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Mitigation of the hyperglycemic effect of streptozotocin-induced diabetes albino rats using biosynthesized copper oxide nanoparticles

  • Ahmed Saber Hussein , Amr H. Hashem EMAIL logo and Salem S. Salem EMAIL logo
Published/Copyright: December 31, 2023
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Biomolecular Concepts
From the journal Biomolecular Concepts Volume 14 Issue 1

Abstract

Diabetes mellitus is a metabolic disorder described by compromised insulin synthesis or resistance to insulin inside the human body. Diabetes is a persistent metabolic condition defined by elevated amounts of glucose in the bloodstream, resulting in a range of potential consequences. The main purpose of this study was to find out how biosynthesized copper oxide nanoparticles (CuONPs) affect the blood sugar levels of diabetic albino rats induced by streptozotocin (STZ). In the current study, CuONPs were successfully biosynthesized using Saccharomyes cervisiae using an eco-friendly method. Characterization results revealed that biosynthesized CuONPs appeared at 376 nm with a spherical shape with sizes ranging from 4 to 47.8 nm. Furthermore, results illustrated that administration of 0.5 and 5 mg/kg CuONP in diabetic rats showed a significant decrease in blood glucose levels accompanied by elevated insulin levels when compared to the diabetic control group; however, administration of 0.5 mg/kg is the best choice for diabetic management. Furthermore, it was found that the group treated with CuONPs exhibited a noteworthy elevation in the HDL-C level, along with a depletion in triglycerides, total cholesterol, LDL-C, and VLDL-cholesterol levels compared to the diabetic control group. This study found that administration of CuONPs reduced hyperglycemia and improved pancreatic function as well as dyslipidemia in diabetic rats exposed to STZ, suggesting their potential as a promising therapeutic agent for diabetes treatment.

Keywords: streptozotocin; copper oxide nanoparticles; diabetes mellitus; insulin resistance; hyperglycemia; hyperlipidemia

Introduction

Nanotechnology has been extensively integrated into several aspects of human existence, including a diverse range of applications [1,2]. These applications notably include medical, biological sciences, diagnostics, medication delivery, food manufacturing, paints, technology, sports, environmental cleaning, cosmetics, and sunblocks [3]. The usage of nanoparticles has unexpectedly increased in a number of biological application domains, healthcare, and materials research in recent years [4,5]. As a result of technological advances in managing materials at the nanoscale for use in therapies, treatments in medicine and healthcare have experienced tremendous change. Consequently, the medicine’s ability to be appropriately targeted and transported to tissues limits organ damage and maximizes the drug’s effectiveness [6]. The distinctive characteristics revealed by nanoparticles make them very suitable for a diverse array of applications as drug delivery in the field of medicine, allowing for more effective and efficient treatment of diseases [2]. Diabetes mellitus (DM) is a medical condition that falls under the category of endocrine metabolic disorders. According to the International Diabetes Federation, 382 million children and adults globally suffered from DM in 2013, and the total number of diabetic patients is expected to increase to more than 592 million by the year 2025 [7]. DM is characterized by hyperglycemia as well as abnormalities in the production and/or action of insulin. Additionally, DM affects the metabolism of lipids, carbohydrates, and proteins [8]. Streptozotocin (STZ) is widely recognized as the primary chemical diabetogenic agent in experimental animals with type 1 and type 2 diabetes [9]. Recently, conventional treatments for diabetes include pharmacological therapies, which are often accompanied by adverse reactions and constrained effectiveness, while there has been a proliferation of synthetic medications used for diabetes management. Hence, it is essential to explore alternative therapy modalities that might offer a hypoglycemic effect. However, a considerable proportion of these pharmaceutical agents are associated with notable adverse effects in the long term. These consequences include the development of drug resistance and hepatotoxicity, as well as gastrointestinal symptoms such as stomach discomfort and diarrhea [10]. Additionally, nanoparticles are used in the manufacturing of electronic devices, where their small size and high conductivity make them essential for creating smaller and more powerful components [11]. Overall, the increasing use of nanoparticles across various disciplines holds great promise for advancing technology and improving the quality of life [12]. Furthermore, Akintelu et al. [13] reported that transition oxides, including ZnO, CuO, TiO2, Fe3O4, and NiO nanoparticles, have been identified as advanced nanomaterials in diverse domains such as energy, environmental, and biological sectors. This is primarily attributed to their notable characteristics of a large surface area and ability for adsorption. Copper is a prevalent transition metal that is often seen in metabolic processes. Copper oxide nanoparticles (CuONPs) are biocompatible, which means they are less likely to be harmful than other metallic nanoparticles that are often used in medical settings. Therefore, there has been a recent surge of interest among researchers in biologically produced metallic oxide nanoparticles due to their diverse therapeutic capabilities [14,15]. Scientists have discovered that these nanoparticles have a notable inhibitory effect on both α-amylase and α-glucosidase, which are recognized as important pharmacological targets in the management of T2DM. According to Sone et al. [16], CuONPs have antioxidant, anticancer, and antibacterial characteristics, making them potentially valuable for biological applications. Furthermore, CuONPs have also been examined by many groups for their in vitro antidiabetic effect [17]. Herein, this study aimed to assess the hypoglycemic effects of biosynthesized CuONPs in two different doses via a biological process in hyperglycemic albino rats.

Materials and methods

Preparation of CuONPs using the S. cerevisiae filtrate

CuONPs were synthesized by dissolving 2 mM of copper acetate in 100 mL of S. cerevisiae filtrate. The mixture was then stirred at 60°C for 10 h. After the incubation period, a dark green color appeared, indicating the formation of CuONPs. CuONPs were separated by centrifugation, and then they were subjected to drying, followed by annealing in a furnace at 150°C for 8 h.

Characterization of CuONPs

UV visible spectra were recorded with a UV-Vis spectrophotometer at a wavelength range of 200–800 nm for the confirmation of CuONP formation. The chemical changes and bonding between functional groups of the synthesized CuONPs were confirmed by Fourier transform infrared (FTIR) investigation. The crystal form of CuONPs was identified using X-ray diffraction (XRD) analysis. The formed CuONP dimensions and form were evaluated using transmission electron microscopy (TEM). Additionally, the nano-structural morphology and elemental composition of the synthesized CuONPs were investigated using scanning electron microscopy with energy-dispersive X-ray spectrometry (SEM-EDX).

Animal profile

Male adult albino rats with an average weight of around 150 ± 10 g were obtained for biological products and vaccines from the Egyptian company (Cairo, Egypt). Rats were placed in metallic cages at 25 ± 2°C with a regulated 12-h light–dark cycle and free access to diet and tap water for 1 week to acclimatize prior to starting the experiment.

Experimental design

Forty male Wistar albino rats (12-week-old) were used in the current study; the experimental animals were randomly categorized into non-diabetic, diabetic control, and diabetic-treated groups. Rats were randomly divided into four groups (10 rats) as follows: GI: non-diabetic rats (negative control); GII: diabetic rats (positive control of diabetes); GIII: diabetic rats (STZ + 0.5 mg/kg CuONPs); and GIV: diabetic rats (STZ + 5 mg/kg CuONPs). Diabetic rats were injected STZ intraperitoneally at a single dose (50 mg/kg body weight) freshly prepared in 0.1 M citrate buffer (pH = 4.5) within 15 min of dissolution to induce type 1 diabetes, while the negative control rats were injected a single dose of citrate buffer as a vehicle without any treatment, a standard diet, and tap water. The diabetic group was fasted for 18 h before STZ induction, while the diabetic-treated groups received STZ in combination with CuONPs for 28 days. Animals were examined for signs of toxicity daily, and blood glucose levels were recorded weekly. The rats, after being subjected to diethyl ether anesthesia, were sacrificed at the end of 28 days post-first week of STZ-induced diabetes. STZ, which is a highly selective pancreatic islet β-cell-cytotoxic agent synthesized by Streptomyces achromogenes, was acquired in the form of lyophilized powder from Sigma-Aldrich (Catalogue No. W302600, St. Louis, Missouri, USA). It is often used in animal models to induce both type 1 and type 2 DM, accompanied by hyperinsulinemia. The entry of STZ into the β cells is caused by glucose transporter-2, resulting in the alkylation of DNA [18].

Induction of STZ-induced hyperglycemia

After an overnight fast, STZ was intraperitoneally infused at a single dose (50 mg/kg body weight) freshly prepared in 0.1 M citrate buffer (pH 4.5) within 15 min of dissolution to induce type 1 diabetes [19]. The negative control group also received a single dose of citrate buffer, which is considered a vehicle. About 72 h later, following the injection, the blood glucose level was measured via the caudal tail vein to confirm diabetes after 1-week post-administration of STZ. Rats with estimated blood glucose levels over 200 mg/dl were chosen for the experiment, while those less than this range were rejected [20,21].

Random blood glucose measurement

Blood samples were collected from the distal caudal vein during the time frame of 9:00 to 10:00 a.m. These samples were then placed onto a test strip and promptly evaluated using a glucose monitoring system (Accu-Check) manufactured by Roche Diagnostics, Germany.

Biological sample collections

On day 28, rats were fasted for 12 h, and under diethyl ether anesthesia, blood samples were obtained from the retro-orbital venous plexus in two parts: the first part was collected on sodium fluoride (to prevent glycolysis according to RBC’s glucose consumption) for glucose monitoring, and the second part was collected without anticoagulants and then left at room temperature for about 45 min for clotting. Then, samples were stored at −80°C for biochemical investigations after being centrifuged at 4,000 rpm for 15 min.

Laboratory investigations

Biochemical investigations

All biochemical measurements were carried out using a spectrophotometer (Cary 100 UV-Vis, USA). For the biochemical tests, an enzymatic method based on Kaplan et al. [22] was used to measure the plasma glucose level, and an anti-rat insulin enzyme-linked immunoassay kit was used to evaluate the serum insulin level [23]. Serum triglycerides (TGs) and total cholesterol concentrations were estimated according to the colorimetric methods defined by Fossati and Prencipe [24] and a spectrophotometric method was used to estimate serum HDL-c levels in accordance with Warnick and Wood [25].

Calculation of insulin sensitivity

The homeostatic model assessment (HOMA) has been extensively used in many research investigations to evaluate the degree of insulin sensitivity and β-cell functions. This approach offers a non-invasive and simple means of estimating these parameters by using fasting blood insulin and glucose levels. In this context, FI stands for the measurement of fasting insulin levels, while FG stands for the measurement of fasting glucose levels, both expressed in millimoles per liter (mmol/L). The HOMA model is used to calculate IR and insulin secretion using the following formula: HOMA-IR was calculated using the formula FBS (mmol/L) * FI (µIU/ml)/22.5 described by Muniyappa and Lee [26] and HOMA-B was calculated using the formula 20*FI (µIU/ml)/[FBS (mmol/L)−3.5] according to Ghasemi et al. [27].

Statistical analysis

SPSS version 26 was used in the current study for data analysis; the experimental groups were compared using a one-way analysis of variance test. Statistical significance was defined as p-values < 0.05. The F-probability test was used to measure the extent of variation among groups. The study adhered to Armitage et al. [28] definition of statistical significance. The data were arranged in a tabular format and graphically shown using graphs.

  1. Ethical approval: The research related to animals' use has been complied with all the relevant national regulations and institutional policies for the care and use of animals. The experimental study was authorized by the ethics committee of the Faculty of Science at Al-Azhar University, Cairo, Egypt (AZHAR 15/2022). These procedures followed the “Guide for the Care and Use of Laboratory Animals” as outlined by the US National Institutes of Health No. 85–23, which ensures the proper use and welfare of experimental animals [29].

Results and discussion

Characterization of CuONPs

The biogenesis of CuONPs was proven by UV-visible spectra, as shown in Figure 1a. It was proven that the manufactured CuONP surface plasmon resonance caused their strongest absorption peak to appear at 376 nm. These results are in line with an earlier study on CuONP biosynthesis, which demonstrates that CuONP characterization is at its pinnacle [30]. FTIR spectroscopy was used to confirm that functional groups were present on the surface of the biosynthetic materials. Figure 1b displays the spectrum of CuONPs. The different functional groups that are present in the synthesized copper oxide NPs are represented by the detected peaks in the spectra. The absorption peaks of the biosynthesized NPs are predicted to be in the range of 3,415, 1,641, 1,409, 1,001, 873, 601, and 488 cm−1, and are attributed to the peak at 3,415 cm−1 to OH stretching. The 873–488 cm−1 absorption peaks are associated with the metal–oxygen (Cu–O) vibration pattern [31]. Primary and secondary alcohols are responsible for the peaks at 1,001 and 1,409 cm−1, respectively. The peak at 1,641 cm−1 is caused by the vibration patterns of aromatic and alkyl nitro compounds. Protein, carbohydrates, alcohol, and phenolic groups are all functional categories found in the extracellular preparations of S. cerevisiae. The extra proteins might make CuONPs more stable by forming a coating that prevents them from adhering to each other.

Figure 1 UV–Vis (a) and FT-IR spectra (b) of CuONPs synthesized by S. cerevisiae.
Figure 1

UV–Vis (a) and FT-IR spectra (b) of CuONPs synthesized by S. cerevisiae.

As shown in Figure 2a, XRD analysis was used to confirm the crystalline structure of CuONPs. The XRD pattern of the biosynthesized CuONPs demonstrates that they were crystallographic [32]. The diffraction peaks of CuONPs are shown in Figure 3 along with the diffraction characteristics for 2θ at 66.1°,61.1°, 51.5°, 48.2°,37.8°, 35.4°, and 33.7°, which correspond to the observations on the Bragg at 022, −113, 020, −202, −111, 111, and 110, respectively. The peaks of CuONPs with card No. 01-1117 (JCPDS File) were identical to those of the JCPDS of CuONPs [31,33]. The findings so unequivocally corroborate the CuONP synthesis. There are no further impurities found in the CuONP diffractogram. This guarantees the purity of the CuONP produced. TEM is most frequently used to determine the size and morphological characteristics of manufactured nanostructures. As verified by the TEM image (Figure 2b), CuONPs are produced in spherical shapes with typical size ranges of 4–47.8 nm. Saravanakumar et al. claimed that T. asperellum-synthesized CuONPs had a particle size range of 10–190 nm and a form that was almost spherical [34]. Other research studies showed that various fungi form CuONPs of various shapes and sizes [31,33].

Figure 2 XRD (a) and TEM analysis (b) of CuONPs synthesized by S. cerevisiae.
Figure 2

XRD (a) and TEM analysis (b) of CuONPs synthesized by S. cerevisiae.

Figure 3 SEM (a) and EDX spectra (b) of biosynthesized CuONPs.
Figure 3

SEM (a) and EDX spectra (b) of biosynthesized CuONPs.

SEM was employed to analyze the surface texture and particle size of CuONPs, as shown in Figure 3a. CuONPs had an almost spherical shape. The powder substance of CuONPs was ascertained via EDX analysis. The EDX spectra of CuONPs showed the presence of a number of distinct bands linked to copper, oxygen, and carbon constituents (Figure 3b). S. cerevisiae compounds are responsible for the carbon, but the Cu and O peaks represent the formation of CuONPs. Furthermore, EDX spectra showed the production of CuONPs that were extremely pure and without any further impurity-related peaks. Hassan et al. claimed that the predominant spectrum of EDX bands for the CuONPs generated biologically was copper and oxygen, with other minor peaks corresponding to macromolecules in the cell filtrate that interacted with CuONPs [35].

General observations

Regarding the STZ-induced-diabetic rat model, diabetes was confirmed in all rats with an elevation in blood glucose levels greater than 200 mg/dl multiple times. Although it is often believed that STZ should be administered at once after dissolution, it is recommended to induce diabetes in animals using solutions that have undergone anomer equilibration [36]. Furthermore, after the administration of STZ at a single dose of 50 mg/kg body weight, the baseline blood glucose levels in all experimental diabetic groups were found to be comparable. However, it was revealed that the blood glucose levels considerably increased from normal to hyperglycemia levels, as shown in Table 1. The antidiabetic effect of CuONPs was recorded at two different doses (0.5 and 5 mg/kg), respectively. The suggested dosages of CuONPs are associated with a study conducted by Eyo et al. [37], who reported that no mortality was seen in rats after oral administration of CuONPs at doses of 5 and 50 mg/kg b.w./day after 14 days. However, more comprehensive investigations would be required to validate the safety concerns associated with the escalated utilization of CuONPs among consumers. So far, this study focuses on many key factors associated with diabetic conditions, including chronic hyperglycemia, resistance to insulin, tolerance to glucose, and dyslipidemia. Following the administration of STZ, adult rats exhibited a range of physiological symptoms, including elevated blood glucose levels, reduced insulin levels, increased appetite (polyphagia), excessive urination (polyuria), excessive thirst (polydipsia), and concurrent weight loss. This shows the destruction of Langerhans islet cells, and the report by Eyo et al. [37] in the same strain of diabetic animal model (Rattus norvegicus) confirmed this in experimental albino rats.

Table 1

In vivo antidiabetic activity of synthesized CuONPs on fasting blood glucose (mg/dl), insulin (µIU/ml), HOMA-IR and HOMA-β levels in STZ-induced diabetic rats

Groups Parameters
Glucose (mg/dl) Insulin (µIU/ml) HOMA-IR HOMA-β
Mean ± SD P-value Mean ± SD P-value Mean ± SD P-value Mean ± SD P-value
Group I (negative control) 76.0 ± 15.5 13.0 ± 2.4 43.4 ± 8.9 3.8 ± 1.1
Group II (positive control of diabetes) 320.8 ± 76.7a 0.001 a 5.2 ± 1.0 0.001 a 75.3 ± 29.1a 0.01 a 0.3 ± 0.1a 0.001 a
Group III (STZ + 0.5 mg CuONPs) 155.8 ± 32.4a,b 0.01 a 9.4 ± 1.7 0.01 a 64.2 ± 13.1 N.S. 1.3 ± 0.4a,b 0.001 a
0.001 b 0.001 b 0.05 b
Group IV (STZ + 5 mg CuONPs) 150.2 ± 34.4a,b 0.01 a 9.4 ± 1.8 0.001 a 61.6 ± 15.9 N.S. 1.4 ± 0.5a,b 0.001 a
0.001 b 0.01 b 0.01 b
F probability P < 0.001 P < 0.001 P < 0.05 P < 0.001

Each value represents the mean values of six records ± SD.

Mean values with dissimilar superscript letters are significantly different at P < 0.05.

aSignificance (P-value) vs negative control group; bsignificance (P-value) vs positive control group.

The percentage of changes (%) is calculated by comparing the treated groups with the negative control.

Diabetic biomarkers used in diagnosis and prognosis

Fasting blood glucose levels in diabetic untreated rats and diabetic treated rats, respectively, were significantly elevated compared to non-diabetic rats. These findings suggest that STZ produces diabetes by damaging the β‐cells of the pancreas. This damage leads to a reduction in the production of endogenous insulin, therefore affecting the absorption of glucose by tissues. This elevation may be attributed to the toxic effects of STZ, which specifically targets and destroys pancreatic beta cells. Consequently, this damage results in a significant increase in blood glucose levels, perhaps resulting from the considerable reduction in insulin secretion caused by STZ. It was found that the blood glucose levels showed an increase in the positive control group of diabetes after induction with STZ on days 14, 21, and 28, compared to the normal group. Our findings agree with the study by Ghasemi and Jeddi [9], which reported that 24 h after injection, STZ has been a useful agent for inducing hyperglycemia in Wistar rats in the last decade. Nonetheless, glucose levels in diabetic rats that received treatment with CuONPs at doses of 0.5 and 5 mg/kg respectively, recorded a statistically significant reduction when compared to diabetic untreated rats; however, administration of CuONPs at a dose of 5 mg/kg is the best dose for antidiabetic control. CuONPs have been recognized as promising agents in the treatment of type 2 diabetes. Hemmati et al. [38] have shown that many trace metals have promising therapeutic properties in the context of blood glucose reduction. Furthermore, the insulin-mimetic properties of these substances are responsible for their hypoglycemic effects [39]. This result is also in line with prior research conducted by Martín Giménez et al. [40], which concluded that CuONPs have favorable therapeutic properties for T2DM treatment. Moreover, the results align with the discovery made by Umar et al. [41], who found that CuONP nanoparticles exhibited a substantial blood glucose level reduction in rats, along with other related parameters. These findings suggest that CuONP nanoparticles have the potential as a promising candidate for therapeutic development in diabetic management at two different doses while the Safety data sheet according to Regulation (EC), Sigma-Aldrich, 2020 and Assy et al. [42] reported the safety profile of CuONP administration at 125 mg/kg via oral gavage daily for 28 days. Furthermore, this dose (125 mg/kg) of CuONPs represents 1/20th of oral LD50 of CuONPs in rats (2,500 mg/kg).

The toxicity of STZ on the pancreatic beta cells responsible for insulin production is pronounced in mammalian organisms. This substance has the ability to specifically target and eliminate the cells that are accountable for the production and secretion of insulin. Consequently, it is used in research studies to develop type 1 DM (T1DM) in animal models by the administration of elevated doses [43]. The findings of insulin levels in rats subjected to STZ and STZ-treated rats administered CuONPs significantly declined as compared to the mean values of non-diabetic rats. The regulating role of insulin seems to be impaired under the hypo-insulinemic situation generated by the diabetogenic effect of STZ, thereby contributing to the observed hepatic glycogen depletion in diabetic rats. These results align with the findings reported by Shivanna et al. [44], which documented a decrease in hepatic glycogen levels in rats with diabetes caused by STZ. These results are consistent with the research conducted by Furman [45], which recorded that the induction of insulin insufficiency and hyperglycemia using STZ in diabetes animal models leads to injury of pancreatic β‐cells. However, insulin levels were significantly elevated in diabetic rats administered CuONPs at doses of 0.5 and 5 mg/kg compared to the mean values of diabetic untreated rats. The observed increase in body weight among hyperglycemic rats subjected to CuONP treatment may be attributed to enhanced metabolic processes that enhance the body’s ability to regulate blood glucose levels [46]. In contrast to the present investigation, a study by He and Zou [47] suggested that the release of generated Cu2+ from CuONPs is regarded as the primary factor contributing to the induction of oxidative stresses and the accumulation of excessive superoxide anions inside the cells. The results suggest the use of copper-chelating compounds as a preferable alternative to conventional antioxidants to mitigate the oxidative stress caused by CuONPs.

The homeostasis state related to STZ-induced hyperglycemia showed a statistically significant increase in the ratio of blood glucose to insulin in the STZ group. This observation might perhaps be attributed to the impairment of beta-cell activity and a substantial reduction in insulin production. The HOMA approach is employed to assess the sensitivity of insulin and β-cell function based on the fasting glucose and insulin levels. The HOMA-IR levels in untreated diabetic rats exhibited a statistically significant increase compared to HOMA-IR values in normal control rats. The elevated rate of gluconeogenesis in individuals with diabetes may be attributed to insufficient insulin levels or insulin resistance. This phenomenon implies that the efficacy of insulin in inhibiting lipolysis in tissues is diminished, perhaps resulting in a higher level of lipid oxidation. Similar results were found in investigations recorded by Amin et al. [48], which found that administering rats a single dose of STZ may kill pancreatic β-cells, which then causes insulin production to drop. Similarly, the represented data are close to those of a study by Ding et al. [49], which found that beta cells worked less well and the ratio of glucose to insulin was higher in rats that had been given STZ to make them diabetic compared to rats that were not diabetic. Nevertheless, no statistically significant disparity was observed between diabetic rats receiving CuONPs at doses of 0.5 and 5 mg/kg compared to non-diabetic rats. However, beta cell function (HOMA-β) levels were significantly lower in diabetic rats that were not treated and in diabetic rats that were treated with CuONPs. These levels were lower than the mean values for diabetic rats that were not treated, whereas the HOMA-β levels in diabetic rats treated with 5 mg/kg CuONPs showed a significant increase compared to the mean values of diabetic untreated rats. This significant improvement may be due to CuONPs having hypoglycemic activity because of their insulin-mimetic actions.

Diabetes patients exhibit changes in lipid profiles along with other metabolic markers. Dyslipidemia is a prevalent biochemical characteristic of problems associated with DM, mostly resulting from resistance to insulin and an insulin shortage. Insulin insufficiency specifically diminishes the activity of lipoprotein lipase, hence disrupting lipoprotein metabolism in individuals with diabetes. In this work, we find significant changes in the lipid profile of diabetic rats compared to normal rats. These changes included raised levels of TGs, t. cholesterol, LDL, and VLDL, as well as lower levels of HDL, showing the presence of hypercholesterolemia in the diabetic rats, as illustrated in Table 2. This study found that there was a substantial increase in blood total cholesterol levels in the diabetic-untreated group compared to the average values seen in non-diabetic rats. The results presented in this study are consistent with the observations made by Divya and Anand [50], who documented significant increases in blood TG and cholesterol levels, as well as anomalies in lipoprotein levels, in animal models with STZ-induced diabetes. In a different study, Pacifico et al. [51] suggested that IR could make it easier for free fatty acids to enter hepatocytes and break down fat in adipose tissues. In contrast, the levels of T. cholesterol in diabetic rats that received treatment with CuONPs at doses of 0.5 and 5 mg/kg b.w., respectively, exhibited a considerable reduction when compared to diabetic-untreated rats. These findings align with those of Umar and Daniel [52], who documented a significant reduction in cholesterol, TGs, LDL, and VLDL levels, accompanied by an elevation in HDL levels, among diabetic rats subjected to nanoparticle treatment in comparison to the diabetic control group. In contrast, a notable elevation in serum lipid levels was seen in the alloxan-induced rats that received treatment with CuONPs compared with the normal control group. The observed phenomenon might be attributed to a disruption in the control of lipase, an enzyme sensitive to hormones, by insulin. This disruption arises from a deficit or lack of insulin, which is induced by β-cell reduction in the islet of Langerhans [53].

Table 2

In vivo antidiabetic activity of synthesized CuONPs on the serum total cholesterol, HDL-C, LDL-C, VLDL-C, non-HDL-C and TG levels (mg/dl) in STZ-induced diabetic rats

Groups Parameters
Total cholesterol (mg/dl) HDL-C (mg/dl) LDL-C (mg/dl) VLDL-C (mg/dl) Non-HDL-C (mg/dl) TG (mg/dl)
Mean ± SD P-value Mean ± SD P-value Mean ± SD P-value Mean ± SD P-value Mean ± SD P-value Mean ± SD P-value
Group I (negative control) 103.2 ± 16.0 30.7 ± 4.1 57.0 ± 14.1 15.5 ± 2.3 72.5 ± 13.2 77.5 ± 10.8
Group II (positive control of diabetes) 185.7 ± 28.0a 0.001 a 18.2 ± 3.9a 0.001 a 134.8 ± 25.1a 0.001 a 32.7 ± 3.4a 0.001 a 167.5 ± 25.0a 0.001 a 164.0 ± 16.6a 0.001 a
Group III (STZ + 0.5 mg CuONPs) 103.2 ± 18.1b 0.001 b 25.7 ± 6.4b 0.05 b 55.7 ± 13.8b 0.001 b 21.8 ± 2.0a,b 0.001 a 77.5 ± 14.5b 0.001 b 108.3 ± 9.4a,b 0.001 a
0.001 b 0.001 b
Group IV (STZ + 5 mg CuONPs) 105.3 ± 17.8b 0.001 b 28.3 ± 6.3b 0.01 b 54.5 ± 17.2b 0.001 b 20.5 ± 1.2a,b 0.01 a 75.0 ± 17.3b 0.001 b 103.7 ± 6.8a,b 0.001 a
0.001 b 0.001 b
F probability P < 0.001 P < 0.01 P < 0.001 P < 0.001 P < 0.001 P < 0.001 P < 0.001

Each value represents mean values of six records ± SD.

Mean values with dissimilar superscript letters are significantly different at P < 0.05.

aSignificance (P-Value) vs negative control group; bsignificance(P-Value) vs positive control group.

The percentage of changes (%) is calculated by comparing the treated groups with negative control.

This study found no significant differences in serum HDL-cholesterol and LDL-cholesterol levels among non-diabetic control, diabetic-untreated, and diabetic-treated groups. However, diabetic rats treated with CuONPs showed significantly elevated HDL-C levels compared to untreated rats. LDL-C levels declined significantly in diabetic rats, while non-HDL cholesterol and TG levels also declined. The decline in lipid profile parameters may be due to impaired fatty acid synthesis, tissue lipases, inhibition of acetyl-CoA carboxylase, and the synthesis of TG precursors. This study suggests these alterations may be attributable to reduced fatty acid synthesis, tissue lipases, acetyl-CoA, and glycerol phosphate synthesis [54]. However, VLDL-C levels were significantly elevated in all experimental groups compared to non-diabetic rats. Diabetes reduces the activity of lipoprotein lipase, an enzyme that hydrolyzes triacylglycerols in VLDL and chylomicrons, and hyperlipidemia is caused by accelerated hepatic biosynthesis and release of VLDL-C without an increase in the lipoprotein lipase clearance from the blood, which relies on a high insulin-to-glucagon ratio. Various studies have found a general elevation in nearly all lipid profiles that are frequently associated with hyperglycemia in conjunction with these purportedly diabetes-induced alterations to carbohydrate metabolism. These alterations in hyperlipidemia in diabetic control rats in our study agree with the results of Mohammed et al. [55]. Although VLDL-C levels indicated a significant decline in diabetic rats after treatment with 0.5 and 5 mg/kg CuONPs compared to the mean values of diabetic untreated rats.

In diabetics, the regulation of T cholesterol, TGs, and lipoprotein is essential because disturbances in lipid metabolism are associated with cardiovascular complications [56]. Non-HDL cholesterol is an estimation of atherogenic lipoproteins and, according to recent guidelines, is a better risk indicator for cardiovascular disease. In accordance, there was a significant elevation in non-HDL cholesterol and TG levels in the diabetic-treated group compared to the mean corresponding values in non-diabetic rats. We regarded dyslipidemia due to diabetes and hyperglycemia as indicators of cardiovascular complications. Hypothesized causes of hypertriglyceridemia in diabetes include an increase in the triacylglycerol lipase activity, which stimulates the release of fatty acids stored within adipocytes. This promotes diabetic hypertriglyceridemia, which is confirmed by Almeida et al. [57]. The high serum total cholesterol content in diabetic rats is primarily due to elevated lipoprotein levels in STZ-induced diabetic rats and significant changes in lipoprotein metabolism, and these levels are characterized by elevated cholesterol and lipid levels and hepatic steatosis. The elevated TG level was increased in the synthesis of TG-rich lipoprotein particles in the liver, which diminished catabolism in diabetic rats. These findings also agree with the study of El-Demerdash et al. [58].

Conclusion

In the current study, CuONPs were successfully biosynthesized using S. cervisiae using an eco-friendly method. The characterization results showed that biosynthesized CuONPs appeared at 376 nm with a spherical shape and sizes ranging from 4 to 47.8 nm. The results revealed that treatment with 0.5 and 5 mg/kg CuONPs had significant antidiabetic effects by effectively lowering elevated levels of blood glucose, Total cholesterol, LDL-C, VLDL-C, and TG in addition to elevating the reduction of HDL-C and insulin levels in diabetic rats caused by STZ, after a treatment period of 28 days. The antidiabetic properties of CuONPs are augmented by their crystalline structure and increased surface area, leading to better absorption and distribution.

Acknowledgement

The authors express their sincere thanks to the Faculty of Science (Boys), Al-Azhar University, Cairo, Egypt, for providing the necessary research facilities.

  1. Funding information: Not applicable.

  2. Conflict of interest: The authors state no conflict of interest.

  3. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2023-10-09
Revised: 2023-12-06
Accepted: 2023-12-07
Published Online: 2023-12-31

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/bmc-2022-0037
Keywords for this article
streptozotocin; copper oxide nanoparticles; diabetes mellitus; insulin resistance; hyperglycemia; hyperlipidemia
Creative Commons
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Articles in the same Issue

  1. Research Articles
  2. Dipalmitoyl-phosphatidylserine-filled cationic maltodextrin nanoparticles exhibit enhanced efficacy for cell entry and intracellular protein delivery in phagocytic THP-1 cells
  3. Potential PDE4B inhibitors as promising candidates against SARS‐CoV‐2 infection
  4. Mitigation of the hyperglycemic effect of streptozotocin-induced diabetes albino rats using biosynthesized copper oxide nanoparticles
  5. Review Article
  6. Proteins turn “Proteans” – The over 40-year delayed paradigm shift in structural biology: From “native proteins in uniquely defined configurations” to “intrinsically disordered proteins”
  7. Communication
  8. 7Be and 22Na radionuclides for a new therapy for cancer
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  11. Setting up multicolour TIRF microscopy down to the single molecule level
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  14. A commentary on the inhibition of human TPC2 channel by the natural flavonoid naringenin: Methods, experiments, and ideas
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