INTRODUCTION:

Diabetes Mellitus is a chronic metabolic disorder characterised by high blood sugar levels accompanied by impaired carbohydrate, lipid, and protein metabolism as a result of insulin function insufficiency, which can be caused by impaired insulin production by the beta cells of Langerhans of the pancreas gland or caused by impaired insulin production by the unresponsiveness of the body's cells to insulin.¹

Diabetes mellitus is one of the causes of high morbidity and mortality, especially in pregnant women, which is often referred to as Gestational Diabetes Mellitus (GDM), mainly due to vascular complications. Gestational Diabetes Mellitus is defined as the glucose intolerance of various degrees that is first detected during pregnancy.^2-9 Gestational Diabetes Mellitus occurs due to increased formation of free radicals through glucose metabolism such as glucose auto oxidation, metabolism of methylglyoxal formation, and oxidative phosphorylation. One type of free radical that is highly reactive is the hydroxyl radical, which is highly toxic because of its ability to diffuse to transfer and then react with membrane lipids to produce malondialdehyde (MDA) products.¹⁰

Gestational Diabetes Mellitus causes blood sugar levels to increase and was first recognised during the second and third trimesters of pregnancy, but is often difficult to find because of the low ability to detect cases. It is rarely known because it is rare for pregnant women to be screened if there are no complaints or indications despite a family history.¹²

Gestational Diabetes Mellitus is one way that the Sustainable Development Goals (SDGs) aim to improve the health of mothers. ¹³The prevalence of Gestational Diabetes Mellitus in Indonesia is 1.9–3.6% in general pregnancy, while the prevalence in pregnant women with a family history of DM is 1.5%, of all pregnancies ranging from 1–14% to gestational diabetes mellitus, and the undiagnosed ranged from 10–25%. In fact, approximately 135,000 pregnant women experience gestational diabetes mellitus every year, which is 3–5%.¹⁴

The impacts that can occur in mothers with gestational diabetes mellitus are preeclampsia, eclampsia, caesarean section, cardiovascular complications, and foetal and maternal death. After the mother has given birth, she can be at risk for recurrent diabetes in the future, and babies born are at high risk for macrosomnia. 15. Based on the data, it was found that the causes of neonatal death were respiratory disorders or abnormalities (35.9%), prematurity (32.4%), sepsis 12%, hypothermia 6.3%, blood disorders/jaundice 5.6%, post-maturity 2.8%, and congenital abnormalities 1.4%.¹⁶

Treatment of gestational diabetes mellitus can be done by changing diet patterns, maintaining body weight, doing physical activity, and administering anti-diabetic drugs orally or giving insulin. However, long-term use of antidiabetic drugs can cause serious side effects on the body's organs, and the treatment is expensive. One of the treatments is to take metformin.¹⁷

Traditional alternative medicine has the advantage that it is easy to obtain, economical, and provides relatively low side effects, although in modern medical practise there are still few that have undergone preclinical and clinical trials.¹⁸ Alternatives include jackfruit seeds (Artocarpus heterophyllus Lam.)ingredients that can be used as an alternative diabetes treatment. Jackfruit seeds contain compounds such as flavonoids, saponins, alkaloids, terpenoids, steroids, and beta-carotene epoxide compounds that have the potential to lower blood sugar levels by inducing insulin secretion.¹⁹

The content of flavonoids in jackfruit seeds are insulin mimetic that can stimulate glycogen synthesis and as an insulin secretagogue that stimulates insulin production and has a protective effect on pancreatic cells.¹²Damage that occurs in pancreatic cells can be modelled in a hyperglycemic animal model using streptozotocin (STZ). Streptozotocin is transported to pancreatic cells via the glucose transporter (GLUT2), where it can cause DNA damage by increasing the activity of poly(ADP-ribose) polymerase (PARP-1).²⁰

Research that has been done (Sarian, 2017) says that flavonoid compounds have antioxidant and antidiabetic effects. The pharmacological properties of flavonoids are their ability as strong antioxidants, which have been reported to play an important role in reducing diabetes mellitus cases. Treatment of diabetes mellitus can be done with insulin. The dose of insulin used must be adjusted to the patient's blood sugar level. The use of insulin can cause weight gain and hypoglycemia. Because of this, there are a number of medicinal plants with anti-diabetic effects and few side effects, especially for pregnant women.²¹

Insulin resistance is a decrease in tissue response to the effects of insulin on glucose metabolism in the form of a decrease in glucose uptake in muscle and fat tissue. There is no interference with other insulin-dependent processes such as mitogenesis, protein synthesis, and triglyceride formation in fat cells.²² Measurement of insulin performance and ineffective pancreatic cell function due to insulin resistance can be used to assess the homeostatic model of insulin resistance (HOMA-IR). The two main pathophysiological mechanisms of HOMA-IR are pancreatic cell dysfunction and insulin resistance.²³

Previous research conducted "Development of Tape Food with Basic Ingredients from Jackfruit Seeds (Concrete) (Artocarpus heterophyllus Lam.) combined with Moringa Leaves (Moringa Oleifera Lam.) as an Antidiabetic Drug" showed that jackfruit seeds can be processed into tape food and have a texture which is semi-solid, aromatic and has a sweet taste and has a high protein content of 5.57% and can be useful as a type 2 Diabetes Mellitus drug.²⁴

Based on the previous research "Potential of Indonesian Plants as Antidiabetics through the Mechanism of Inhibition of -glucosidase Enzymes" and the results obtained that herbal medicines from plants in Indonesia have the potential as anti-diabetics, one of which is Jackfruit Seed (Artocarpus heterophyllus Lam.) macerated using ethanol 70 %.²⁵

The study "Activity of 70% Ethanol Extract of Jackfruit Seeds (Artocarpus heterophyllus Lam.) in Reducing Blood Sugar Levels of Streptozotocin-Induced Gestational Diabetes Rats" using the Tukey test showed a decrease in blood glucose levels in the test group of jackfruit seed preparation with a dose of 400 mg/kg BW, which is comparable to the positive group given Metformin at 51.37 mg/kgBW.²⁶

Based on the explanation above, the researcher is interested in conducting research on "The Effect of Ethanol Extract of Jackfruit (Artocarpus heterophyllus Lam.) seeds on Reducing Blood Sugar Levels and Anti-Inflammation in Wistar Streptozotocin-induced Gestational Diabetes Mellitus."

MATERIALS AND METHODS:

This study used a laboratory experimental research design with a post-test only control group design on Wistar White Rats with Gestational Diabetes Mellitus. Samples were obtained by a simple random sampling method. Therefore, experimental animals, experimental sites, and other research materials can be said to be homogeneous, while the Jackfruit Seed (Artocarpus heterophyllus Lam.) uses a purposive sampling method. This study will measure the effects of the ethanol extract of Jackfruit seeds (Artocarpus heterophyllus Lam.) in antidiabetic and anti-inflammatory treatments.

Each treatment group contained at least 5 Wistar White Rats with Gestational Diabetes Mellitus. The researchers chose to use 5 Wistar White Rats with Gestational Diabetes Mellitus in each group to maintain the mortality of experimental animals with a total of 3 treatment groups with doses of 100, 200, and 400 mg/kgBW/day¹⁹ so that the total number of research samples was 30 tails, which were divided into: group 1, normal control, which was not given any treatment, Group 2, negative control (injected STZ), group 3, positive control (injected STZ) + Metformin, group 4, (injected STZ) treatment with Ethanol Seed Extract of Jackfruit (Artocarpus heterophyllus Lam.) dose of 100 mg/kgBW/day, group 5, (injected with STZ)extract treatment of Jackfruit (Artocarpus heterophyllus Lam.) seed ethanol at a dose of 400 mg/kgBW/day.

RESULTS:

Blood Sugar Level Check:

The results showed that rats after diabetes induction after treatment of jackfruit seed ethanol extract at weeks 1 to 2 are shown in Table 1.

Table 1. KGD Analysis

Group	Mean
A	104.76±43.699
B	156.41±53.787
C	46.891±13.954
D	153.50±41.197
E	99.866±11.827
F	69.841±36.018
Nilai P	0.003

The lowest spectrophotometer KGD levels were in group C given Streptozotocin 45mg/kg BW + Metformin 45mg/kg BW, which was then followed by Group F given Streptozotocin 45mg/kg BW + ethanol extract of jackfruit seeds 400mg/kg BW with an average KGD 46,891 mg/dl with a standard deviation of 13,954. p- value 0.003 which means there is a significant difference between groups. However, group F showed a decrease in KGD, but in group C the decline in KGD was better than group F because metformin had a strong hypoglycemic ability compared to the other groups.

HOMA-IRCheck:

Table 2. HOMA-IR Analysis

Group	Mean
A	3.645±1.874
B	8.283±5.141
C	2.543±2.142
D	4.185±1.974
E	3.651±1.003
F	1.365±0.385
Nilai P	0.026

The highest HOMA-IR was found in the BD group given Streptozotocin 45mg/kg BW with a mean of 8,283 and a standard deviation of 5,141, while the lowest was in the F group given Streptozotocin 45mg/kg BW + jackfruit seed ethanol extract 400mg/kg BW with a mean of 1,365. with a standard deviation of 0.385. p - value was 0.026, meaning that there was no significant difference between groups, although statistically it did not show significance, but in group E, insulin resistance decreased compared to other groups receiving extracts or oral hypoglycemic drugs.

Insulin Check:

Table 3.Insulin Analysis

Group	Mean
A	0.749±0.225
B	0.596±0.125
C	0.660±0.050
D	1.347±1.065
E	0.814±0.154
F	0.724±0.280
Nilai P	0.388

The highest insulin levels were found in group D, given Streptozotocin 45mg/kg BW + jackfruit seed ethanol extract 100mg/kg BW, with a mean of 1,347 and a standard deviation of 1,065. The lowest insulin levels were found in group E, given Streptozotocin 45mg/kg BW + jackfruit seed ethanol extract 200mg/kg BW with a mean of 0.814 and a standard deviation of 0.154 with a p value of 0.388, meaning there was no significant difference between groups, but the extract in group D could increase insulin secretion higher than the other groups.

MDA Check:

Table 4. Activity MDA Analysis

Group	Mean
A	0.9521±0.4504
B	0.9182±0.3832
C	0.6610±0.3706
D	0.4285±0.3787
E	0.8205±0.5126
F	0.7158±0.4849
Nilai P	0.568

The highest MDA levels were in group D, given Streptozotocin 45mg/kg BW + ethanol extract of jackfruit seeds 100mg/kg BW, with a mean of 0.4285 and a standard deviation of 0.3787. The lowest MDA level was in group A as a normal control with a mean of 0.9521 and a standard deviation of 0.4504 with a p value of 0.568, meaning that there was no significant difference between groups. Group E extract was able to reduce oxidative stress activity better than other groups.

Interleukin-6 Check:

Table 5. Interleukin-6 Analysis

Group	Mean
A	0.031±0.045
B	0.090±0.054
C	0.093±0.012
D	0.166±0.210
E	0.078±0.044
F	0.075±0.054
Nilai P	0.511

The highest levels of Interleukin-6 were in group D given Streptozotocin 45mg/kg BW + jackfruit seed ethanol extract 100mg/kg BW with a mean of 0.166 6 with a standard deviation of 0.210, the lowest levels were in Group C given Streptozotocin 45mg/kg BW + induction Metformin 45mg/kg BW with a mean of 0.093 with a standard deviation of 0.012. p value is 0.511 which means there is no significant difference between groups.

DISCUSSION:

Jackfruit seed ethanol extracts 400mg/kg BW was able to reduce KGD and showed a significant difference between groups. These findings indicate that the ethanolic extract of jackfruit seeds contains flavonoids, alkaloids, saponins, steroids and terpenoids. Flavonoid compounds are a group of compounds that can be used to lower blood glucose levels. Although the group given ethanol extract of jackfruit seeds 400mg/kg BW showed a decrease in KGD, the reduction in KGD was better in group F who was given metformin 45 mg/kgBW because Metformin had a strong hypoglycemic ability compared to the other groups.

The lowest insulin levels were found in group E given Streptozotocin 45mg/kg BW + jackfruit seed ethanol extract 200mg/kg BW with a mean of 0.814 and a standard deviation of 0.154 insulin.

Flavonoids are antioxidants that have potential as free radical scavengers, metal chelators, and inhibitors of fat oxidation because they have a structure consisting of a hydroxyl group on the third carbon, has a double bond between the second and third carbons, the position of the fourth carbon has a carbonyl group and polyhydroxylation on the aromatic ring A and B.²⁷ Some other seed like Cumin (Cuminum cyminum) also have diuretic and antiinflammatery effect.²⁸

To assess oxidative stress levels through MDA markers, which were lower in group E given Streptozotocin 45mg/kg BW + jackfruit seed ethanol extract 200mg/kg BW, due to the high antioxidant activity of SOD which can reduce free radicals so that oxidative stress decreases in this group.

The lowest level of Inter Leukin - 6 was in group C which was given Streptozotocin 45mg/kg BW + Metformin 45mg/kg BW with a mean of 0.093 with a standard deviation of 0.012. Jackfruit seed ethanol extract contains triterpenoids where these compounds are related to membrane stability. Triterpenoid compounds from ligustrum have the ability to inhibit the activity of the cyclooxygenase enzyme in converting arachidonic acid into prostaglandins as inflammatory mediators.

CONCLUSION:

Ethanol extract of jackfruit seeds can reduce blood sugar levels with a dose of extract 400mg/kg BW with a p value of 0.003 better than the treatment and control groups.

ACKNOWLEDGMENT:

Authors are thankful to the Universitas Methodist Indonesia and Lincoln University College for academic support.

REFERENCES:

1. Departemen kesehatan republik indonesia, “Perlunya deteksi dini untuk cegah dan kurangi risiko diabete,” Perlunya deteksi dini untuk cegah dan kurangi risiko diabetes, 2016, [Online]. Available: www.depkes.go.id.

2. Lakshmi. K. Effectiveness of Nursing care of antenatal mothers with Gestational diabetes mellitus. Asian J. Nursing Education and Research. 2020; 10(3): 286-290. https://doi.org/10.5958/2349-2996.2020.00060.9

3. Sachin B. Somwanshi, Punam D. Bairagi, Kiran B. Kotade. Study of Gestational Diabetes Mellitus: A Brief Review. Asian J. Pharm. Res. 2017; 7(2): 118-123. https://doi.org/10.5958/2231-5691.2017.00020.X

4. Arul Mozhi. D, Vijaya Manickam. R, Mangala Gowri. Gestational Diabetes Mellitus –Prevention by Life Style Modification. Int. J. Adv. Nur. Management 2(3): July-Sept., 2014; Page 177-179.

5. Smitha K.R, Sandhya D’Almeida. Effectiveness of Self-Instructional Module on Knowledge Regarding Self-Care Management of Gestational Diabetes Mellitus among Antenatal Women Visiting Selected Antenatal Clinic at Mangalore”. Int. J. Adv. Nur. Management 3(1):Jan. - Mar., 2015; Page 42-45.

6. Marie Rosy, Litty Stanley. Evaluate The Effect of Post Prandial Exercise on Blood Sugar Level of Antenatal Mothers with Gestational Diabetes Mellitus at Women and Children‘s Hospital, Alappuzha. Int. J. Nur. Edu. and Research 2(4): Oct.- Dec. 2014; Page 350-355.

7. Sumanpreet Kaur, Harmanpreet Kaur. A Descriptive Study to Assess the Knowledge Regarding Diabetes Mellitus among the Residents of Selected Rural Community, Gurdaspur, Punjab. Int. J. Nur. Edu. and Research. 2017; 5(1): 19-26.

8. P. Maheshwari, T.S. Shanmugarajan. Gestational Diabetes mellitus effects on Macrosomia and risk of Developing Type 2 Diabetes in Tertiary care hospital. Research J. Pharm. and Tech. 2017; 10(6): 1589-1991. https://doi.org/10.5958/0974-360X.2017.00279.7

9. Maheshwari. P, Guna. B, Ranjith Kumar M, Renugadevi. S. Drug Utilization and Evaluation of Gestational Diabetes Mellitus. Research J. Pharm. and Tech 2017; 10(12): 4206-4208. https://doi.org/10.5958/0974-360X.2017.00768.5

10. Tandi J, Claresta JA, Ayu G, Irwan I. Effect of ethanol extract of kenikir (Cosmos caudatus Kunth.) leaves in blood glucose, cholesterol and histopathology pancreas of male white rats (Rattus norvegicus). Indonesian Journal of Pharmaceutical Science and Technology. 2018 Jun 28;1(1):70-8.

11. Hardyanti, S. 2019. Gambaran Kejadian Diabetes Melitus Gestasional (DMG) Di Kabupaten Sleman Kota Yogyakarta Tahun 2018 [skripsi]. Yogyakarta: Program Studi Kebidanan Program Sarjana Terapan Fakultas Ilmu Kesehatan Universitas ‘Aisyiyah Yogyakarta.

12. Sulistiyah S, Ismiatun L, Ernawati N, Shella S. Faktor Pendukung Timbulnya Resiko Gestasional Diabetes Mellitus Pada Ibu Hamil di BPS Kabupaten Malang. Jurnal Kesehatan Hesti Wira Sakti. 2017 Apr 15; 5(2):108-15.

13. Rahmawati F, Natosba J, Jaji J. Skrining diabetes mellitus gestasional dan faktor risiko yang mempengaruhinya. Jurnal Keperawatan Sriwijaya. 2016 Jan 22; 3(2):33-43.

14. RAHAYU VA, Herlina H, Solihah I. Uji Aktivitas Antidiabetes Ekstrak Etanol Daun Kenikir (Cosmos Caudatus Hbk) Terhadap Tikus Jantan Galur Wistar Yang Diinduksi Aloksan (Doctoral dissertation, Sriwijaya University).2018

15. Rahayu A, Rodiani R. Efek Diabetes Melitus Gestasional terhadap Kelahiran Bayi Makrosomia. Medical Journal of Lampung University [MAJORITY]. 2016 Nov 1; 5(4):17-22.

16. Kurniawan MB, Wiwin NW. Hubungan Antara Diabetes Melitus Gestasional Dan Berat Badan Lahir Dengan Kejadian Respiratory Distress Syndrome (RDS) Pada Neonatus di RSUD Abdul Wahab Sjahranie Samarinda. Borneo Student Research (BSR). 2020 Aug 4; 1(3):1805-12.

17. Introduction: Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018 Jan;41(Suppl 1):S1-S2. doi: 10.2337/dc18-Sint01.

18. Candra S, Widodo S A. Pengaruh pemberian ekstrak buah belimbing wuluh (Averrhoa blimbi L.) terhadap penurunan kadar glukosa darah tikus wistar yang diinduksi aloksan (Doctoral dissertation, Fakultas Kedokteran).2012

19. Dwitiyanti M, Efendi K, Rachmania RA, Septiani R. Aktivitas Ekstrak Etanol 70% Biji Nangka (Artocarpus heterophyllus Lam.) dalam Penurunan Kadar Gula Darah Tikus Diabetes Gestasional yang Diindukasi Streptozotocin. Jurnal Jamu Indonesia. 2019;4(1):1-7. doi: 10.29244/jji.v4i1.84.

20. Siahaan JM. Pengaruh Ekstrak Buah Labu Siam (Sechium edule Jacq. Swartz.) Terhadap Stress Oksidatif dan Resistensi Insulin pada Tikus Putih Jantan Galur Wistar Model Diabetes Mellitus Tipe 2.2020

21. Sutrisna EM, Tanti Azizah S, Lutfiana Dewi I. Antidiabetic activity of ethanolic extract of Eugenia polyantha wight leaf from indonesia in diabetic rat wistar strain induced by alloxan. Asian Journal of Pharmaceutical and Clinical Research. 2016; 9(1):374-76.

22. Purnamasari E, Poerwantoro B. Diabetes Mellitus dengan Penyulit Kronis. Majalah Kesehatan PharmaMedika. 2011; 3(2):276-81.

23. Siahaan JM, Illyas S, Lindarto D, Nainggolan M. The effect of ethanol and ethyl acetate fraction of chayote fruit (Sechium edule jacq. swartz) on the oxidative stress and insulin resistance of male white rat model type 2 diabetes mellitus. Open Access Macedonian Journal of Medical Sciences. 2020 Dec 15; 8(A):962-9. https://doi.org/10.3889/OAMJMS.2020.4517

24. Santosoa J, Ratnaningsihb D. Pengembangan Makanan Tape dengan Bahan Dasar dari Biji Buah Nangka (Beton)(Artocarpus heterophyllus Lam.) yang Dikombinasikan dengan Daun Kelor (Moringa Oleifera Lam.) sebagai Obat Antidiabetes Development of Food “Tape” with Basic Material from Jackfruit Seeds (Concrete)(Artocarpus heterophyllus Lam.) Combined with Moringa Oleifera.2019

25. Margono RS, Sumiati T. Potensi Tanaman Indonesia sebagai Antidiabetes melalui Mekanisme Penghambatan Enzim α-glukosidase. Jurnal Farmamedika (Pharmamedika Journal). 2019 Dec 12; 4(2):86-92. doi: 10.47219/ath.v4i2.84.

26. Dwitiyanti D, Rachmania A, Efendi K, Atmojo TT. Potensi Biji Buah Nangka (Artocarpus Heterophyllus L.) Dalam Menghambat Reseptor Alfa-Glukosidase Pada Tikus Diabetes Mellitus Gestasional Yang Terinduksi Streptozotosin Secara In Vivo Dan In Silico. InProsiding Seminar Nasional Berseri 2018 (pp. 118-130).

27. Hasim H, Arifin YY, Andrianto D, Faridah DN. Ekstrak Etanol Daun Belimbing Wuluh (Averrhoa bilimbi) sebagai Antioksidan dan Antiinflamasi. Jurnal Aplikasi Teknologi Pangan. 2019 Aug 12; 8(3):86-93. doi: 10.17728/jatp.4201

28. Bose D. Potentials of Cuminum cyminum in Microbial Control. International Journal of Advancement in Life Sciences Research. 2018 May 1:8-12. https://doi.org/10.31632/ijalsr.2021.v04i03.004

Received on 12.04.2022 Modified on 03.06.2022

Research J. Pharm. and Tech 2023; 16(2):804-808.

DOI: 10.52711/0974-360X.2023.00138