Acta Pharm. Sci.

Vol 60:(4), 2022

DOI: 10.23893/1307-2080.APS6026

The effect of breadfruit (Artocarpus altilis

(Parkinson) Fosberg) leaf extract on blood
glucose, lipid profiles, and weight loss in
alloxan-induced diabetic rats
Hardi HARDI1, Yulia Yusrini DJABIR2*, Hesty SETIAWATI1, Subehan LALLO3
1 Faculty of Pharmacy, Hasanuddin University, Makassar, Indonesia
2 Laboratory of Clinical Pharmacy, Faculty of Pharmacy, Hasanuddin University, Makassar, Indonesia
3 Laboratory of Phytochemistry, Faculty of Pharmacy, Hasanuddin University, Makassar, Indonesia

ABSTRACT
Diabetes mellitus is associated with abnormalities in lipid metabolism and weight
loss. This study aimed to examine breadfruit (Artocarpus altilis (Parkinson) Fos-
berg) leaf extract’s effects on lipid profiles and weight loss in alloxan-induced dia-
betic rats. Forty-five male Wistar rats were injected with alloxan and divided into
treatment groups: placebo, Artocarpus altilis leaf extract (100, 200, or 400 mg/kg)
or insulin (6U/200 g). Five additional rats were included as normal controls. Fol-
lowing 14 days of treatments, Artocarpus altilis extract lowered the blood glucose
(BG) level, but only significant at 400 mg/kg dose. Eighty percent of rats in the pla-
cebo group had a significant weight loss compared to 40% of rats in the 400 mg/kg
group. The placebo group had significantly higher total cholesterol (TC) compared
to controls (p<0.05) and the Artocarpus altilis extract treatment significantly re-
duced the TC level (p<0.05). In conclusion, Artocarpus altilis extract treatment
improves BG, lipid metabolism, and weight loss in alloxan-induced diabetic rats.
Keywords: Artocarpus altilis, breadfruit, alloxan, dyslipidemia, weight loss

*Corresponding author: Yulia Yusrini DJABIR

E-mail: yulia.yusrini@unhas.ac.id
ORCIDs:
Hardi HARDI: 0000-0002-2070-203X
Yulia Yusrini DJABIR: 0000-0002-5891-7247
Hesty SETIAWATI: 0000-0001-5705-4737
Subehan LALLO: 0000-0003-1746-1682
(Received 07 Feb 2021, Accepted 11 Aug 2022)

Acta Pharmaceutica Sciencia. Vol. 60 No. 4, 2022 413

 INTRODUCTION

Diabetes mellitus (DM) is a condition characterized by hyperglycemia due to in-

sulin resistance. It is estimated that people with diabetes mellitus have reached
463 million worldwide and are predicted to rise to 578 million by 20301. In ad-
dition to hyperglycemia, diabetes mellitus is associated with dyslipidemia due to
insulin modulation on lipid metabolism, which subsequently alters the activities
or the transport of lipid metabolism enzymes. The impact of diabetic-induced
dyslipidemia includes vascular complications, which lead to increased comorbid-
ity in DM patients2.

Weight loss is one of the clinical symptoms of non-insulin or insulin-dependent

DM. In the absence of insulin, the transport of blood glucose into the cells is
averted. As the cells fail to receive glucose as the primary energy source, the body
stimulates excessive mobilization of fat from the adipose tissues3, leading to dia-
betic weight loss. There is evidence that diabetic patients who lost weight without
having a lifestyle change had increased risks of mortality compared to those who
did not lose weight4.

The use of herbal products and supplements has increased rapidly over the past
three decades, with no less than 80% of people relying on herbal products5. It
has been reported that more than 1200 traditional plants may have been used as
the folklore of antidiabetic treatments6. Artocarpus altilis (Parkinson) Fosberg or
breadfruit is one of the plants that have been empirically used for DM treatments
and lipid disorders. In animal studies, Artocarpus altilis leaf extract was found
to increase pancreatic beta cell number in streptozotocin-induced diabetic rats7.
In line with this, Artocarpus altilis leaf extract also improves Langerhans islands
and exocrine tissue structures in the pancreas of alloxan-induced diabetic rats8, 9.
It is believed that Artocarpus altilis roles are not limited to glucose control since
Artocarpus altilis leaf extract was also beneficial to reduce free fatty acid levels
in obese rats10. Therefore, this study aimed to examine the effect of Artocarpus
altilis leaf extract administration on lipid profiles and weight loss in diabetic rats
induced by alloxan injection. The lipid profiles examined include cholesterol, tri-
glycerides, low-density lipoprotein (LDL), and high-density lipoprotein (HDL)
levels.

METHODOLOGY

Preparation and extraction of Artocarpus altilis

Artocarpus altilis leaves were harvested in Gowa, South Sulawesi. Only leaves
with yellowish color were handpicked from the trees based on the empirical use
of Artocarpus altilis leaves as a diabetes treatment in the area. The Artocarpus

414 Acta Pharmaceutica Sciencia. Vol. 60 No. 4, 2022

altilis leaves were authenticated by Dr. A. Mu’Nisa from the Department of Biol-
ogy, State University of Makassar, Indonesia, with an authentication number of
096/SKAP/LAB.BIOLOGI/VII/2019. The herbarium specimen was collected and
deposited in the Laboratory of Pharmacognosy, Hasanuddin University, Indone-
sia. The leaves were cleaned with tap water, sorted, dried, and finely chopped.
Artocarpus altilis leaves (150 g) were macerated using 70% ethanol (2.5 L) for
three days with an occasional stirring. The result of maceration was evaporated
using a rotary vacuum evaporator at 175 mbar coupled with a water bath at 400C
until thick extract was obtained. The remaining solvent was further reduced using
a desiccator.

Chemical preparation

Alloxan monohydrate was purchased from Sigma Aldrich. Diagnostic kits for cho-
lesterol, triglycerides, LDL, and HDL were purchased from Human Diagnostics
Worldwide (Germany).

Animal preparation

Fifty male Wistar rats were purchased from an animal laboratory breeding facility
(UD. Wistar, Yogyakarta, Indonesia). Animals were accustomed to the laboratory
environment for 14 days before starting the experiment. Animals received stand-
ard food and water ad libitum.

Experimental procedures

Forty-five rats were intraperitoneally injected with alloxan at a dose of 155 mg/
kg. The alloxan dose was chosen based on a previous study11 and adjusted in our
preliminary study. Ten minutes after injection, rats were given 5% glucose (2 ml)
through oral gavage to prevent hypoglycemia in rats. The blood glucose levels
were checked daily with a glucometer. After three days post-alloxan injection,
only rats with blood glucose levels> 200 mg/dl were defined as diabetic and re-
ceived treatments according to their groups.

Group I was given a placebo (sodium carboxyl methylcellulose, Na CMC 1%, n=5);
group II was given Artocarpus altilis leaf extract at the dose of 100 mg/kg; group
III was given Artocarpus altilis leaf extract at the dose of 200 mg/kg; group IV
was given Artocarpus altilis leaf extract at the dose of 400 mg/kg; group V re-
ceived insulin injection at the dose 6 IU/200 g. An additional group of rats (n=5)
that did not receive alloxan injection was also involved as normal controls.

Rats were weighed every day before receiving treatments to adjust the dose ac-
cordingly. The Artocarpus altilis extract treatments, as well as insulin injections,
were done once daily for 14 consecutive days. Blood samples were withdrawn at

Acta Pharmaceutica Sciencia. Vol. 60 No. 4, 2022 415

 the end of experiments to measure cholesterol, triglyceride, LDL, and HDL levels.
All lipid fractions were measured using Humalyzer 3500 according to the kits’
instructions.

Statistical analysis

All data are presented as mean ± SEM. Kolmogorov-Smirnov analysis is used

to test data distribution, while Levine’s test is used to determine the data’s
homogeneity. Normally distributed data were analyzed using one-way ANOVA
followed by a Least Significance Difference (LSD) post hoc test. Meanwhile,
not normally distributed data were analyzed with a Kruskal-Wallis analysis,
followed by a Mann-Whitney test. A significant difference was considered
achieved when P<0.05.

RESULTS and DISCUSSION

Dyslipidemia in diabetic patients is common since insulin-dependent path-

ways of lipid metabolisms were considerably altered12. Effective treatment of
diabetic-induced dyslipidemia can significantly reduce the risk of cardiovas-
cular disorders. In an effort to find an effective treatment for diabetic-induced
dyslipidemia, this study examined the effectiveness of Artocarpus altilis leaf
extract in improving lipid metabolism in diabetic rats.

In this study, 25 out of 45 rats experienced hyperglycemia or increased blood glu-

cose level after 72 hours from alloxan (155 mg/kg BW) injection. A previous review
has pointed out that alloxan’s diabetogenic effect could be unpredictable, as al-
loxan may induce diabetes in 33% to 60% of rats injected with 150 mg/kg to 170
mg/kg of alloxan13. Some factors may influence alloxan diabetogenic effects, in-
cluding the route and rate of injection, animal age, and type of diet14. Two different
pathogenesis were associated with alloxan-induced diabetes: 1) through a selective
inhibition of insulin secretion by specific inhibition on glucokinase; 2) induction of
the formation of ROS, causing selective necrosis of beta-pancreatic cells.

The increase in blood glucose levels varied among rats after alloxan injection,
but most rat BG levels reached >300 mg/dl, and the average BG levels were not
significantly different among groups. Figure 1 shows the blood glucose level
after 14 days of treatment administration. It is found that only the highest dose
of Artocarpus altilis extract (400 mg/kg) significantly reduced the blood glu-
cose level, which was similar to that seen with insulin treatment (p<0.05).

The body weights of alloxan-induced diabetic rats are depicted in Table 1.

Eighty percent of the placebo group, while only 40% of rats treated with extract
400 mg/kg or insulin, experienced weight loss.

416 Acta Pharmaceutica Sciencia. Vol. 60 No. 4, 2022

Table 1. The profile of rat body weight before alloxan injection (baseline), after treatment, and
overall changes in body weight of rats

Percentage of
Baseline weight Post-treatment Weight change
Groups an animal with
(a) (b) (b-a)
weight loss (%)
Normal (n=5) 243.4±20.0 g 259.2±18.3 g +15.8±6.0 g 0

Placebo (n=5) 210.4±15.3 g 188.8±13.3 g -21.6±13.1 g 80

Ext 100 (n=5) 239.0±17.8 g 224.6±35.5 g -14.4±19.4 g 40

Ext 200 (n=5) 232.4±17.8 g 216.0±17.8 g -16.4±9.3 g 80

Ext 400 (n=5) 206.0±3.3 g 205.0±16.2 g -1.0±14.3 g 40
Insulin (n=5) 226.0±14.4 g 225.2±7.3 g -0.8±11.3 g 40

+ weight change=weight gain; -weight change=weight loss

Weight loss could happen as the body has to compensate for the lack of energy
production from glucose by switching the source of ATP to non-carbohydrate
molecules, such as fat and protein from muscle tissues15. The body weight
changes varied in each treatment group. While the normal group gained
weight after 14 days of the experiment (15.8±6.0 g), a significant weight loss
was shown in the placebo, extract 100 and extract 200 groups, with an aver-
age of weight loss of 21.6±13.1 grams, 14.4±19.4 grams, and 16.4±9.3 grams,
respectively. Meanwhile, the insulin group and the 400 mg/kg Artocarpus al-
tilis extract group did not experience a marked decrease in their body weights.
This result could suggest a potential role of Artocarpus altilis leaf extract to
improve glucose metabolism in diabetic rats.

Figure 2 shows the levels of total cholesterol, triglycerides, LDL, and HDL in
alloxan-induced diabetic rats following 14 days of treatment. It is revealed that
the normal groups had total cholesterol (TC) levels of 41 to 116 mg/dl, with
an average of 71 ±12.3 mg/dl. Meanwhile, the diabetic rats that only received
a placebo had increased TC level (175 ±22.8 mg/dl), which was significantly
elevated compared to normal control. The Artocarpus altilis extract of 100
mg/kg, 200 mg/kg, and 400 mg/kg were found effective to lower the TC levels
of alloxan-induced diabetic rats (P<0.05), which was similar to that achieved
with the insulin treatment (P<0.05).

As seen in Figure 1, the placebo group had a slightly increased triglyceride level
compared to the normal group (65.6±2.7 mg/dl vs. 78.3±6.3 mg/dl); however,
it did not reach statistical significance. Out of the treatments given, only 100
mg/kg of Artocarpus altilis extract administration resulted in a reduction of

Acta Pharmaceutica Sciencia. Vol. 60 No. 4, 2022 417

 triglyceride level compared to the placebo group. Unlike the TC and triglycer-
ide levels, the HDL levels of diabetic rats were not significantly altered com-
pared to the normal group. Interestingly, there was an increase in LDL level
withrats100
of diabetic weremg/kg of Artocarpus
not significantly altered comparedaltilis extract
to the normal and
group. a reduced
Interestingly, there LDL
was an level with

insulin treatment; yet, these changes did not reach statistical significance
increase in LDL level with 100 mg/kg of Artocarpus altilis extract and a reduced LDL level with insulin com-
treatment;
pared yet, to
these changes
the normaldid notgroup.
reach statistical significance compared to the normal group.

Figure
Figure 1. The
1. The blood bloodlevels
glucose glucose levels in non-diabetic
in non-diabetic (normal)
(normal) and diabetic and diabetic
rats after receiving rats after receiving a
a placebo,
placebo,
Artocarpus leaf Artocarpus leaf400
extract 100, 200, extract 100,
mg/kg, 200, 400
or insulin mg/kg,
injection. or insulin
*P<0.05 injection.
between *P<0.05
the placebo group between the
placebo
and normal group#P<0.05
controls. and normal controls.
between treatment#P<0.05 between
groups and placebo. treatment groups and placebo.

The common characteristics of diabetic dyslipidemia include hypertriglyceridemia, low HDL

The and
cholesterol, common characteristics
elevated LDL, of diabetic
with hypertriglyceridemia dyslipidemia
being more include hypertriglyceri-
dominant16. Interestingly, alloxan
demia,
injection low only
in this study HDL cholesterol,
slightly and elevatedinLDL,
induced hypertriglyceridemia rats. Thewithbe-hypertriglyceridemia
discrepancy may originate
ingfact
from the more
that alloxan-induced . Interestingly,
dominant16diabetes alloxan injection
had different mechanisms in this
only slightly
from that develop study
in humans.
induced hypertriglyceridemia in rats. The discrepancy may originate from the
fact that alloxan-induced diabetes had different mechanisms from that devel-
op in humans.

418 Acta Pharmaceutica Sciencia. Vol. 60 No. 4, 2022

Figure
Figure2.2.The
The lipid profilesofofnon-diabetic
lipid profiles non-diabetic (normal)
(normal) andand diabetic
diabetic ratsrats
afterafter receiving
receiving placebo,
placebo,
Artocarpus leaf
Artocarpus leafextract
extract100
100mg/kg,
mg/kg,200 mg/kg,
200 mg/kg,400400
mg/kg, or insulin
mg/kg, injection.
or insulin A. Total
injection. A. Total cholesterol;
cholesterol; B. Triglyceride; C. High-density lipoprotein; D. Blood glucose. *P<0.05 between
B. Triglyceride; C. High-density lipoprotein; D. Blood glucose. *P<0.05 between the placebo group
the placebo group and normal controls. #P<0.05 between the treatment and placebo groups.
and normal
^P<0.05 controls.
between #P<0.05
the insulin andbetween
EXT 100the treatment and placebo groups. ^P<0.05 between the insulin
groups.
and EXT 100 groups.
Alloxan shares a similar molecular structure with glucose, hence. its cellular
Alloxan shares a similar molecular structure with glucose, hence. its cellular uptake is also facilitated
uptake is also facilitated by GLTU2 in beta-pancreatic cells. Alloxan diabe-
by GLTU2 in beta-pancreatic cells. Alloxan diabetogenicity comes from the selective inhibition of
togenicity comes from the selective inhibition of glucose-stimulated insulin re-
glucose-stimulated insulin release
lease through glucokinase through glucokinase
inactivation and ROSinactivation
production and
17 ROS production . Meanwhile,
. Meanwhile, the
17

the developmentofofdiabetes
development diabetes mellitus
mellitus in
inhumans
humans is is
farfar
more complex,
more involving
complex, a range
involving a of factors,
range of genetics,
including factors, nutritional
includingstate,
genetics, nutritional .state,
and environment 18
and environment
Dyslipidemia . Dys-
found in diabetes
18 mellitus type 2
lipidemia
patients found in diabetes
is progressively mellitus
developed type
due to 2 patients
insulin is progressively
resistance. developed
In contrast, alloxan injection acutely
damages the Langerhans islands of the pancreatic tissues, leading to a degeneration ofthe
due to insulin resistance. In contrast, alloxan injection acutely damages beta-pancreatic
Langerhans
cells islands
and a massive of the pancreatic
reduction tissues, leading
in insulin production to a19degeneration
and release of beta-is repeatedly
. This form of diabetes
pancreatic cells and a massive reduction in insulin production and release19.
associated with persistent ketoacidosis and hypercholesterolemia 20; yet, a significant increase in LDL
This form of diabetes is repeatedly associated with persistent ketoacidosis and
and triglyceride levels or 20
a reduction in HDL levels may inconsistently be observed in alloxan-induced
hypercholesterolemia ; yet, a significant increase in LDL and triglyceride lev-
diabetic rats 21, 22
.
els or a reduction in HDL levels may inconsistently be observed in alloxan-
induced
At the dosediabetic
of 400 mg/kg,
22
.
rats21,Artocarpus altilis extract improved blood glucose levels and prevented weight
loss in alloxan-induced diabetic rats. In addition to its hypoglycaemic effect, the administration of
Artocarpus altilis leaf ethanol extract significantly improved total cholesterol level compared to placebo

Acta Pharmaceutica Sciencia. Vol. 60 No. 4, 2022 419

 At the dose of 400 mg/kg, Artocarpus altilis extract improved blood glucose
levels and prevented weight loss in alloxan-induced diabetic rats. In addition
to its hypoglycaemic effect, the administration of Artocarpus altilis leaf etha-
nol extract significantly improved total cholesterol level compared to placebo
(p<0.05) and triglycerides, to a lesser extent, with the low dose. The effect of
Artocarpus altilis leaf extract treatments was similar to insulin in reducing to-
tal cholesterol levels in alloxan-induced diabetic rats. This result may indicate
the potential roles of Artocarpus altilis leaf extract as an alternative treatment
for diabetic hypercholesterolemia. Another study also reported the antidia-
betic effect of Artocarpus altilis extract occurred along with an improvement
in histological structures of the islets of Langerhans23. Indeed, the protective
effect of Artocarpus altilis extract has also been demonstrated in the liver and
kidneys of alloxan-treated animals24. The antidiabetic, antihypercholester-
olemic, and organ protective effects of the Artocarpus altilis leaf extract may
be related to the presence of high content of a range of phytochemicals con-
tent, including polyphenol compounds and flavonoids. It has been shown that
flavonoids and flavonoid-rich extracts, such as luteolin, curcumin, wild berry
extract, hawk tea, and anthocyanin extract, may inhibit cholesterol uptake via
inactivation of a cholesterol transporter, the Niemann–Pick C1-like 1 (NPC1L1)
protein, resulting in a decrease of blood cholesterol levels25. Further study is
still warranted to elucidate the specific bioactive compounds and the putative
mechanisms underlying the therapeutic potential of Artocarpus altilis extract.

STATEMENT OF ETHICS

All animal procedures have been approved by the institutional ethics commit-
tee at the Faculty of Medicine, Hasanuddin University, with an ethical clear-
ance number of 544/UN4.6.4.5.31/PP36/2019.

CONFLICT OF INTEREST

The authors declare to have no conflict of interest

ACKNOWLEDGMENT

The authors would like to thank the Indonesian Ministry of Research, Technol-
ogy, and Higher Education for the research grant support.

420 Acta Pharmaceutica Sciencia. Vol. 60 No. 4, 2022

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