Research ArticleExperimental Studies
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Efficacy and Mechanisms of Action of Oxytocin in NA/STZ-induced Diabetic Wistar Rats: Roles of Adipocytokines, PI3K/AKT, and AMPK Signaling Pathways

TAREK M. ALI, NOUR Y.S. YASSIN, AHMAD EL ASKARY, OSAMA M MEHANNA, AMGAD G. ELSAID, AMAL A. KHALIEFA and OSAMA M. AHMED
In Vivo November 2025, 39 (6) 3333-3350; DOI: https://doi.org/10.21873/invivo.14131

Abstract

Background/Aim: Type 2 diabetes mellitus (T2DM) is a prevalent disorder characterized by an increased concentration of blood glucose and impaired insulin function. Throughout the course of the disease, β-cell function fails and insulin production decreases. Studying the molecular systems responsible for insulin production, release, and action is crucial for the management and treatment of the disease. Thus, this study aimed to scrutinize the therapeutic efficacies of oxytocin (OXT) on nicotinamide (NA)/streptozotocin (STZ)-induced diabetes in rats and elucidate the underlying mechanisms.

Materials and Methods: Wistar rats were supplied a single intraperitoneal (i.p.) dose of NA (120 mg/kg) 15 min before an i.p. injection of STZ (60 mg/kg) after fasting for 16 h. Ten days later, the diabetic rats were orally administered OXT every day for eight weeks at dose levels 0.5, 1, and 2 IU/kg.

Results: The treatment of diabetic rats with OXT significantly improved oral glucose tolerance, serum insulin and C-peptide concentrations, and pancreatic islets’ structure and function. Furthermore, the activities of liver glucose-6-phospatase and glycogen phosphorylase significantly decreased. OXT treatment also resulted in an increase in serum adiponectin levels, while the levels of serum resistin, omentin, vaspin, and free fatty acids significantly decreased. Additionally, OXT significantly alleviated the mRNA levels of components of the PI3K-AKT and AMPK signaling pathways as well as their effectors including PPARγ, insulin receptor (IR), IR substrates 1 and 2 (IRS1 & IRS2), PI3K, AKT, AMPK, and glucose transporter 4 (GLUT4) in visceral adipose tissues of diabetic rats.

Conclusion: OXT can exert antidiabetic effects and may be useful for developing multiple targeted therapeutic strategies for diabetes treatment. The effects may be mediated via improvement in β-cell function, insulin secretory response, and insulin sensitivity.

Keywords:

Introduction

Approximately 90% to 95% of all cases diagnosed with diabetes mellitus (DM) are classified as type 2 DM (T2DM), which is characterized by high blood sugar levels, resistance to insulin, and a notable reduction in insulin production (1, 2). Globally, the prevalence of DM has increased, thereby becoming a severe public health problem (3, 4).

The primary cause of T2DM is insulin resistance, which also plays a significant role in the onset and progression of the disease. Insulin resistance occurs when insulin does not function or regulate properly, preventing target tissues such as skeletal muscle, adipose tissue, and the liver from responding normally to typical levels of insulin. When the body develops insulin resistance, insulin-sensitive cells are less able to utilize glucose effectively, which increases the risk of developing DM (5). Hence, correcting insulin resistance is a crucial therapeutic approach for T2DM. A study by Meng et al. discovered that two different signaling pathways, adenosine monophosphate-activated protein kinase pathway (AMPK) and phosphatidylinositol 3-hydroxykinase (PI3K)/protein kinase B (AKT/PKB), play crucial roles in maintaining glucose homeostasis by regulating glucose uptake and metabolism (6).

Elevated blood glucose concentration stimulates the release of insulin, which then binds to and activates its receptor, inducing tyrosine phosphorylation of insulin receptor (IR) substrates (IRS). This phosphorylation activates PI3K and AKT and controls glucose metabolism leading to an increase in glycogen synthesis and decrease in gluconeogenesis (7). Furthermore, activation of the PI3K/AKT signaling pathway increases cell surface expression of glucose transporter 4 (GLUT4), which mediates uptake of glucose into cells, lowering its blood levels (8). AMPK is a crucial protein kinase that also controls the metabolism of fatty acids and glucose (9). Activation of AMPK increases the production of glucose transporters, which facilitate absorption of glucose. It also stimulates glycolysis and improves fatty acid oxidation. Hence, the pharmaceuticals that have the potential to control the signaling proteins implicated in these processes show great promise for treating T2DM (10).

Oxytocin (OXT), synthesized in the hypothalamus, is involved in social behaviors such as maternal bonding (11). OXT has a therapeutic effect on individuals with DM by stimulating the production of insulin (12) and the regeneration of β-cells (13). A study by Aulinas et al. also found that long term OXT treatment of rats with DM lowered their blood sugar levels (14). There is also evidence that in individuals with metabolic syndrome, whether they have prediabetes or not, there is a link between OXT and glucose intolerance (15).

OXT increases the absorption of glucose in muscle cells. The expression of OXT-specific receptors in the Langerhans cells of rats indicates its role in the secretion of insulin and glucagon (16). Both asprosin and glucagon hormones increase blood glucose levels by stimulating liver glycogenolysis. Furthermore, the impact of OXT on insulin release from β-cells is regulated centrally by vagal cholinergic neurons, which innervate β-cells, as well as by activating expression of protein kinase C and phosphoinositide in β-cells (17).

OXT prevents body weight gain by stimulating fatty acid β-oxidation and lipolysis, while also enhancing motor activity (18). This effect is likely due to increased insulin synthesis, which promotes glucose transport across cell membranes and leads to a greater reduction in blood glucose levels.

To verify the therapeutic potential of OXT, it is essential to determine whether OXT can enhance the initial phase of insulin release during the early stages of DM (13). Insulin up-regulates glycogen synthesis and inhibits gluconeogenesis and glycogenosis via modifying the phosphoenolpyruvate carboxykinase (PEPCK) enzyme (19). PEPCK enables the conversion of oxaloacetate into phosphoenolpyruvate, promotes glycogenolysis and lowers blood sugar levels in individuals with diabetes (20).

This study aimed to evaluate the effects of different doses of OXT on glucose homeostasis, insulin sensitivity, adipocytokines, and pancreatic islet function and structure in nicotinamide (NA)/streptozotocin (STZ)-induced diabetic rats. In addition, it sought to examine the impact of OXT on key components of the PI3K/AKT, AMPK, and PPARγ signaling pathways.

Materials and Methods

Chemicals and drugs. NA and STZ were purchased from Sigma/Aldrich Chemical Company (St. Louis, MO, USA). STZ was preserved at −20°C, whereas NA was maintained at 2-4°C. Syntocinon (OXT) was obtained from Novartis (Lichtstrasse, Basel, Switzerland). All chemicals were of analytical quality.

Experimental animals. The study included fifty adult male Wistar rats, 130±10 g, purchased from VACSERA (Helwan Station, Cairo, Egypt). The selection criteria included healthy rats with no signs of disease or infection. Before the experiment began, the animals were closely monitored for two weeks to make sure they didn’t get infections. The animals lived in polypropylene boxes with good air flow in the animal house of the Zoology Department, Faculty of Science, University of Beni-Suef, Egypt. They were provided food and water ad libitum under a 12/12-hour light/dark cycle. The temperature was kept at a standard level (20 to 25°C). All experiments were performed according to the rules and guidelines of the animal care of the Faculty of Science Institutional Animal Ethics Committee, University of Beni-Suef, Egypt (Ethical Approval number: BSU/FS/2018/33). All precautions were taken to minimize the number of animals used, as well as to reduce pain, distress, and discomfort of the animals.

Induction of experimental diabetes mellitus in rats. After 16 h of fasting, a single intraperitoneal (i.p.) dose of 60 mg/kg b.w. STZ was administered to the rats. This was carried out fifteen minutes following an intraperitoneal dose of 120 mg/kg b.w. NA (21, 22). To treat the hypoglycemia that STZ caused after its injection, a 5% glucose solution was added to the rats’ drinking water. After 10 days of STZ injections, overnight-fasted rats were intragastrically intubated with glucose (3 g/kg b.w.). Following two-hours of glucose administration, blood samples were taken from the tail lateral vein and the blood glucose concentrations were measured using a glucometer (GM100; Bionime Corporation, Taichung, Taiwan, ROC). Rats with blood glucose levels between 180 and 300 mg/dl were included in the experiment.

Study design. After induction diabetes with NA/STZ administration, the rats were allocated into five groups (10 rats each) as indicated in Figure 1 and below:

Figure 1.
Figure 1.

Schematic figure of experimental design and animal grouping.

The first group, designated as the normal control (NC), consisted of healthy non-diabetic rats administered the same volume of the vehicle (0.9% NaCl; isotonic solution) every day for eight weeks by oral gavage. The second group, designated as the diabetic control group (DM), consisted of diabetic rats administered the same volume of the vehicle (0.9% NaCl) every day for eight weeks by oral gavage. The third group (OXT 0.5) consisted of diabetic rats that were daily administered OXT by oral gavage for eight weeks at a dose of 0.5 IU/kg b.w. The fourth group (OXT 1.0) consisted of diabetic rats that were daily administered OXT by oral gavage for eight weeks at a dose of 1.0 IU/kg b.w. The fifth group (OXT 2.0) consisted of diabetic rats that were daily administered OXT by oral gavage for eight weeks at a dose of 2.0 IU/kg b.w. OXT was dissolved in 0.9% NaCl before oral administration.

Serum collection. Following an overnight fasting, the rats were anaesthetized with diethyl ether inhalation, blood was withdrawn from the jugular vein into gel and clot activator tubes, and the rats were abruptly subjected to cervical decapitation. Following a 15-min centrifugation at 1,000 ×g, sera were rapidly separated, aliquoted into three Eppendorf tubes for each rat, and kept at −30°C until used.

Biochemical analyses. OGTT (Oral glucose tolerance test). By the end of the experiment (the day before sacrifice), overnight-fasted rats were orally administered glucose in distilled water (3 g/kg b.w), and glucose levels in the blood, collected from the lateral tail vein at 0, 60, 120, and 180 min after oral glucose loading, were measured using a glucometer (GM100; Bionime Corporation).

Measurement of serum insulin, C-peptide, adiponectin, resistin, omentin, and vaspin levels. Serum insulin was determined using the DRG® Rat ELISA kit (Catalog No: EIA-4127; DRG International, Inc. Springfield, NJ, USA). Serum fasting C-peptide (Catalog No: MBS704133), and resistin (Catalog No: MBS013451) were estimated using Rat ELISA kits from MyBiosource (San Diego, CA, USA). Rat ELISA kits obtained from CUSABIO (Houston, TX, USA) were used to measure serum omentin (Catalog No: CSB-E09747r), adiponectin (Catalog No: CSB-E07271r), and vaspin (Catalog No: CSB-E09813r) concentrations.

Detection of liver glucose-6-phosphatase (G6P) and glycogen phosphorylase activities, and serum free fatty acid (FFA) levels. The activities of liver G6P and glycogen phosphorylase were estimated based on the procedures described by Begum et al. (23) and Stalmans and Hers (24), respectively. FFA levels in the serum were estimated using FFAs assay kit (Roche Diagnostics GmbH, Mannheim, Germany) according to the manufacturer’s instructions.

Ribonucleic acid (RNA) isolation and quantitative real time-polymerase chain reaction (qRT-PCR) analysis. IR, IRS1, IRS2, PI3K, AKT, AMPK, GLUT4, and PPARγ mRNA levels in visceral adipose tissues were estimated using qRT-PCR. Qiagen tissue RNA isolation kits (QIAGEN, Germantown, MD, USA) were utilized to isolate the total RNA from frozen visceral adipose tissues. The concentration of RNA was measured at 260 nm. The reverse transcriptase qRT-PCR kit (Thermo Fisher Scientific, Waltham, MA, USA) was used to convert RNA into complementary DNA (cDNA). The next step was carried out using 2 μg of cDNA template, SYBR®-Green Master Mix (Thermo Fisher Scientific), and the relevant primers. The 2−ΔΔCt technique, as described by Rao et al. (25) was employed to compute levels of gene expression relative to those of β-actin. The qRT-PCR analyses were conducted in triplicate.

Histological investigation. For each group of rats, pancreas was fixed overnight in 10% neutral buffered formaldehyde solution before embedding in paraffin. Tissues were sectioned into 5-μm thick slices and the modified aldehyde fuchsin method was applied for staining (26, 27).

Immunohistochemical investigation. Pancreas tissue samples embedded in paraffin were used to prepare 5 μm thick sections. These sections mounted onto slides with a positive charge (Fisher Scientific, Pittsburgh, PA, USA). The immunostaining was conducted using the protocols outlined by Ahmed and Ahmed (28), Ahmed et al. (29) and Sayed et al. (21). After the sections were deparaffinized, rehydrated, received treatment for antigen retrieval, and sealed, they were put in a 3% H2O2 solution for 15 min to inhibit endogenous peroxidase activity. The reactions were blocked with bovine serum albumin and then the sections were treated overnight at 4°C with the primary insulin specific antibody (AA 46-59, antibodies-online.com, Limerick, PA, USA) at a dilution of 1:200. The peroxidase-labeled secondary antibody (1:200) was applied to the sections after they had been washed with PBS for 30 min. The bound antibody complexes were visualized by adding the 3,3-diaminobenzidine (DAB) substrate. Hematoxylin was then used to stain the sections mounted on slides. Afterward, the stained slices were analyzed using a light microscope at high-power (×400). Expression intensities were analyzed using ImageJ.

Statistical analysis. We used GraphPad prism 5 (GraphPad Software, San Diego, CA, USA) to perform a one-way ANOVA test followed by a Tukey’s post hoc test for statistical analysis. The data are expressed as mean±SE. p-Values <0.05 were considered to indicate significant differences.

Results

OXT ameliorates oral glucose tolerance (OGT) in diabetic rats. OGT was detected by measuring blood glucose concentrations at 0, 60, 120 and 180 min after oral glucose loading (Figure 2). For all-time points, the average blood glucose levels of diabetic control rats were significantly higher than those of normal control rats. Compared with the diabetic control group, OXT treatment (0.5 IU/kg, 1.0 IU/kg & 2.0 IU/kg) significantly lowered blood glucose levels at all examined time points. The effect of OXT at doses 1.0 IU/kg and 2.0 IU/kg was more potent on OGT of diabetic rats than that of the lowest dose (0.5 IU/kg). Moreover, the improvement effect of OXT at 1.0 IU/kg was the most potent.

Figure 2.
Figure 2.

Effects of oxytocin (OXT) on oral glucose tolerance (OGT) in diabetic rats. NC: Normal control group; DM: diabetes mellitus group; OXT 0.5: diabetes mellitus group treated with oxytocin at the dose of 0.5 IU/kg; OXT 1.0: diabetes mellitus group treated with oxytocin at the dose of 1.0 IU/kg; OXT 2.0: diabetes mellitus group treated with oxytocin at the dose of 2.0 IU/kg.

Effect of OXT on serum insulin and C-peptide levels. Figure 3 shows that insulin and C-peptide levels in the serum of the diabetic control group were significantly lower (p<0.001) than those in the normal control group. When diabetic rats were administered OXT, their serum insulin levels raised significantly at the doses of 0.5 IU/kg (p<0.05), 1.0 IU/kg (p<0.001), and 2.0 IU/kg (p<0.001). OXT 0.5 IU/kg, 1.0 IU/kg, and 2.0 IU/kg had a significant effect on the levels of serum C-peptide (p<0.001, p<0.01, p<0.01, respectively).

Figure 3.
Figure 3.

Effects of oxytocin (OXT) on serum insulin (A) and C-peptide (B) concentrations in diabetic rats. The results are shown as mean±SE. **p<0.01, ***p<0.001 indicate the level of significance compared to the normal control group (NC), and #p<0.05, ##p<0.01, ###p<0.001 indicate the level of significance compared to the diabetes mellitus group (DM). OXT 0.5: Diabetes mellitus group treated with oxytocin at the dose of 0.5 IU/kg; OXT 1.0: diabetes mellitus group treated with oxytocin at the dose of 1.0 IU/kg; OXT 2.0: diabetes mellitus group treated with oxytocin at the dose of 2.0 IU/kg.

Effect of OXT on serum adiponectin, resistin, omentin, and vaspin levels. Adiponectin levels in the sera of the diabetic control rats were much lower (p<0.001) than those in the normal control group. We noticed a significant rise in the levels of adiponectin after eight weeks of treatment with OXT at 0.5 IU/kg (p<0.01), 1.0 IU/kg (p<0.001), and 2.0 IU/kg (p<0.001) in comparison with the diabetes control. This indicates that a dose of 1.0 IU/kg of OXT raised the amount of adiponectin in diabetic rats more than the doses of 0.5 IU/kg and 2.0 IU/kg (Table I).

View this table:
Table I.

Effect of oxytocin (OXT) on serum adiponectin, resistin, omentin, and vaspin levels.

In contrast to adiponectin, the diabetic rats exhibited a significant rise in serum resistin, omentin, and vaspin levels (p<0.001) compared with the normal control rats. In the OXT (0.5 IU/kg, 1.0 IU/kg, and 2.0 IU/kg) treatment groups, the levels of resistin, omentin, and vaspin were significantly (all p<0.001) lower than those in the diabetic control. When diabetic rats were administered OXT at a dose of 0.5 IU/kg, the levels of omentin and vaspin were much higher than those at doses of 1.0 IU/kg and 2.0 IU/kg (Table I).

Effects OXT on liver G6P and glycogen phosphorylase activities and serum FFAs level. Table II shows that the diabetic rats had significantly higher levels of G6P and glycogen phosphorylase activities (p<0.001) as well as FFA concentration (p<0.05). When OXT (0.5 IU/kg, 1.0 IU/kg, and 2.0 IU/kg) was administered, the levels of G6P (p<0.001), glycogen phosphorylase (p<0.001), and FFAs (p<0.05) in the serum were significantly lower than those in the diabetes group. OXT at a dose of 1.0 IU/kg had a stronger affect than the other doses regarding the levels of G6P and glycogen phosphorylase in the liver, and FFAs in the serum.

View this table:
Table II.

Effect of oxytocin (OXT) on liver G6P and glycogen phosphorylase activities and serum FFAs level.

Effect of OXT on GLUT4 and PPARγ expression in visceral adipose tissues. The expression of GLUT4 in visceral adipose tissues of diabetic rats was significantly lower (p<0.001) when compared to normal control rats. When OXT (0.5 IU/kg, 1.0 IU/kg, and 2.0 IU/kg) was administered to diabetic rats, the expression of GLUT4 increased significantly (p<0.001) compared to its level in the diabetic rats. OXT exerted the highest effect at the dose of 1.0 IU/kg (Figure 4A).

Figure 4.
Figure 4.

Effects of OXT on visceral adipose tissue GLUT4 (A) and PPARγ (B) gene expression in diabetic rats. The results are shown as mean±SE. **p<0.01, ***p<0.001 indicate the level of significance compared to NC, and ###p<0.001 indicates the level of significance compared to DM. NC: Normal control group; DM: diabetes mellitus group; OXT 0.5: diabetes mellitus group treated with oxytocin at dose 0.5 IU/kg; OXT 1.0: diabetes mellitus group treated with oxytocin at dose 1.0 IU/kg; OXT 2.0: diabetes mellitus group treated with oxytocin at dose 2.0 IU/kg; GLUT4: glucose transporter type 4; PPARγ: peroxisome proliferator-activated receptor gamma.

The results also showed that the mRNA levels of PPARγ in visceral adipose tissues were significantly lower in diabetic rats in comparison with the normal control rats (p<0.001). However, OXT treatment (0.5 IU/kg, 1.0 IU/kg, and 2.0 IU/kg) significantly (p<0.001) increased the levels of PPARγ compared to the levels found in the diabetic control group; the dose of 2.0 IU/kg of OXT was the most effective (Figure 4B).

Effect of OXT on key signaling intermediates in the PI3K/AKT signaling pathway in visceral adipose tissues. In the DM groups, as shown in Figure 5A, the visceral adipose tissue mRNA expression of key signaling molecules in the PI3K/AKT pathway were significantly different from those in the NC group. In particular, IR, IRS1, IRS2, PI3K, and AKT levels were much lower (p<0.001) in diabetic rats in comparison with normal control rats. These changes in expression were greatly improved by administering OXT at doses of 0.5 IU/kg, 1.0 IU/kg, and 2.0 IU/kg (p<0.001). The results of all three doses were more or less similar.

Figure 5.
Figure 5.

Effects of oxytocin (OXT) on (A) PPARγ (B) IR, (C) IRS1, (D) IRS2, (E) PI3K, and (F) AKT gene expression in diabetic rats. The results are shown as mean±SE. *p<0.05, **p<0.01, ***p<0.001 indicate the level of significance compared to NC, and ###p<0.001 indicates the level of significance compared to DM. NC: Normal control group; DM: diabetes mellitus group; OXT 0.5: diabetes mellitus group treated with oxytocin at dose 0.5 IU/kg; OXT 1.0: diabetes mellitus group treated with oxytocin at dose 1.0 IU/kg; OXT 2.0: diabetes mellitus group treated with oxytocin at dose 2.0 IU/kg; IR: insulin receptor; IRS1: insulin receptor substrate 1; IRS2: insulin receptor substrate 2; PI3K: phosphatidylinositol 3-kinase; AKT: Akt kinase or protein kinase B.

Effect of OXT on AMPK signaling gene expression. As shown in Figure 6, the level of AMPK was significantly (p<0.001) lower in diabetic rats compared to healthy control. OXT (0.5 IU/kg, 1.0 IU/kg, and 2.0 IU/kg) increased AMPK expression compared to diabetic rats (p<0.001). Furthermore, AMPK expression increased more with OXT at a dose of 1.0 IU/kg than 0.5 IU/kg and 2.0 IU/kg doses.

Figure 6.
Figure 6.

Effects of oxytocin (OXT) on AMPK gene expression in diabetic rats. The results are shown as mean±SE. ***p<0.001 indicates the level of significance compared to NC, and ###p<0.001 indicates the level of significance compared to DM. NC: Normal control group; DM: diabetes mellitus group; OXT 0.5: diabetes mellitus group treated with oxytocin at dose 0.5 IU/kg; OXT 1.0: diabetes mellitus group treated with oxytocin at dose 1.0 IU/kg; OXT 2.0: diabetes mellitus group treated with oxytocin at dose 2.0 IU/kg; AMPK: adenosine monophosphate (AMP)-activated protein kinase.

Effect of OXT treatment on histological changes of pancreas. The pancreatic islets in the healthy control group had a well-organized and intact structure when examined under a light microscope (Figure 7A). The number of pancreatic exocrine acinar cells in the diabetic control was much lower than that in the normal control group. The shape of islets was not normal, and both the number and size of islet cells were diminished (Figure 7B). When diabetic rats were administered OXT at low, middle, and high doses, the size of the islets of Langerhans and the number of α-cells and β-cells within the islets were higher compared to the control group (Figure 7C-E). The high dose seemed to be the most effective in improving the integrity of the islets and the number of islet cells.

Figure 7.
Figure 7.

Photomicrographs of pancreatic section of normal (A), diabetic control (B), and diabetic rats administered oxytocin (OXT) 0.5 IU/kg (C), OXT 1.0 IU/kg (D) and OXT 2.0 IU/kg (E) (magnification, ×400). Photomicrograph A shows normal organized pancreatic islets of Langerhans (IL) with normal α-cells (a), β-cells (b) and δ-cells (d) and pancreatic acini (PA).

Photomicrograph B shows necrosis (nc), pyknotic nuclei (pk) in the islets of Langerhans (IL) that contain decreased number of α-cells (a), β-cells (b) and δ-cells (d). Photomicrographs C, D and E show marked improvements in the islets of Langerhans (IL) and increase in the number of α-cells (a), β-cells (b) and δ-cells (d) in diabetic rats treated with OXT 0.5 IU/kg, OXT 1.0 IU/kg and OXT 2.0 IU/kg. OXT 0.5: Diabetes mellitus group treated with oxytocin at dose 0.5 IU/kg; OXT 1.0: Diabetes mellitus group treated with oxytocin at dose 1.0 IU/kg; Diabetes mellitus group treated with oxytocin at dose 2.0 IU/kg.

Effect of OXT treatment on the immunohistochemical staining of insulin in the pancreas in diabetic rats. Figure 8A-F shows the variations in insulin granule concentration in the islets of Langerhans among the various groups. When compared to the normal control (Figure 8A), the concentration of insulin granules in the diabetic rats (Figure 8B) was significantly lower. The three OXT dosages administered to diabetic rats increased the expression of insulin in the pancreatic islets (Figure 8C-E). The OXT dose of 1.0 IU/kg was the most potent in increasing the concentration of insulin granules than the doses 0.5 IU/kg and 2.0 IU/kg OXT.

Figure 8.
Figure 8.

Immunohistochemical staining of insulin granules in the pancreatic islets in normal rats (A), diabetic control (B), and diabetic rats that were administered OXT at doses of 0.5 IU/kg (C), 1.0 IU/kg (D), and 2.0 IU/kg (E). The arrows indicate the brown staining of insulin granules. Compared to the normal control group, the number of insulin granule-positive cells was significantly lower in the diabetic groups, and significantly higher in the diabetic groups that were administered different doses of OXT compared to the diabetic control group. The results are shown as mean±SE. ***p<0.001 indicates the level of significance compared to NC, and ###p<0.001 indicates the level of significance compared to DM. NC: Normal control group; DM: diabetes mellitus group; OXT 0.5: diabetes mellitus group treated with oxytocin at dose 0.5 IU/kg; OXT 1.0: diabetes mellitus group treated with oxytocin at dose 1.0 IU/kg; OXT 2.0: diabetes mellitus group treated with oxytocin at dose 2.0 IU/kg; AMPK: adenosine monophosphate (AMP)-activated protein kinase.

Discussion

T2DM is a common metabolic disease characterized by an imbalance in energy intake, leading to metabolic stress, inflammatory responses, and elevated levels of fatty acids (30). Metabolic stress, persistent hyperglycemia and elevated fatty acid levels lead to dysfunctions in the islet beta cells in association with insulin resistance (21, 31-33). Malfunctions of the islet beta cells and insulin resistance increase the possibility of developing nephropathy, neuropathy, and cardiovascular disease (34-36) leading to a significant strain on the healthcare system. While there are multiple treatment options available for T2DM, including meglitinides, sulfonylureas, metformin, and alpha-glucosidase inhibitors, all of them have adverse effects. For instance, sulfonylureas can lose effectiveness and increase the risk of hypoglycemia (37). Similarly, metformin can cause intestinal discomfort and reduce the absorption of vitamin B12. Therefore, the pathogenesis and therapeutic strategies need further exploration.

OXT is a hormone mostly linked to the processes of labor and lactation. OXT and its receptor have the potential to be used as drug therapies due to their wide range of physiological actions (38). OXT may also have beneficial metabolic effects. It has the potential to control the absorption of glucose and the sensitivity to insulin through both direct and indirect effects (39). Furthermore, it has the potential to induce regenerative alterations in the islet cells of the pancreas in patients with diabetes. Infusing OXT, OXT analogs, or OXT agonists to activate the OXT receptor pathway could be a potential method for managing diabetes and its complications. In addition, OXT enhances insulin sensitivity through several mechanisms: 1) reducing lipotoxicity and glucotoxicity, as demonstrated by Westwright (40), 2) modulating chemokines and cytokines such as PI3K and adiponectin, and 3) decreasing fat mass, resulting in a drop in leptin levels (39, 41).

OGT is an excellent method to determine early abnormalities in the regulation of blood glucose levels (42, 43). The OGT results of our study showed that OXT effectively reduced the blood glucose levels following glucose administration compared to the diabetic control group. In addition to the alleviation of the blood glucose levels upon treatment with OXT, the liver G6P and glycogen phosphorylase activities were significantly down-regulated. The reduction in the levels of these two glucose-metalizing enzymes in the liver upon treatment with OXT reflects a decrease in glycogenolysis and decrease in the hepatic glucose output resulting in lower blood glucose levels.

The results of our study indicate that OXT effectively prevents loss of pancreatic β-cell function. This leads to a notable improvement in insulin secretion and a rise in the levels of C-peptide and insulin, compared to non-treated diabetic rats. Our findings align with those of Tura et al. (44), who assessed pancreatic β-cell activity using blood C-peptide and insulin levels.

OXT affects insulin release mainly through the vagal cholinergic neurons that form synapses with β-cells, and peripherally via activating protein kinase C and phosphoinositide in β-cells (17). Furthermore, histological and immunohistochemical investigations of the pancreas showed that treatment with OXT can improve islets’ histological architecture, integrity and function manifested by increase islets’ size, number of islet cells and insulin production in β-cells. These improvements were associated with increased serum C-peptide and insulin levels. Thus, OXT has not only the ability to increase regeneration of β-cells in the islets of Langerhans of diabetic rats, but also increases their efficiency to produce and release insulin. However, the study is limited by its focus on animal models, and additional studies are required to examine whether these effects apply to human subjects.

Many researchers have stated that adiponectin contributes to insulin’s function, and its levels in the blood are linked to insulin sensitivity in both healthy people and patients with diabetes (45-48). Resistin, on the contrary, has a strong effect on insulin and leads to high blood sugar levels, adipocyte proliferation, and obesity (49, 50). Several studies have presented positive links between insulin resistance and resistin in T2DM (51-54). Abell et al. (55) suggested omentin as a marker predictive of diabetes. Youn et al. (56) suggested that higher vaspin production might be a way for the body to counteract insulin resistance or problems with glucose metabolism. In the present investigation, we found that the levels of adiponectin in the blood were much lower in diabetic rats compared to normal control rats. However, the levels of resistin, omentin, and vaspin were much higher. Many earlier studies (21, 57-60) found the same results indicating the important roles of the alterations in the levels of adiponectin, resistin, omentin, and vaspin in the incidence and evolution of T2DM. Serum adiponectin levels increased significantly when diabetic rats were treated with OXT, while serum resistin, omentin, and vaspin levels decreased significantly. The higher doses (1.0 IU/kg and 2.0 IU/kg) were more effective than the lower dose (0.5 IU/kg). The higher amounts of these adipokines may play important roles in how well OXT functions to improve insulin sensitivity in diabetic rats.

It has been suggested that elevated levels of FFAs in the blood can lead to insulin resistance in T2DM (61) as well as in β-cell damage and dysfunction (21, 62). In this study, treating diabetic rats with OXT led to a significant drop in the level of serum FFAs. This drop in FFAs levels may play a significant role in the improvement of β-cells function and structural integrity and enhancement of tissue insulin sensitivity.

To determine the molecular process underlying OXT effects on T2DM, various components of PI3K/AKI and AMPK signaling pathways were investigated. The PI3K/AKI signaling pathway is widely recognized to have an essential role in insulin signal transduction and the regulation of glucose metabolism (63). Normally, insulin functions by binding to its receptor on the surface of cells (IR), which then triggers the IR’s intrinsic tyrosine kinase activity. This leads to the autophosphorylation of IR and the phosphorylation of other substrates (64). The IR that has undergone phosphorylation has the ability to attach to IRS1 and transmit insulin signals (65). IRS1 triggers the phosphorylation of AKT through the activation of PI3K (66). When this pathway is activated, plasma glucose is transported into the cytoplasm of hepatocytes through GLUT2. This leads to the production of glycogen (67) (Figure 9). The mRNA levels of IR, IRS1, IRS2, PI3K, and AKT in visceral adipose tissues were all greatly reduced in diabetic rats (p<0.001), showing that the PI3K/AKT pathway is impaired. These are all characteristics of T2DM that have been previously documented (68-70). Nevertheless, following eight weeks of treatment with OXT, deficiencies in the PI3K/AKT signaling pathway were improved, especially the expression levels of IR, IRS1, IRS2, PI3K, and AKT (Figure 9). The active PI3K can enhance insulin sensitivity by activating AKT and the mammalian target of rapamycin (mTOR) (Figure 9) (71). The alterations have the potential to impact cellular functions such as glucose uptake, insulin expression and release, cell growth, and cell survival (72).

Figure 9.
Figure 9.

Schematic illustration of the mechanisms by which oxytocin (OXT) improves glycemic control, lowers free fatty acids (FFAs), and enhances glucose and lipid metabolism. OXT activates the PI3K/AKT signaling pathway by up-regulating the expression of IR, IRS1, IRS2, PI3K, and AKT, which in turn stimulate glucose uptake (via increased GLUT4 expression) and suppress lipolysis. Additionally, OXT up-regulates AMPK expression, thereby promoting cellular glucose uptake, glycolysis, and lipid oxidation. GLUT4: Glucose transporter type 4; IR: insulin receptor; IRS1: insulin receptor substrate 1; IRS2: insulin receptor substrate 2; PI3K: phosphatidylinositol 3-kinase; PIP3: phosphatidylinositol (3,4,5)-trisphosphate; PTEN: phosphatase and tensin homolog; AKT: Akt kinase or protein kinase B; AMPK: adenosine monophosphate (AMP)-activated protein kinase; mTOR: mammalian target of rapamycin.

Therefore, the administration of OXT most likely stimulated the proliferation of pancreatic β-cells, enhanced insulin secretion by raising cell count, and relieved aberrant glucose metabolism linked to diabetes. AKT plays a vital role in regulating glucose homeostasis (73). When rats were treated with OXT, AKT activation increased glucose uptake through increased expression of GLUT4 (Figure 9). Furthermore, administration of OXT at a dose of 1.0 IU/kg had stronger effects on G6P and glycogen phosphorylase levels compared to OXT doses of 0.5 and 2.0 IU/kg.

It is well-established that activating AMPK can alleviate insulin resistance and improve lipid metabolism (10). Phosphorylation and activation of AMPK lead to the transport of glucose transporters to the cell surface and the uptake of glucose, as well as the stimulation of glycolysis and the rise in lipid oxidation (74, 75). The current study shows that diabetic rats exhibited hyperglycemia together with reduced levels of serum adiponectin and PPARγ mRNA in visceral adipose tissue. The administration of OXT increased the adiponectin level and PPARγ expression, and subsequently stimulated AMPK by increasing the AMPK expression. The increased expression of AMPK caused an elevation in the mRNA levels of GLUT4. In addition, the up-regulation of AMPK promoted the process of lipid oxidation, as indicated by the reduction in FFAs in diabetic groups treated with OXT. Moreover, OXT at a dose of 1.0 IU/kg had a greater effect on increasing the levels of PPARγ and adiponectin compared to doses of 0.5 IU/kg and 2.0 IU/kg of OXT. This dose also influenced the expression of AMPK and GLUT4. These findings show that OXT’s (at a dose of 1.0 IU/kg) stronger effect against diabetes may be due in part to GLUT4 activation through PPARγ, adiponectin/AMPK.

Conclusion

OXT exhibits potent antidiabetic effects, primarily through its insulinotropic action and its ability to enhance tissue insulin sensitivity. The insulin-sensitizing effects are mediated by modulation of adipokines, up-regulation of PPARγ, and activation of the PI3K/AKT and AMPK pathways. Future studies should investigate the long-term efficacy and optimal dosing of OXT in clinical settings. Although this study establishes a link between OXT and the PI3K/AKT and AMPK pathways, it does not address downstream effectors such as mTOR and FOXO1. Therefore, further research is warranted to validate the impact of OXT on these downstream targets.

Acknowledgements

The Authors would like to acknowledge the Deanship of Graduate Studies and Scientific Research, Taif University for funding this work.

Footnotes

  • Authors’ Contributions

    Conceptualization, T.M.A., N.Y.Y. and A.E.A.; methodology, T.M.A., O.M.M., A.E., A.A.K. and O.M.A.; software, A.E.A., O.M.M., A.E. and O.M.A.; validation, T.M.A., N.Y.Y. and A.A.K.; formal analysis, T.M.A., O.M.M., A.E. and A.A.K.; investigation, N.Y.Y., A.E., A.A.K. and O.M.A.; resources, T.M.A., A.E.A. and O.M.A.; data curation, A.E.A., O.M.M., A.E., A.A.K. and O.M.A.; writing – original draft preparation, T.M.A., N.Y.Y., A.E., A.A.K. and O.M.A.; writing – review and editing, T.M.A., N.Y.Y., A.E.A. and O.M.M.; visualization, T.M.A., N.Y.Y. and A.E.A.; supervision, T.M.A., A.E., A.A.K. and O.M.A.; project administration, T.M.A., A.E.A. and O.M.M.; funding acquisition, T.M.A. All Authors have read and agreed to the published version of the manuscript.

  • Conflicts of Interest

    The Authors declare no conflicts of interest in relation to this study.

  • Funding

    The Authors would like to acknowledge the Deanship of Graduate Studies and Scientific Research, Taif University for funding this work.

  • Artificial Intelligence (AI) Disclosure

    No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.

  • Received July 18, 2025.
  • Revision received August 24, 2025.
  • Accepted September 11, 2025.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Efficacy and Mechanisms of Action of Oxytocin in NA/STZ-induced Diabetic Wistar Rats: Roles of Adipocytokines, PI3K/AKT, and AMPK Signaling Pathways
TAREK M. ALI, NOUR Y.S. YASSIN, AHMAD EL ASKARY, OSAMA M MEHANNA, AMGAD G. ELSAID, AMAL A. KHALIEFA, OSAMA M. AHMED
In Vivo Nov 2025, 39 (6) 3333-3350; DOI: 10.21873/invivo.14131
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