Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Sep;203(9):4659-4670.
doi: 10.1007/s12011-025-04518-z. Epub 2025 Jan 18.

Zinc Combined with Metformin Corrects Zinc Homeostasis and Improves Steroid Synthesis and Semen Quality in Male Type 2 Diabetic Mice by Activating PI3K/AKT/mTOR Pathway

Huanhuan Li #  1 , Menghui Zhang #  2 , Jing Ma  1 , Wen Li  3 , Xuan Liu  4 , Yuanjing Li  5 , Jiaoying Ma  1 , Dan Yang  6 , Yanqing Tie #  7   8 , Hongzhong Bai #  9 , Shusong Wang #  10   11   12
Affiliations

Zinc Combined with Metformin Corrects Zinc Homeostasis and Improves Steroid Synthesis and Semen Quality in Male Type 2 Diabetic Mice by Activating PI3K/AKT/mTOR Pathway

Huanhuan Li et al. Biol Trace Elem Res. 2025 Sep.

Abstract

Male infertility is a common complication of diabetes. Diabetes leads to the decrease of zinc (Zn) content, which is a necessary trace element to maintain the normal structure and function of reproductive organs and spermatogenesis. The purpose of this study was to investigate the effect of metformin combined with zinc on testis and sperm in diabetic mice. 10 of 50 male mice were randomly divided into control group (group C), and the remaining 40 mice were randomly divided into untreated diabetes group (group D), diabetes + zinc group (group Z, 10 mg/(kg • d)), diabetes + metformin group (group M, 200 mg/(kg • d)), and diabetes + zinc + metformin group (group ZM, Z 10 mg/(kg • d) + M 200 mg/(kg • d)), with 10 mice in each group. Mice fasted overnight were killed, and testes and sperm were collected for further experiments. In group D, the structure of testis was disordered, and the structure of sperm tail was destroyed and the deformity rate increased. In group D, total zinc, free zinc ions, metallothionein (MT), and metal transcription factor (MTF1) in testis were significantly decreased, while the expressions of zinc transporters ZNT7, ZIP13, and ZIP14 were significantly increased. In group D, the fluorescence intensity of free zinc in sperm tail, the expression of MT2, and MTF1 mRNA decreased significantly, while the expression of ZNT7, ZIP13, and ZIP14 mRNA increased significantly. Estrogen (E2) levels, steroid synthesis-related proteins (including CYP19A1, 3β-HSD, LHR, and STAR), and PI3K/AKT/mTOR pathway-related proteins (PI3K, p-AKT/AKT, p-mTOR/mTOR) expression were significantly decreased in group D. In addition, zinc combined with metformin activates PI3K/AKT/mTOR pathway, corrects zinc homeostasis imbalance in testis and sperm, and improves testosterone synthesis and semen quality in male type 2 diabetic mice.

Keywords: Diabetes; Sperm; Testis; Testosterone; Zinc.

PubMed Disclaimer

Conflict of interest statement

Declarations. Ethical Approval: Ethical approval for this study was obtained from the Ethics Committee of Hebei Reproductive Health Hospital (ethics approval date and number: 02.28.2023/SZJKKYLL-2023011). Conflict of Interest: The authors declare no competing interests.

Similar articles

See all similar articles

References

    1. Wang H, Ai J, Shopit A, Niu M, Ahmed N, Tesfaldet T, Tang Z, Li X, Jamalat Y, Chu P, Peng J, Ma X, Qaed E, Han G, Zhang W, Wang J, Tang Z (2022) Protection of pancreatic β-cell by phosphocreatine through mitochondrial improvement via the regulation of dual AKT/IRS-1/GSK-3β and STAT3/Cyp-D signaling pathways. Cell Biol Toxicol 38(3):531–551
    1. He Z, Yin G, Li QQ et al (2021) Diabetes mellitus causes male reproductive dysfunction: a review of the evidence and mechanisms. In Vivo 35(5):2503–2511
    1. Wang L, Gao P, Zhang M, Huang Z, Zhang D, Deng Q, Li Y, Zhao Z, Qin X, Jin D, Zhou M, Tang X, Hu Y, Wang L (2017) Prevalence and ethnic pattern of diabetes and prediabetes in China in 2013. JAMA 317(24):2515–2523
    1. Bener A, Al-Ansari AA, Zirie M, Al-Hamaq AO (2009) Is male fertility associated with type 2 diabetes mellitus? Int Urol Nephrol 41(4):777–784
    1. Huang R, Chen J, Guo B, Jiang C, Sun W (2024) Diabetes-induced male infertility: potential mechanisms and treatment options. Mol Med 30(1):11

MeSH terms

LinkOut - more resources