Abstract
Approximately 90% of male diabetes mellitus patients have varying degrees of testicular dysfunction. The molecular mechanism underlying diabetes-induced testicular damage has not been thoroughly elucidated. In this research, we sought to determine the influence of metformin (Met) on diabetes-induced testicular injury and the mechanism involved with a focus on testicular dysfunction, apoptosis, autophagy, and prokineticin 2 (PK2) signalling. In our study, C57BL/6J mice were randomly divided into the normal control group, the diabetes group, and the Met-treated group. Streptozotocin (50 mg·kg−1·d−1) was injected intraperitoneally into the mice for 5 days in a row to induce type 1 diabetes, which was diagnosed by a blood glucose level ≥ 16.7 mmol/L after 7 days. The experimental animals were orally administered Met (250 mg·kg−1·d−1) for 16 weeks. Properties of testicular function, including sperm motility and the total concentration of epididymal sperm, were assessed. Changes in testicular structure, such as the blood-testis barrier, histological pathology, and organelles, were observed. The levels of apoptosis and expression of related proteins, such as Bax and Bcl-2, were measured. Moreover, autophagy-related proteins, including Beclin-1, p62, and LC3B, as well as the PK2/PKR pathway, which consists of PK2, PKR1, PKR2, AKT, and GSK3β, were analysed. Upon the induction of diabetes, reproductive capacity was significantly impaired and a disordered arrangement of testicular seminiferous tubules and destroyed organelles in spermatogenic cells was observed. Met administration preserved testicular function and structure. In addition, in mice with diabetes, the levels of PK2, PKR2, p-Akt, and p-GSK3β were significantly decreased at different times, while that of PKR1 was markedly increased, and these changes were normalized by Met. Furthermore, diabetic mice showed increased apoptosis and decreased autophagy in the testes, the effects of which were nullified by Met. These results suggest that Met rescues diabetes-induced testicular damage by attenuating apoptosis and inducing autophagy. This effect is likely mediated by the PK2/PKR/AKT/GSK3β signalling pathway.
Highlights
Diabetes mellitus is a disorder of glucose metabolism caused by an absolute or relative insufficiency of insulin secretion
The findings of our study indicate that the prokineticin 2 (PK2)/Prokineticin receptors (PKRs) pathway plays an irreplaceable role in diabetic testicular injury and that Met protects against STZ-induced testicular impairment, apoptosis, and autophagy by regulating PK2/PKRs and restores the phosphorylation of the AKT/GSK3β signalling pathway in the testes
Apoptosis and autophagy are caused by glucose toxicity-induced testicular injury in patients with diabetes [15, 16]
Summary
Diabetes mellitus is a disorder of glucose metabolism caused by an absolute or relative insufficiency of insulin secretion. According to a prediction by the International Diabetes Federation [1], the number of diabetic patients will increase to 693 million in 2045, accounting for approximately 10% of the global population. Researchers have elucidated that testicular dysfunction occurs in a startling number of diabetes cases and that testicular dysfunction has become a Oxidative Medicine and Cellular Longevity prevalent complication of diabetes. 94.4% of diabetes cases are associated with hypotestosteronaemia, which can lead to diabetic erectile dysfunction [2], and the incidence of sexual and reproductive dysfunction in diabetic patients is 5-10 times higher than that in nondiabetic patients [3, 4]. The precise molecular mechanism by which testicular dysfunction is caused by diabetes remains unclear, and no specific medicines are available for treatment
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