INTRODUCTION:

The prevalence of diabetes mellitus (DM), a chronic illness, is steadily rising. Diabetes complications that necessitate emergent care, such as diabetic ketoacidosis and hyperglycemic hyperosmolar condition, frequently manifest in the emergency room¹. A serious heterogeneous metabolic disease, diabetes mellitus (DM) is typified by abnormal protein, lipid, and carbohydrate metabolisms that not only result in hyperglycemia but also in the dysfunction of several organs, including the heart, kidneys, nerves, eyes, and blood vessels^2,3,4. One of the leading causes of illness and mortality in human populations is diabetes mellitus ⁵. The failure of the wound healing process is also largely caused by a number of intricate pathophysiological variables⁶.

Hyperglycemia is a condition where blood sugar levels exceed the normal limits, which is one of the characteristic symptoms of diabetes mellitus. Diabetes mellitus is a disease caused by a disorder or dysfunction of metabolism in the pancreas, particularly the beta cells of the pancreas. The beta cells of the pancreas function as the site of insulin production and secretion, which helps control blood sugar levels⁷. There are two techniques for measuring blood sugar levels, one of which is the random blood sugar test (GDS). The random blood sugar test (GDS) is a blood sugar test that can be measured at any time without considering the last time you ate or drank. Unlike the fasting blood sugar test (GDP)⁸. This examination is conducted after fasting for at least 8 hours and is done in the morning. The cause of increased blood sugar can occur due to factors such as food, lifestyle, stress, and even the use of chemicals. The use of chemicals here includes both medications and other substances.The cause of high blood sugar can occur due to factors such as food, lifestyle, stress, and even the use of chemicals. The use of chemicals here can be in the form of medications or others⁹.

Diabetes mellitus and the associated complications are metabolic diseases with high morbidity that result in poor quality of health and life. The lack of diagnostic methods for early detection results in patients losing the best treatment opportunity. Oral hypoglycemics and exogenous insulin replenishment are currently the most common therapeutic strategies, which only yield temporary glycemic control rather than curing the disease and its complications¹⁰.

Streptozotocin was initially recognized as an antibiotic in the 1950s and was discovered in soil strains. This substance uses the microbe Streptomyces achromogenes, and in the mid-1960s, several researchers discovered that streptozotocin is selectively toxic to the beta cells of the Langerhans islets in the pancreas. Therefore, this substance is used in several studies on diabetic animal models and as a medical treatment for beta cancer cells, and it received approval as a chemotherapy drug by the Food and Drug Administration in 1982 and was marketed under the name Zanosar¹¹. STZ or streptozotocin has antibiotic and antineoplastic properties, which are very significant due to its high toxicity to beta cells, making it widely used in treating pancreatic cancer. In addition, researchers around the world have long used STZ to induce insulin resistance in test animals for studies related to diabetes. STZ is usually active in malignant diseases such as Hodgkin and other malignancies like carcinoma. Usually prepared in the form of an injection solution¹². STZ will not be active when administered orally and is best given intraperitoneally and intravenously. However, if given intravenously, STZ will be quickly cleared from the plasma, and after 3 hours of administration, STZ cannot be detected, although its metabolites can be detected within 24 hours. STZ is concentrated in several tissues such as the kidneys, liver, and pancreas. Whereas if STZ is administered intraperitoneally, the highest concentration is found in the liver and kidneys¹³. However, the kidneys will excrete 60-70% of the administered dose of STZ from the body through urine. It should be noted that stz cannot penetrate the blood-brain barrier in humans or animals, but its metabolites in humans are easily distributed to the cerebrospinal fluid¹⁴.

Speaking of the use of chemicals and drugs, the use of cytotoxic chemicals is often employed for human benefit in addressing various health issues, one of which is the use of streptozotocin in research related to diabetes mellitus. Diabetes mellitus (DM) is a metabolic disorder characterized by elevated blood sugar levels. In several scientific studies on diabetes, excessively high blood sugar levels are mostly caused by an unhealthy lifestyle, such as consuming foods high in sugar and fat^15-17. In this study, a cytotoxic substance, namely streptozotocin, was used. Streptozotocin itself is a compound that causes damage to proteins, cell membranes, and even DNA (Deoxyribonucleic acid) by forming highly reactive free radicals, leading to impaired insulin production by beta cells in the islets of Langerhans in the pancreas¹⁸. Some experts mention that streptozotocin enters the beta cells of the Langerhans islets in the pancreas through GLUT 2 (glucose transport 2) and ultimately causes alkylation¹⁹. This research was conducted to determine the relationship between increased blood sugar levels and their effect on the histopathological appearance of the pancreas, particularly the beta Langerhans cells, in Wistar white rat model animals using the cytotoxic diabetogenic agent streptozotocin administered via intraperitoneal injection ²⁰.

MATERIAL AND METHODS:

1. Ethical Approval:

Health research ethics committee Faculty of medicine Universitas Hasanuddin, Makassar, Indonesia (Approval No. 241/UN.4.6.4.5.31/PP36/2024).

2. Population and Sample:

The research subjects used in this study are white rats. (Rattus norvegicus). The samples used have the following criteria:

1. Male with an average weight of 250 grams

2. Not suffering from any disease and have never received treatment.

Where the rats were grouped based on treatment as follows: Group A (control group), Group B (STZ 35 mg/kgBW), Group C (STZ 40mg/kgBW), Group D (STZ 50mg/kgBW), and Group E (STZ 60mg/kgBW).

3. Data Source:

The sources of data used in this research are:

Primary data is data obtained directly by observing the research object and treating the research object, resulting in new data that is then re-tested through several stages of research.

4. Procedur of Research:

In general, this study will examine whether there are morphological abnormalities in the histopathological picture of the pancreas, specifically the islets of Langerhans, in white rats (Rattus norvegicus) that occur due to an increase in blood sugar levels beyond the normal range after being induced by STZ. STZ will be injected intraperitoneally into the four groups with graded doses.

Group A: Control group, only given standard feed during the study. For 3 days, GDS and BW examinations were conducted; after 72 hours, surgery and termination were performed, followed by histopathological examination of the pancreatic organ under a microscope.

Group B: Rats were adapted for 7 days and then injected with STZ at a dose of 35mg/kgBW. For 3 days, GDS and BW examinations were conducted, and after 72 hours, surgery and termination were performed, followed by histopathological examination of the pancreas organ under a microscope.

Group C: Rats were adapted for 7 days and then injected with STZ at a dose of 40mg/kgBW. For 3 days, GDS and BW examinations were conducted. After 72hours, surgery was performed, and the rats were terminated, followed by histopathological examination of the pancreas under a microscope.

Group D: The rats were adapted for 7 days and then injected with STZ at a dose of 50mg/kgBW. For 3 days, GDS and BW examinations were conducted, and after 72 hours, surgery and termination were performed, followed by histopathological examination of the pancreas organ under a microscope.

Group E: The rats were adapted for 7 days and then injected with STZ at a dose of 60mg/kgBW. For 3 days, GDS and BW examinations were conducted, and after 72 hours, surgery and termination were performed, followed by histopathological examination of the pancreas organ under a microscope.

RESULTS:

Table 1. The body weight of white rats (Rattus norvegicus) was measured initially and after the Homogeneity test and the One Way ANOVA test.

S. No.	Group	Weight (gram)	Homogeneity Test	One Way ANNOVA
1	Group A	250	0.577	P= 0,002
2	Group B	282	0.051
3	Group C	269	0.948
4	Group D	265	0.125
5	Group E	278	0.472

Explanation: The average figures among the four groups above differ significantly with the Homogeneity test and the One Way ANOVA test at a 95% confidence level.

Source: Primary Data

Table 2. The body weight of white rats (Rattus norvegicus) before being induced with STZ and after the Homogeneity test and One Way ANOVA test.

S. No.	Group	Weight (gram)	Homogeneity Test	One Way ANNOVA
1	Group A	421	0.637	P= 0,001
2	Group B	323	0.025
3	Group C	350	0.962
4	Group D	409	0.827
5	Group E	413	0.217

Explanation: The average figures among the four groups above differ significantly with the homogeneity test and the one-way ANOVA test at a 95% confidence level.

Source: Primary Data

Table 3. The body weight of white rats (Rattus norvegicus) on the first day after being induced with a graded dose of STZ and after the homogeneity test and one-way ANOVA test.

S. No.	Group	Weight (gram)	Homogeneity Test	One Way ANNOVA
1	Group A	305	0.714
2	Group B	276	0.262
3	Group C	308	0.472	P= 0,001
4	Group D	393	0.314
5	Group E	277	0.262

Explanation: The average figures among the four groups above differ significantly with the homogeneity test and the one-way ANOVA test at a 95% confidence level.

Source: Primary Data

Table 4. The body weight of white rats (Rattus norvegicus) on the second day after being induced with a graded dose of STZ and after the homogeneity test and one-way ANOVA test.

S. No.	Group	Weight (gram)	Homogeneity Test	One Way ANNOVA
1	Group A	307	0.502
2	Group B	278	0.017
3	Group C	293	0.103	P= 0,001
4	Group D	270	0.405
5	Group E	262	0.734

Explanation: The average figures among the four groups above differ significantly with the homogeneity test and the one-way ANOVA test at a 95% confidence level.

Source: Primary Data

Table 5. The body weight of white rats (Rattus norvegicus) on the third day after being induced with a graded dose of STZ and after the homogeneity test and one-way ANOVA test.

S. No.	Group	Weight (gram)	Homogeneity Test	One Way ANNOVA
1	Group A	306	0.972
2	Group B	280	0.161
3	Group C	291	0.980	P= 0,001
4	Group D	268	0.792
5	Group E	259	0.683

Explanation: The average figures among the four groups above differ significantly with the homogeneity test and the one-way ANOVA test at a 95% confidence level. Source: Primary Data

Table 6. Blood sugar levels when the white rat (Rattus norvegicus) first arrived and after the normality test, homogeneity test, and one-way ANOVA test.

S. No.	Group	Weight (gram)	Homogeneity Test	One Way ANNOVA
1	Group A	109
2	Group B	133
3	Group C	112	0,181	P= 0,001
4	Group D	124
5	Group E	113

Explanation: The average figures among the four groups above differ significantly with the homogeneity test and the one-way ANOVA test at a 95% confidence level.

Source: Primary Data

Table 7. Blood sugar levels of white rats (Rattus norvegicus) on the first, second, and third days after induction with a graded dose of STZ and after the homogeneity test and one-way ANOVA test.

S. No.	Group	Weight (gram)	Homogeneity Test	One Way ANNOVA
1	Group A	127
2	Group B	122
3	Group C	293	0,005	P= 0,001
4	Group D	464
5	Group E	450

Explanation: The average figures among the four groups above differ significantly with the homogeneity test and the one-way ANOVA test at a 95% confidence level.

Source: Primary Data

Figure 1. Group 1: Group A (control), Group 2: Group B (stz 35 mg/kgBW), Group 3: Group C (stz 40 mg/kgBW), Group 4: Group D (stz 50 mg/kgBW), and Group 5: Group E (stz 60 mg/kgBW)

Source: Primary data

Figure 2. Group 1: Group A (control), Group 2: Group B (stz 35 mg/kgBW), Group 3: Group C (stz 40 mg/kgBW), Group 4: Group D (stz 50 mg/kgBW), and Group 5: Group E (stz 60 mg/kgBW)

Source: Primary data

Figure 3. Explanation: group 1: group A (control), group 2: group B (stz 35 kg/bb), group 3: group C (stz 40 kg/bb), group 4: group D (stz 50 kg/bb), and group 5: group E (stz 60 kg/bb).

Source: Primary data

Figure 4. Explanation: group 1: group A (control), group 2: group B (stz 35 mg/kgBW), group 3: group C (stz 40 mg/kgBW), group 4: group D (stz 50 mg/kgBW), and group 5: group E (stz 60 mg/kgBW)

Source: Primary data

Figure 5. Histopathological description of the pancreas organ, specifically the Langerhans islet cells of group A mice (control)

Figure 6. Histopathological description of the pancreas organ, particularly the Langerhans islet cells in group B rats (STZ dose 35 mg/kgBW)

Figure 7. Histopathological description of the pancreas organ, particularly the Langerhans islets cells in group C rats (STZ dose 40 mg/kgBW)

Figure 8. Histopathological description of the pancreas organ, specifically the Langerhans islet cells in group D rats (STZ dose 50 mg/kgBW)

Figure 9. Histopathological description of the pancreas organ, particularly the Langerhans islet cells in group D rats (STZ Dose 60 mg/kgBW)

DISCUSSION:

Streptozotocin, or 2-deoxy-2-(([methyl(nitroso)amino] carbonyl)amino)-(α and β)-D-glucopyranose, is a natural antibiotic produced by Streptomyces achromogenes, and its toxicity to pancreatic β cells, or diabetogenic action, has been reported since 1963. The metabolism of STZ in rats. The STZ molecule (molecular formula = C₈H₁₅N₃O₇, molecular weight ≈ 265) has two parts: the glucopyranosyl group, which facilitates its absorption by pancreatic β cells through the glucose transporter 2 (GLUT2), and the nitroso-urea group, which damages the pancreatic β cells. STZ is widely used to induce diabetes in various animals because it selectively increases degenerative changes and necrosis of pancreatic β cells, resulting in insulin deficiency and impaired glucose oxidation. High blood glucose levels will increase oxidative stress through enzymatic and non-enzymatic processes. In the enzymatic process, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase can disrupt and damage cell function and produce reactive oxygen species, which can oxidize low-density lipoprotein (LDL). The non-enzymatic process will alter gene expression (growth factors and cytokines), disrupt antioxidant defenses (increased oxidative stress), and cause β-cell dysfunction^21,22.

STZ has a specific, rapid, and irreversible cytotoxic action on pancreatic cells. The destructive effect of STZ on β-cells begins 10 minutes after its IV injection; this idea is supported by experiments showing that IP NA injection together with or 10 minutes after STZ injection almost completely protects the pancreas of male Wistar rats from the destructive effects of STZ^23,24.

In the β cells of rodents, GLUT2 is the dominant glucose transporter. (Berger dan Zdzieblo, 2020). To support the hypothesis that the cytotoxic effects of STZ are associated with glucose transport capacity, RIN cells (rat insulinoma cell line), which do not express GLUT2 and instead express GLUT1, show resistance to STZ toxicity compared to RIN cells that express GLUT2 and those that are not transfected, respectively. Excessive expression of GLUT2 in RIN cells leads to high-affinity transport of STZ and, consequently, β-cell toxicity. Additionally, human islets, where GLUT3, and particularly GLUT1, play a major role in glucose transport, are resistant to STZ. (Berger dan Zdzieblo, 2020). Additionally, KATP channel-deficient mice are resistant to the diabetogenic effects of STZ due to lower GLUT2 activity. STZ causes pancreatic cell death (apoptosis and necrosis) through various mechanisms, including DNA alkylation, depletion of cellular NAD+ and thus energy deficiency, increased oxidative stress, and increased production of nitric oxide. Okoduwa et al.'s research shows that STZ-treated rats exhibit altered eating behavior and fluid intake patterns. Specifically, STZ-treated rats experience hyperglycemia and show significantly higher food and fluid intake compared to non-diabetic controls²⁵.

In this study, there was a drastic weight loss at STZ doses starting from 40kg/bw with the rats' body weight reaching >200grams. However, this did not occur if STZ was administered at doses below 40kg/bw. This study is in line with the research by Deeds et al., which shows that diabetes conditions caused by STZ initially lead to weight loss followed by stabilization or weight gain after an adaptive response is formed. Weight loss of up to 40% was observed within 14 days after STZ injection in the high-dose model. Nevertheless, the rats tend to survive well with islet transplantation and develop functional grafts. Dekel et al. reported STZ-related weight loss in heavier ICR mice, but these animals experienced lower blood glucose levels.

Previous research has shown significant physiological and histological changes in Wistar rats administered a diabetogenic agent with graded doses. For example, variations in body weight can be associated with catabolic processes and muscle atrophy triggered by hyperglycemia, which is characteristic of diabetes induction. The observed differences in blood glucose levels confirm the dose-dependent diabetogenic effects, consistent with the mechanism of agents like streptozotocin (STZ) that selectively damage pancreatic beta cells^26,27.

In this study, a significant increase in blood sugar levels was observed in white rats with an optimal dose starting from 50mg/kg, indicating a relationship between the injected STZ dose and the resulting diabetic condition. Based on the research by Ghasemi et al., doses of 10 mg/kg, 20mg/kg, and 25mg/kg of STZ do not have a hyperglycemic effect. Doses of 30mg/kg and higher create progressive hyperglycemia, with plasma glucose levels reaching a plateau at 60mg/kg when measured 48 hours after IV injection; there is no difference in fasting plasma glucose at doses of 60, 80, and 120mg/kg in male rats. A dose of 30-40mg/kg STZ produces transient diabetes with spontaneous recovery, but a dose of 50-70 mg/kg results in long-term diabetes associated with severe hyperglycemia and major clinical signs of diabetes. Although doses of 35-65mg/kg STZ (IP or IV) are used to induce type 1 diabetes in rats, 60mg/kg has been recommended as the commonly used diabetogenic STZ dose in rodents. However, it has been reported that an IP dose of STZ 40mg/kg is optimal for inducing diabetes with moderate hyperglycemia in Wistar rats. Overall, STZ doses < 35mg/kg, 40-55mg/kg, and 60 mg/kg play a major role in glucose transport, resistant to STZ. When diabeticogenic doses of STZ (45-65mg/kg) are injected into male Wistar white rats, a triphasic response is observed in blood glucose concentration. Furthermore, KATP channel-deficient rats are resistant to the diabetogenic effects of STZ due to lower GLUT2 activity.

The administration of streptozotocin has a significant effect in increasing blood glucose levels in diabetic rats. Research shows that streptozotocin induction results in increased blood glucose levels and clinical signs towards diabetes mellitus. This is consistent with the nature of streptozotocin, which typically induces symptoms in three phases after administration: an initial increase in blood glucose levels (hyperglycemia), followed by a decrease in blood glucose levels (hypoglycemia), and then a phase of permanent hyperglycemia.
STZ causes pancreatic B cell death (apoptosis and necrosis) through various mechanisms, including DNA alkylation, depletion of cellular NAD+ levels and thus energy deficiency, increased oxidative stress, and increased nitric oxide production. Excessive expression of GLUT2 in RIN cells leads to high-affinity transport of STZ and, consequently, cell toxicity. Additionally, human islets, where GLUT3, and particularly GLUT1, are considered low (sub-diabetogenic), medium, and high doses, respectively^28,29.

The STZ dose must be optimized so that diabetes is successfully induced and, at the same time, significant mortality can be avoided. (Goyal et al., 2016). Factors that need to be considered when using STZ dosage include the age of the animal, sex, strain, and route of administration. Therefore, it is recommended to produce a permanent STZ dose.

This study shows that there are histological changes in the pancreas organ of white rats, specifically hypertrophy of the Langerhans islet cells. A study has proven that there are pathological changes occurring in the form of hypertrophied Langerhans islets, which are observed to be caused by the efforts of pancreatic β cells to compensate for the insulin demand imposed by insulin resistance.¹⁸

The damage to the Langerhans islands that occurs after subsequent STZ injections is manifested by characteristics such as irregular pancreatic islet borders and a decrease in the number of pancreatic islets, consistent with previous research conducted on therapeutic compound investigations using STZ-induced rodent models.

The histopathological changes observed in the liver tissue of STZ-induced rats in this study included hydropic degeneration of hepatocytes and mild lobular inflammation. In previous studies, STZ-induced rat models were reported to experience fatty liver and histopathological changes, including lipid accumulation and lobular inflammation. Additionally, significant changes in pancreatic histology include the loss of pancreatic islets, increased hypertrophy of the islets, and increased fatty changes in the exocrine pancreas with a significant increase in hydropic degeneration of hepatocytes compared to healthy controls. These histopathological changes correspond to the body weight, food/caloric and water intake, as well as the biochemical parameters of the same rats previously published.

The results of another study are consistent with the findings of previous research, which showed significant physiological and histological changes in Wistar rats given a diabetogenic agent with graded doses. For example, variations in body weight can be associated with catabolic processes and muscle atrophy triggered by hyperglycemia, which are characteristic of diabetes induction. The observed differences in blood glucose levels confirm the dose-dependent diabetogenic effects, consistent with the mechanism of agents like streptozotocin (STZ) that selectively damage pancreatic beta cells.

Further histological examination validated these findings, revealing dose-dependent changes, including beta cell degeneration, reduced islet size, and increased infiltration of inflammatory cells. These changes underscore the impact of dose-dependent effects on pancreatic function and structure, providing a robust model for studying the pathophysiology of diabetes and potential therapeutic interventions.

CONCLUSION:

Based on the results of the hypothesis test and the discussion that has been conducted, it can be concluded that there are differences in body weight, blood sugar levels, and pancreatic histology in Wistar rats with graded doses. Based on the results of the one-way ANOVA statistical test, it is concluded that the administration of graded STZ doses affects body weight, random blood sugar levels, and the histopathological picture of the pancreas in the group of white rats. (Rattus Norvegicus). The first hypothesis proposed in this study is "It is suspected that there are differences in body weight, blood sugar levels, and pancreatic histology in Wistar white rats given graded doses of STZ This study successfully concluded that the administration of graded doses of STZ significantly affects body weight, random blood sugar levels, and the histopathological appearance of the pancreas.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

ACKNOWLEDGMENTS:

Thank you to all parties who have helped with this publication.

REFERENCES:

1. Burnett C, Evans DD, Mueller K. Managing Diabetes Mellitus in the Emergency Department. Adv Emerg Nurs J. 2024; 01; 46(1): 58-70. doi: 10.1097/TME.0000000000000500. PMID: 38285424.

2. Bishwanath Mishra, Durga M. Kar, Laxmidhar Maharana, Sujit Dash, Ganesh P. Mishra. Hypoglycemic activity of Methanol Fraction of Solanum torvum (Swartz) fruits in normal and Streptozotocin induced Hyperglycemic rat models. Research Journal of Pharmacy and Technology. 2022; 15(4): 1443-8. doi: 10.52711/0974-360X.2022.00239

3. Kadali SLDVRM, Das MC, Bayya MHRKG, MVK. Preliminary phytochemical screening and evaluation of effect of aqueous and ethanolic leaf extracts of Chloroxylon swietenia on blood glucose in streptozotocin induced diabetic rats. Research Journal of Pharmacy and Technology. 2019; 12(11): 5295-5300.

4. Devi MRC, Ramesh B. Hypoglycemic activity of Leaves of Bougainvillea spectabilis extract in streptozotocin-induced diabetic rats. Asian Journal of Pharmacy and Technology. 2018; 8(2): 99-103.

5. Tathagata Roy, Susanta Paul, Victor Roy Chowdhury, Arijit Das, Srikanta Chandra, Avik Das, Abhishek Jana, Muniraj Bhattacharya, Nibir Ghosh. Antihyperglycemic activity of Ficus carica leaves extracts on Streptozotocin induced diabetic rats. Research Journal of Pharmacy and Technology. 2021; 14(8): 4151-6. doi: 10.52711/0974-360X.2021.00718

6. Muhammad Luthfi, Tantiana, Aisyah Ekasari Rachmawati, Fathilah Binti Abdul Razak. Platelet Derived Growth Factor Expression after Administration of Okra Fruit Extract on Diabetic Wistar rats. Research Journal of Pharmacy and Technology. 2023; 16(11): 5329-3. doi: 10.52711/0974-360X.2023.00863

7. Ceriello A, Prattichizzo F. Variability of risk factors and diabetes complications. Cardiovasc Diabetol. 2021; May 7; 20(1): 101. doi: 10.1186/s12933-021-01289-4. PMID: 33962641; PMCID: PMC8106175.

8. Darenskaya MA, Kolesnikova LI, Kolesnikov SI. Oxidative Stress: Pathogenetic Role in Diabetes Mellitus and Its Complications and Therapeutic Approaches to Correction. Bull Exp Biol Med. 2021; May; 171(2): 179-189. doi: 10.1007/s10517-021-05191-7. Epub 2021 Jun 26. PMID: 34173093; PMCID: PMC8233182.

9. Imad S. Mahmoud, Khalil I. Altaif, Abdulrasool M. Wayyes, Watheq Mohammed Al – Jewari, Iyad A. Hailat, Moeen F. Dababneh. Diabetic Mellitus as a Predisposing factor in enhancing infections by Candida species and their Antifungal susceptibilities. Research Journal of Pharmacy and Technology. 2023; 16(11): 5189-2. doi: 10.52711/0974-360X.2023.00841

10. Sun Y, Tao Q, Wu X, Zhang L, Liu Q, Wang L. The Utility of Exosomes in Diagnosis and Therapy of Diabetes Mellitus and Associated Complications. Front Endocrinol (Lausanne). 2021; Oct 26; 12: 756581. doi: 10.3389/fendo.2021.756581. PMID: 34764939; PMCID: PMC8576340.

11. Capdevila J, Ducreux M, García Carbonero R, Grande E, Halfdanarson T, Pavel M, Tafuto S, Welin S, Valentí V, Salazar R. Streptozotocin, 1982-2022: Forty Years from the FDA's Approval to Treat Pancreatic Neuroendocrine Tumors. Neuroendocrinology. 2022; 112(12): 1155-1167. doi: 10.1159/000524988. Epub 2022 May 10. PMID: 35537416.

12. Szkudelski T. The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res. 2001; 50(6): 537-46. PMID: 11829314.

13. Rizk FH, El Saadany AA, Atef MM, Abd-Ellatif RN, El-Guindy DM, Abdel Ghafar MT, Shalaby MM, Hafez YM, Mashal SSA, Basha EH, Faheem H, Barhoma RA. Ulinastatin ameliorated streptozotocin-induced diabetic nephropathy: Potential effects via modulating the components of gut-kidney axis and restoring mitochondrial homeostasis. Pflugers Arch. 2023; Oct; 475(10):1161-1176. doi: 10.1007/s00424-023-02844-6. Epub 2023 Aug 10. PMID: 37561129; PMCID: PMC10499971.

14. Akinlade OM, Owoyele BV, Soladoye AO. Streptozotocin-induced type 1 and 2 diabetes in rodents: a model for studying diabetic cardiac autonomic neuropathy. Afr Health Sci. 2021; Jun; 21(2): 719-727. doi: 10.4314/ahs.v21i2.30. PMID: 34795728; PMCID: PMC8568204.

15. Sen S, Chakraborty R. Treatment and Diagnosis of Diabetes Mellitus and Its Complication: Advanced Approaches. Mini Rev Med Chem. 2015; 15(14): 1132-3. doi: 10.2174/138955751514151006154616. PMID: 26459815.

16. Rozalia Mamari, Rama Ibrahim. The effect of Chronic treatments of Type 2-diabetes mellitus on COVID-19 Morbidity and Symptoms Severity. Research Journal of Pharmacy and Technology. 2023; 16(11): 5130-6. doi: 10.52711/0974-360X.2023.00831

17. Shimizu K, Oniki K. [Development of a Novel Method for the Treatment and Prevention of Diabetes Mellitus]. Yakugaku Zasshi. 2019; 139(1): 39. Japanese. doi: 10.1248/yakushi.18-00163-F. PMID: 30606926.

18. Cheng AYY, Gomes MB, Kalra S, Kengne AP, Mathieu C, Shaw JE. Applying the WHO global targets for diabetes mellitus. Nat Rev Endocrinol. 2023; Apr; 19(4): 194-200. doi: 10.1038/s41574-022-00793-1. Epub 2023 Jan 16. PMID: 36646874.

19. Hardianto D. Bioteknologi dan Biosains Indonesia A Comprehensive Review of Diabetes Mellitus: Classification, Symptoms, Diagnosis, Prevention, and Treatment [Internet]. Tanggerang selatan, Banten; 2020 Dec. Available from: http://ejurnal.bppt.go.id/index.php/JBBI

20. Abdollahi M, Hosseini A. Streptozotocin. In: Encyclopedia of Toxicology: Third Edition. Elsevier; 2014. p. 402–4.

21. Kalkışım ŞN, Uzun ÖK, Öksüz CE. Pancreas: anatomy, variation, clinical and surgical perspective [Internet]. Available from: https://www.researchgate.net/publication/367531985

22. Capdevila J, Ducreux M, García Carbonero R, Grande E, Halfdanarson T, Pavel M, et al. Streptozotocin, 1982-2022: Forty Years from the FDA’s Approval to Treat Pancreatic Neuroendocrine Tumors. Neuroendocrinology. 2022; 112(12): 1155–67.

23. Ryadinency R, Hadisaputro S, Rachmawati B. Effect of zinc supplementation on triglyceride and malondialdehyde levels: Study on diabetic wistar rats induced with streptozotocin. Med J Indones. 2018; 27(2): 14–8.

24. Ghasemi A, Jeddi S. Streptozotocin As a Tool for Induction of Rat Models of Diabetes: a Practical Guide. EXCLI J. 2023; 22: 274–94.

25. Okoduwa SIR, Umar IA, James DB, Inuwa HM. Appropriate insulin level in selecting fortified diet-fed, streptozotocin-treated rat model of type 2 diabetes for anti-diabetic studies. PLoS One. 2017; 12(1): 1–21.

26. Deeds MC, Anderson JM, Armstrong AS, Gastineau DA, Hiddinga HJ, Jahangir A, et al. Single dose streptozotocin-induced diabetes: Considerations for study design in islet transplantation models. Lab Anim. 2011; 45(3): 131–40.

27. Berger C ZD. Glucose Transporters in Pancreatic Islets. Pflugers Arch. 2020; 472(1249): 72.

28. Goyal SN. Challenges and issues with streptozotocin-induced diabetes – A clinically relevant animal model to understand the diabetes pathogenesis and evaluate therapeutics. Chem Biol Interact. 2016; 244(49).

29. Wickramasinghe ASD, Attanayake AP, Wijesiri TW, Peiris HH, Mudduwa LKB. Pancreatic and hepatic histopathology of high-fat diet fed streptozotocin-induced Wistar rat model of type 2 diabetes mellitus. Ceylon J Sci. 2024; 53(2): 235–42.

Received on 14.12.2024 Revised on 15.04.2025

Accepted on 19.06.2025 Published on 01.10.2025

Available online from October 04, 2025

Research J. Pharmacy and Technology. 2025;18(10):4969-4976.

DOI: 10.52711/0974-360X.2025.00718

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.