Combined Zinc and Metformin Attenuated Impairment of Corpus Cavernosum Function, Imbalance of Zinc Homeostasis, Apoptosis, and Fibrosis in STZ-Induced Diabetic Mice by Inhibiting the TGF-β1/Smad3 Pathway

Abstract

Erectile dysfunction (ED) is a common complication of diabetes. Diabetes leads to the decrease of zinc (Zn) content, and zinc deficiency can cause sexual dysfunction, hypoplasia of sexual organs, and secondary sexual characteristics. The purpose of this study was to explore the protective effect of metformin combined with zinc on erectile function in diabetic mice induced by streptozotocin (STZ). Ten of 50 male mice were randomly selected as the control group (group C), and the remaining 40 mice were randomly divided into the diabetes treatment group (group D), diabetes + zinc group (group Z), diabetes + metformin group (group M), and diabetes + metformin + zinc group (group ZM), with 10 mice in each group. The diabetic mouse model was induced by high-fat diet (HFD) and STZ. Diabetic mice in group Z were given oral zinc (10 mg/kg) once a day for 4 weeks, group M diabetic mice were given metformin (200 mg/kg) once a day for 4 weeks, diabetic mice in group ZM were given metformin and zinc once a day for 4 weeks, and group C and group D were given the same amount of sterile water. The mice that fasted overnight were killed, and blood samples and penises were collected for further experiments. The combined treatment of zinc and metformin can reduce penis weight and improve the structural damage of the cavernous body caused by diabetes. The combined treatment of zinc and metformin can improve the serum zinc content and the fluorescence intensity of free zinc ions in penis and correct the unbalanced zinc homeostasis by changing the expressions of zinc transporter (ZnT3, ZnT8, ZIP10, and ZIP14) in penis tissue. The results showed that combined treatment with zinc and metformin can increase the expression of Bcl-2, decrease the expression of Bax and caspase-3, and decrease the apoptosis index of cavernous cells caused by diabetes. In addition, the combined treatment of zinc and metformin can increase the levels of SOD, NO, and cGMP in penis tissue; decrease MDA level; inhibit TGF-β1/Smad3 pathway-related proteins; increase the expression levels of eNOS, α-SMA, and CD31 proteins; and reduce collagen deposition in the penis. In a word, we found that zinc combined with metformin can inhibit the TGF-β1/Smad3 pathway; correct the imbalance of zinc homeostasis in the cavernous body; reduce the levels of oxidative stress, fibrosis, and apoptosis; and improve the structural damage of the cavernous body in male type 2 diabetic mice.

Keywords: Apoptosis; Diabetes; Erectile dysfunction (ED); TGF-β1/Smad3 pathway; Zinc.