Diabetes mellitus is a serious metabolic disease characterized by chronic hyperglycemia that can cause micro- and macrovascular complications [49]. Most diabetic drugs have adverse side effects, necessitating the introduction of alternative modalities such as natural products [50]. Recently, venomous products of some animals, including honey bees, have received great attention in the development of treatments for various diseases, including diabetes [51].
The study investigated the potential therapeutic effects of BPF from Egyptian HBV on STZ-induced DM1. The results showed that the STZ-diabetic rats had significantly higher plasma glucose levels than the normal control. However, BPF-treated rat groups showed a highly significant improvement in plasma glucose levels compared to the STZ-induced DM1 group. Additionally, BPF has been reported to have hypoglycemic effects, possibly through its ability to increase insulin secretion and enhance insulin sensitivity [52]. In support of this, bradykinin, a component of BPF, can upregulate insulin receptor tyrosine kinase activity and increase insulin-stimulated glucose uptake [52], leading to improved glucose metabolism and insulin sensitivity [53, 54].
BPF has been reported to possess antioxidant, anti-inflammatory, and antifibrotic properties, which may contribute to its hepatoprotective effects [53–56]. The results of this study suggest that BPF has a protective effect against STZ-induced liver damage by decreasing plasma ALT and AST concentrations in male albino rats. This is consistent with our previous study [57], which investigated the protective effect of BPF on the haematological parameters of diabetic male rats due to its antioxidant properties.
Our results suggest that BPF has a potential therapeutic effect in reducing the severity of histological changes and upregulating GLUT4 expression in the liver tissue of STZ-induced diabetic rats [58, 59]. The upregulation of GLUT4 expression by BPF treatment is particularly noteworthy [58, 59]. GLUT4 plays a critical role in glucose uptake and utilization by cells, especially in insulin-sensitive tissues such as the liver and skeletal muscle. The decrease in GLUT4 expression in diabetic rats is well-documented and is associated with insulin resistance and hyperglycemia [58, 59]. Therefore, the upregulation of GLUT4 expression by BPF treatment may improve glucose uptake and utilization in liver tissue, leading to better glycemic control in diabetic rats [58, 59].
Our findings are consistent with previous studies that have reported the beneficial effects of BPF on glycemic control, insulin sensitivity, and oxidative stress in diabetic rats [60, 61]. El-Sayed et al. reported that BPF treatment improved glycemic control and increased insulin sensitivity in STZ-induced diabetic rats [60]. Similarly, El-Sayed et al. [61] demonstrated that BPF has potent antioxidant activity and can protect pancreatic β-cells from oxidative stress-induced damage in diabetic rats.
Previous studies have suggested that BPF may improve insulin signaling by activating the adenosine monophosphate-activated protein kinase (AMPK) pathway [60, 61]. The activation of the AMPK pathway has been shown to improve insulin sensitivity and glucose uptake in insulin-sensitive tissues, such as the liver and skeletal muscle. The present study suggests that BPF from HBV may have therapeutic benefits in the treatment of insulin resistance and diabetes by potentially regulating resistin and apelin mRNA and protein expressions in rats. BPF may modulate the expression of genes involved in glucose and lipid metabolism, protein synthesis, and degradation, and have antioxidant and anti-inflammatory effects that can indirectly affect protein expression [60, 61].
The study found a significant increase in resistin mRNA in the diabetic STZ-treated rats compared with the control group and all BPF-treated groups. This suggests that the down-regulation in resistin gene expression by BPF may be a mechanism responsible for the antidiabetic effect of the compound. Resistin is a hormone produced by adipose tissue and has been linked to insulin resistance and DM2 [62]. Previous studies have reported inconsistent findings on the relationship between resistin and diabetes. A study found no significant difference or elevation in plasma resistin levels in patients with DM2 and controls [63]. However, our findings are in line with a previous study that reported increased resistin mRNA levels in response to acute hyperglycemia in mice [63].
Also, the study found an increase in apelin mRNA in STZ-treated diabetic rats. Apelin is a peptide hormone that has been linked to glucose metabolism and insulin sensitivity [64]. However, the relationship between apelin and insulin is still being investigated, with some studies reporting a synergy between the two, while others report no significant relationship [64, 65]. The differences in these findings may be due to the type of model used in the study (in vivo versus ex vivo) and the specific population being studied.
Proteins can serve as diagnostic and prognostic markers, and their expression profiles can be used to analyze the normal or pathological state of tissues. The study found a lack of ankyrin repeat domain-containing protein (ANKRD) protein expression in the STZ-induced DM1 rats, which was significantly upregulated in the BPF-treated rats. ANKRD proteins are known to be involved in glucose metabolism and insulin signaling pathways [66]. The upregulation of ANKRD protein expression by BPF treatment may improve insulin sensitivity and glucose uptake in liver tissue, leading to better glycemic control in diabetic rats [66]. However, the present study found no significant change in albumin protein levels in either STZ-treated or BPF-treated rats compared to the control group, suggesting that BPF may not have a significant effect on liver function or protein synthesis [67, 68]. Moreover, Simsa and Mráz [69] and Waldmann [70] reported that albumin catabolism may differ fundamentally from the catabolism of the other plasma protein since albumin is duration withdrawal the only plasma protein that is not a glycoprotein [71].
Overall, the study provides evidence that BPF from Egyptian HBV has potential therapeutic effects in the treatment of STZ-induced DM1 in male albino rats. BPF treatment improved glycemic control, insulin sensitivity, and liver function, as well as upregulated GLUT4 and ANKRD protein expression in liver tissue. BPF may also regulate resistin and apelin mRNA and protein expressions, suggesting a potential mechanism for its antidiabetic effects.
Mechanism of BPF exerts its’ antihyperglycemic and antioxidant effects in DM1:
The mechanisms by which BPF exerts its antihyperglycemic and antioxidant effects in DM1 are not fully understood, but several possible mechanisms have been proposed based on the followings:
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In the current study, BPF may exert its antihyperglycemic effects by increasing insulin sensitivity and stimulating insulin secretion from pancreatic beta cells. The same findings were reported by Abdelnour et al. [72, 73]. Additionally, BPF may protect pancreatic beta cells from oxidative stress-induced damage, which could help to preserve their function and enhance insulin secretion [74].
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BPF has been reported to exhibit antioxidant properties, which could help to protect against oxidative stress-induced damage in various tissues. Oxidative stress is known to contribute to the development and progression of diabetes and related complications. BPF has been shown to scavenge free radicals and increase the activity of antioxidant enzymes, such as superoxide dismutase and catalase, which could help to reduce oxidative stress and protect against tissue damage [74].
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Modulation of apelin and resistin levels: As mentioned earlier, BPF treatment was found to modulate the expression of apelin and resistin mRNA and protein in the blood plasma of STZ-induced diabetic rats. These proteins are known to be involved in glucose metabolism and insulin resistance, and modulation of their levels by BPF could contribute to its antihyperglycemic effects [75].
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Furthermore, BPF has been shown to enhance insulin sensitivity in diabetic animal models. A study conducted by El-Sayed et al. demonstrated that BPF treatment improved glucose tolerance and insulin sensitivity in STZ-induced diabetic rats [60].
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The improvement in insulin sensitivity observed in this study may be attributed to the upregulation of GLUT4 expression in liver tissue, as observed in the present study, and the increased expression of insulin receptor substrate-1 (IRS-1) and GLUT4 in the skeletal muscle and adipose tissue [58, 59].
These findings suggest that BPF may exert its antidiabetic effect by improving insulin signaling and glucose uptake in insulin-sensitive tissues. It is important to note that the use of venom-derived compounds for therapeutic purposes is a relatively new field of research, and the development of new drugs based on these compounds can be challenging due to their complex structures and potential toxicity [76]. Thus, extensive preclinical and clinical studies are needed to assess the safety and efficacy of venom-derived compounds before they can be used for human therapy.
Diabetes is a complex disease that requires a combination of lifestyle changes, medication, and regular monitoring of blood glucose levels for effective management. Although BPF may have therapeutic potential for diabetes, it is unlikely to be a standalone treatment for DM1 and should be used as part of a comprehensive diabetes management plan that includes other treatments.
Based on the findings of this study, some potential therapeutic strategies for the management of diabetes and associated complications could include the use of BPF to:
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Improve glucose metabolism: BPF treatment was found to improve plasma glucose levels in STZ-induced diabetic rats, indicating its potential use as a glucose-lowering agent.
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Reduce liver damage: BPF treatment was found to reduce the levels of liver enzymes, ALT and AST, in STZ-induced diabetic rats, indicating its potential use in protecting liver function and preventing liver damage caused by diabetes.
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Modulate apelin, resistin, C-RP, and GLUT4 levels: BPF treatment was found to modulate the expression of apelin, resistin, and C-RP proteins in the blood plasma and GULT4 in liver tissue of STZ-induced diabetic rats. Since apelin, resistin, and GLUT4 are known to be involved in glucose metabolism and insulin resistance, BPF may have the potential as a therapeutic agent for diabetes by modulating their levels.
Overall, this study provides valuable insights into the potential therapeutic effects of BPF in the management of diabetes and associated complications and may open up avenues for further research on the development of BPF-based therapies for diabetes.