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. 2025 Sep;8(5):e70103.
doi: 10.1002/edm2.70103.

Trifolium pratense-Derived Exosome Improved Serum Biochemical Parameters and Pancreatic Genes in STZ-Induced Diabetic Rats

Amir Hossein Khazaei  1 , Azam Bozorgi  1   2 , Elham Ghanbari  1   2 , Maryam Bozorgi  1   3 , Mozafar Khazaei  1
Affiliations

Trifolium pratense-Derived Exosome Improved Serum Biochemical Parameters and Pancreatic Genes in STZ-Induced Diabetic Rats

Amir Hossein Khazaei et al. Endocrinol Diabetes Metab. 2025 Sep.

Abstract

Introduction: Plant-derived exosomes (PDEs) are promising nanotherapeutics for improving chronic diseases, such as diabetes mellitus. Trifolium pratense (TP) is a flowering herb with potent antioxidant and antidiabetic properties. The present study aimed to explore the diabetic-healing effects of TP-derived exosomes (TPDEs) in streptozotocin (STZ)-induced diabetic rats.

Methods: TPDEs were isolated using polyethylene glycol precipitation and serial centrifugation and characterised. STZ-induced diabetic rats were treated with TPDE doses (0, 100, 200, and 400 μg/kg) for 28 days. Biochemical factors (fasting blood sugar (FBS), insulin, C-peptide, total antioxidant capacity (TAC), and nitric oxide (NO)) were evaluated in serum samples. Also, the expression of PDX1, insulin, NGN3, and SIRT1 genes in pancreas tissues was assessed using real-time PCR.

Results: TPDE treatment decreased the serum levels of FBS and NO while increasing c-peptide, insulin, and TAC levels. It also significantly enhanced the expression of insulin, PDX1, NGN3, and SIRT1 genes. TPDEs at doses of 100 to 200 μg/kg showed the most significant antidiabetic effects.

Conclusion: TPDEs significantly improved diabetes-induced alterations in serum insulin levels, antioxidant status, and pancreas-related gene expression. It can be considered a novel complementary treatment for diabetes.

Keywords: Trifolium pratense; diabetes; plant‐derived exosomes.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
T. pratense fresh plant. (A) Before harvesting; (B) Cleaned aerial parts.
FIGURE 2
FIGURE 2
Characterisation of TPDE. (A) TPDEs participated using PEG; (B) DLS data; (C) Zeta potential data. DLS, dynamic light scattering; PEG, polyethylene glycol; TPDE, T. pratense ‐derived exosome.
FIGURE 3
FIGURE 3
The analysis of FBS and body weight in healthy (control) and STZ‐induced diabetic rats treated with TPDEs. (A) FBS; (B) Body weight. Different letters indicate significant differences between groups. B, body weight; FBS, fasting blood sugar. (a, b: p < 0.001, c, d: p < 0.05, ac: no significant differences with a and c, ns: non‐significant).
FIGURE 4
FIGURE 4
The analysis of NO and TAC in healthy (control) and STZ‐induced diabetic rats treated with TPDEs. (A) NO; (B) TAC. Different letters indicate significant differences between groups. NO, nitric oxide; TAC, total antioxidant capacity (a, b: p < 0.05, c, d: p < 0.001, ab: no significant differences with a and b, ns: non‐significant).
FIGURE 5
FIGURE 5
The analysis of insulin and C‐C‐peptide in healthy (control) and STZ‐induced diabetic rats treated with TPDEs. (A) Insulin; (B) C‐C‐peptide. Different letters indicate significant differences between groups (a, b, c: p < 0.001, ac: no significant differences with a and c).
FIGURE 6
FIGURE 6
The expression of PDX1, insulin, NGN3, and SIRT1 in pancreas tissue of healthy (control) and STZ‐induced diabetic rats treated with TPDEs. (A) PDX1, (B) Insulin, (C) NGN3; (D) SIRT1. NGN3, Neurogenin 3; PDX1, pancreatic and duodenal homeobox 1; SIRT1, Sirtuin 1. (a: p < 0.05, b–e: p < 0.001).
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