shows the computed dosages for each of
The C. papaya fruit was manually harvested in the treatments. The approximate effective dosages were
Saguing, Makilala, Cotabato. The fruit was thoroughly
washed to remove foreign bodies and was entirely Table 1.Computed dosage of C. papaya extract
peeled. After the peeling, the seed of the fruit were for each treatment
removed. After being sliced into chunks, the fruit was
processed in a juicer machine. 88 ml of C. papaya pulp Treatments Trial 1 Trial 2 Trial 3
was stored in a closed container, 20°C.
Treatment
Selection of Inducer 0.02 mL 0.02 mL 0.02 mL
1
Hydrochlorothiazide (HCTZ) belongs to the Treatment
thiazide class of diuretic, acting on the kidneys to re- 0.10 mL 0.10 mL 0.10 mL
2
duce sodium (Na) reabsorption in the distal convoluted Treatment
tubule. It was used as an inducing agent in the experi- 0.39 mL 0.39 mL 0.39 mL
3
mentation because its adverse effect is the increase of
blood glucose level when administered (Mycek, et al., Treatment
1.57 mL 1.57 mL 1.57 mL
1997). 4
Treatment
Stabilization and Preparation of Test Animals 5.66 mL 5.66 mL 5.66 mL
5
Eighteen (18) healthy albino mice were divided Treatment
into six groups (six treatments) with three replications 0 mL 0 mL 0 mL
6
in each treatment. Each mouse was weighed using a
digital weighing scale and after acclimation for 48 computed using the protocol used in “Use of Moving Av-
hours with normal pellet and water diet ad libitum, were erages and Interpolation to Determine Median-Effective
fasted for twelve (12) hours before the procedures Dose” (Thompson, 1947).
(Conour, et al., 2006).

Page 2 of 7
 Table 2. ANOVA between the six treatments
Source of Variation SS df MS F P-value F crit
Between Groups 160.13 5.00 32.03 14.91 8.87E-10 3.31
Within Groups 141.75 66.00 2.15
Total 301.88 71.00
The result of the ANOVA shows that the six treatments have a significant difference since the F value of
14.91111 is greater than the F critical value of 3.308125.

Figure 1. Reduction Percentage Graph of the BGL

Figure 1 shows the graph of the BGL reduction percentage of the mice. All treatments showed an as-
cending graph. Treatment 5 showed the highest displacement percentage after 1, 3, 5, and 7 hours of admin-
istration, followed by treatment 4, 3, 2, 1, and 6 (Negative Control) consequently.

Relationship of Dosage Selection with the BGL given to the observations was 5.66 mL. This treatment
The increasing dosages in table 1 shows a pat- gave the highest mean BGL displacement of 19 mg/dl.
tern that as the dosage increases, the efficacy of the In treatment 5, there had been an average of 3.04 %
plant extract also increases within the given time. Table BGL displacement.
2, showing the BGL displacement every two (2) hours
upon administration up to seven (7) hours clearly sup- Table 3. Blood Glucose Displacement
ports the magnified effect of the plant extract in in- Treat-
creased dosages. Treatment 1 was administered the ment Repli- To- Mean
least amount of the pure plant extract, from the initial t=0 t=1 t=3 t=5 t=7
(Papaya cation tal Variance
BGL of 156, after 1 hour, dropped to 155 and conse- Extract)
quently displaced 1 mg/dl every 2 hours until the 7th
hour. Considering the 0 mg/dl displacements in two of 1 156 1 1 1 0 3
T1 0.02
the three trials of treatment 6 (negative control), this 2 166 2 1 1 0 4 3.333
mL
only shows that even a small amount of the plant ex- 3 146 1 1 1 0 3
tract affects the BGL of the subject. In table 3, the av- 1 143 3 2 1 1 7
T2 0.1
erage BGL displacement in treatment one is 3.33 mg/dl 2 151 4 1 0 1 6 8
mL
which is higher than the control group that recorded 3 131 2 2 1 1 7
2.33mg/dl. Still, this does not show any significant dif- 1 146 4 1 1 0 6
T3 0.39 157 5 2 1 1 9 8.33
ference in terms of BGL displacements as shown in the 2
mL
post ANOVA test, t-test. In the two-tailed critical value 3 140 4 3 2 1 10
of 2.82, treatments 1 and 5 had a tabular value of -6.13. 1 130 6 4 2 1 13
T4 1.57
2 117 7 4 2 3 16 14
This computed value is assumed to be due to mL
3 145 6 4 2 1 13
the difference of the dosage given in each treatment.
Treatment 1 was administered with 0.02 mL and treat- 1 162 7 6 5 2 20
T5 5.66 179 7 6 3 2 18 19
ment 5 with 5.66 mL, wherein the BGL readings in each 2
mL
treatment are significantly different. 3 152 8 5 4 2 19
T6 Nega- 1 171 1 0 1 0 2
Effective Dose tive Con- 2 165 0 1 0 1 2 2.332
Treatment 5, with the most amount of the plant trol 3 162 0 1 0 1 3
extract obviously had the highest BGL displacement.
This shows that most effective dosage of administration The table shows the BGL displacement of
of the fruit extract in the experimentation each treatment, showing treatment 5 with the highest
mean variance of BGL displacement within 7 hours.

Page 3 of 7
 Table 4. t-Test: Two-Sample Assum-
ing Equal Variances
Treatment Treatment Treatment Treatment Treatment Treatment Treatment Treatment Treatment Treatment Treat- Treatment Treatment Treatment Treatment
Treatment 2
1 1 3 1 3 1 5 1 6 2 ment 3 2 4 2 5

Page 4 of 7
Mean 0.83 1.58 0.83 2.08 0.83 2.08 0.83 4.75 0.83 0.5 1.58 2.08 1.58 3.5 1.58 4.75
Variance 0.33 1.17 0.33 2.45 0.33 2.45 0.33 4.57 0.33 0.27 1.17 2.45 1.17 4.09 1.17 4.57
Observa- 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12

Pooled 0.75 1.39 1.39 2.45 0.3 1.81 2.63 2.87

Hypothe-
sized
0 0 0 0 0 0 0 0
Mean
Difference
df 22 22 22 22 22 22 22 22
t Stat -2.12 -2.6 -2.6 -6.13 1.48 -0.91 -2.89 -4.58
P(T<=t) 0.02 0.01 0.01 1.80E-06 0.08 0.19 0 7.40E-05

t Critical 2.51 2.51 2.51 2.51 2.51 2.51 2.51 2.51

P(T<=t) 0.05 0.02 0.02 3.60E-06 0.15 0.37 0.01 0

t Critical 2.82 2.82 2.82 2.82 2.82 2.82 2.82 2.82

Not Significant Not Significant Not Significant Significant Not Significant Not Significant Significant Significant
Treatment Treatment Treatment Treatment Treatment Treatment Treatment Treatment Treatment Treat- Treat- Treatment Treatment
Treatment 6
2 3 4 3 5 3 6 4 5 mentT 4 ment 6 5 6
Mean 1.58 0.5 2.08 3.5 2.08 4.75 2.08 0.5 3.5 4.75 3.5 0.5 4.75 0.5
Variance 1.17 0.27 2.45 4.09 2.45 4.57 2.45 0.27 4.09 4.57 4.090909 0.2727 4.57 0.27

Observa- 12 12 12 12 12 12 12 12 12 12 12 12 12 12

Pooled 0.72 3.27 3.51 1.36 4.33 2.181818 2.42

Hypothe-
sized
0 0 0 0 0 0 0
Mean
Difference
df 22 22 22 22 22 22 22
t Stat 3.12 -1.92 -3.49 3.33 -1.47 4.974937 6.69
P(T<=t)
0 0.03 0 0 0.08 2.80E-05 5.00E-07
one-tail
t Critical 2.508324
2.51 2.51 2.51 2.51 2.51 2.51
one-tail 55
P(T<=t)
0 0.07 0 0 0.16 5.60E-05 1.00E-06
two-tail
t Critical 2.818756
2.82 2.82 2.82 2.82 2.82 2.82
two-tail 06

Significant Not Significant Significant Significant Not Significant Significant Significant

Table 4 shows the Post ANOVA test results where the following treatment comparisons showed significant differences: Treatment 1 and Treatment 5, Treatment 2 and Treatment
4, Treatment 2 and Treatment 5, Treatment 2 and Treatment 6, Treatment 3 and Treatment 5, Treatment 3 and Treatment 6, Treatment 4 and Treatment 6, and Treatment 5 and Treatment 6
DISCUSSION
Induction of Hyperglycemia
Hydrochlorothiazide is a diuretic characterized by
its ability to reduce osmotic pressure in the kidneys, caus-
ing less water to be reabsorbed by the collecting ducts.
This leads to increased urinary output. HCTZ is often used
in the treatment of hypertension, congestive heart failure,
symptomatic edema and the prevention of kidney stones
(Mills, 2007). Hydrochlorothiazide (HCTZ) is a thiazide
diuretic indicated for the treatment of mild to moderate hy-
pertension. Thiazides work,at least in part, by inhibiting
sodium reabsorption in the distal convoluted tubule (DCT)
(Ali et. al., 2012; Ecelbarger & Tiwari, 2006). Oral admin-
istration of HCTZ results in diuresis within 2 hours
(Bharbaiya et. al., 1982), indirectly leading to an initial re-
duction in plasma volume that attenuates with long-term
treatment (Shah et. al., 1978).
During the seven-hour duration of the experimen-
tation, the urinal activity of the test animals had a high fre-
quency, this is due to the diuretic effect of the drug.
Relationship of Dosage Selection with the BGL
Treatment 2 with an average BGL displacement of
8 mg/dL followed by treatment three with 8.33 mg/dL,
treatment four with 14 mg/dL, and treatment which had the
highest average BGL drop of 19 mg/dL had significant
BGL drops within 7 hours compared to the normal BGL
drop shown in treatment six. This further supports the fore
mentioned direct relationship of dosage and BGL as ob-
served in the results wherein as the the dosage increases,
the BGL decrease.
The results of the study is similar with the results
of the study entitled “Glucose-lowering Effect of Artocar-
pus camansi blanco (Kamansi) Leaf Extract in Alloxan-
induced Diabetic Abino Mice ” (Amande, 2015) wherein
the same formula of computation was used to determine
the approximate effective doses in increasing manner. The
results of the study also coincides with other studies that
utilized other plants such as: Lippia javanica (Arika et. al.,
2015), Maytenus putterkloides (Njogu et. al., 2016), Calot-
ropis gigantea (Rathod et. al., 2011), Cassia javanica
(Kumavat et. al., 2012), Flacourtia jangomas (Singh and
Singh, 2010), Clausena anisata (Ojewole, 2002) among
many others.
Hypoglycemic Effect of Saponin
The compound which brings the excessive sugar
level towards the normal range by certain biochemical re-
actions is known as hypoglycemic component. There are
several classes of organic compound which possess hypo-
glycemic activity such as terpenoids, steroids, saponins
flavonoids, alkaloids, glycans proteins (Harintenaina et al.,
2006).
The results of the experimentation coincide with the result
of the research conducted in Nigeria on the hypoglycemic
effect of saponin from the root of Garcinia kola (Smith et.
al., 2012), where it was stated that the anti-diabetic effect
of it was partly due to the insulin released from the existing
cells of the subject’s pancreas. Saponin is assumed to be
the main phytochemical present in C. papaya that triggers
Page 5 of 7
the hypoglycemic effect the study.
The study entitled Hypoglycemic Effect of saponin
from Tribulus terrestris states that level of serum glucose
could be significantly reduced by saponin from T. terrestris,
which was the rate of 26.25% and 40.67% in normal mice
and diabetic mice in respectively. This agrees with the re-
sults of the study with respect to the BGL of the albino mice
7 hours after the administration of the unripe C. papaya ex-
tract that was found to have presence of saponins.
Another study conducted by Sui, Lu, Li, Cai (1994)
corroborates with the hypoglycemic effect of saponins in
unripe C. papaya pulp stating that the results it which the
study conducted in 1994 showed that ASS (100, 200 mg/kg,
ip) could decrease various cases of experimental hypergly-
cemias induced by injection of adrenaline, glucose and
alloxan, without affecting the levels of blood sugar in normal
mice.
This also shows congruence with the past study
with results that showed that the saponins extracted from
their study exhibited strong inhibition of lipid peroxidation
and increased the levels of antioxidant enzymes (superoxide
dismutase and catalase) in the serum, liver and pancreas
when compared to the diabetic control (p ≤ 0.05). Moreover,
their results suggest that saponins from S. anguivi fruit can
enhance the hypoglycemic, hypolipidemic and antioxidant
properties in alloxan-induced diabetic rats, and may have
the potential to be used in the prevention or in the manage-
ment of diabetes (Elekofehinti et al., 2013). It could be de-
deuced that the biochemical reaction that occurs in S. an-
guivi may be similar to that of the unripe papaya wherein the
saponins were responsible for the inhibition of some meta-
bolic pathways resulting/ inducing to hypoglycemia.
CONCLUSION
The study was conducted in order to determine the
potential of the unripe C. papaya pulp as hypoglycemic
agent and to provide a prophylaxis for hyperglycemia and in
further cases, diabetes. This study was tested using a
standard glucometer device with albino mice as subject ani-
mals. After administering the pure plant extract, their blood
sugar level lowered showing treatment 5, the most effective
dose among the six treatments. The greatest displacement
within the given tine intervals was recorded in treatment 5
showing the effect of the pure unripe papaya pulp extract
treatments were given specific dosages using the approxi-
mate effective dosage formula. There is a significant differ-
ence in the level of effectiveness of the unripe C. papaya
pulp in lowering the BGL upon administration in albino mice
within the given time. There is a significant difference among
the treatments. The treatment in lowering BGL of mice using
the post ANOVA test, t-test was done to obtain the treat-
ment comparisons that showed significant differences. The
highest dosage of administration recorded the highest level
of displacement which was the most effective dose, 5.66
mL.
ACKNOWLEDGEMENTS
The researchers would like to extend their profound
gratitude and appreciation to Faith Crischelle R. Maldepeña,
for giving them the inspiration of conducting this kind of
study and for her full support and attention in dealing
with every detail of their study. Her guidance and pieces
of advice gave them hope to pursue and continue their
study amidst trials and conflicts. Without her, this study
would be beyond impossible.
To Dr. and Mrs. Rufino Sorupia, for welcoming
the researchers in their home in times of paper and prac-
tical works, for their support and assistance whether fi-
nancial and moral.
To the rest of the researchers’ parents, Engr.
Joel Ganancial and Mr. and Mrs. Cristulo B. Malde-
peña Jr., for providing them the financial and moral
needs in the process of conducting the study. Their un-
derstanding and consideration during the sleep overs
and overtime sessions would never be put to oblivion and
will always be remembered.
To Mrs. Bernadette Cortez, Mrs. Lourdes G. Ka-
hulugan, and Mrs. Ana Marie O. Cornell, for monitor-
ing and keeping in touch with the researchers so that
they may be aware of the rules and regulations as well
as their tie pace. Also, for their efforts to provide the re-
searchers resources to finish the conduct of their study.
To Mr. Ziggy Ryan O. Amores, for his patient
assistance and openness in imparting his knowledge to
the researchers that greatly contributed to the accom-
plishment of their study. He mentored the researchers
beyond technicalities and also in the fun and unique way
of dealing with life.
Most importantly, to the Almighty Father, to
whom all glory and honor they offer their strength,
knowledge and wisdom He has graced them to be able
to finish the study. Without him, all of this would be noth-
ing.
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