Effects of Betulinic Acid on the Male Reproductive System of a Streptozotocin-Nicotinamide-Induced Diabetic Mouse Model

Abstract

PurposeThe present study was conducted to evaluate the favorable or harmful effects of betulinic acid (BA) on a diabetic reproductive system.Materials and MethodsIn this experimental study, 60 male Naval Medical Research Institute mice (20∼25 g) were randomly divided into 6 groups: control, diabetes, diabetes+BA (10, 20, and 40 mg/kg), and diabetes+ metformin (200 mg/kg). A diabetic model was induced by a single dose of streptozotocin (STZ) (65 mg/kg) injection intraperitoneally 15 minutes after an intraperitoneal administration of nicotinamide (NA) (120 mg/kg). BA and metformin were gavaged for 2 weeks after confirmed diabetes induction in the treatment groups. One day after the last treatment, plasma luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels were evaluated. The cauda epididymis and testis were removed to analyze the sperm count and testis histopathology.ResultsLH levels increased in diabetic (p<0.001) and diabetic BA-treated mice (p=0.009). Plasma levels of testosterone (p< 0.001) and sperm count (p=0.04) decreased in these groups when compared to the control group. Furthermore, administration of 10 mg/kg (p=0.001), 20 mg/kg (p=0.004), or 40 mg/kg (p<0.001) of BA led to a greater reduction in plasma testosterone levels compared to the diabetes group. Seminiferous tubule vacuole numbers increased in diabetic and diabetic BA-treated mice, but testis morphology and FSH level assessment revealed no significant differences between the groups.ConclusionsSTZ-NA can induce diabetic alterations in the male reproductive system and the administration of BA in diabetic treated mice resulted in a worse outcome.

Comparison of male reproductive parameters in mice with type 1 and type 2 diabetes

“…The increase of collagen fibers in the testis of animals with DM 72 Day A may have been caused by increased expression of transforming growth factor beta 1 and nitric oxide synthase [51][52][53][54]. Similar to our study, previous studies have demonstrated decreases of sperm concentration in DM human and animal models [5,6,37,42,[55][56][57][58], which may be due to impaired spermatogenesis [5,6,12,57,[59][60][61]. The increase of total abnormal sperm morphology in both groups of DM mice in our study was consistent with the find-ings of previous studies [23,37,42,[62][63][64][65].…”

“…The T2DM mice received an HFD (60 kcal% fat, D12492, Research Diet) for 14 consecutive days and were then induced with a single dose of STZ of 85 mg/kg BW [20,21] followed by continuous feeding with an HFD as previously described [26][27][28]. On days 3,6,12,18,24,30,36,42,48,54,60,66, and 72, the mice in both DM groups were assessed for actual DM induction using a blood glucose oxidase reaction monitoring system with blood from a tail prick. Mice were considered to have DM when their blood glucose levels were greater than 250 mg/dL.…”

“…The worldwide prevalence of both type 1 and type 2 diabetes mellitus (T1DM and T2DM, respectively) is rapidly increasing [1,2]. Various disorders can result from T1DM and T2DM, including male repro-ductive dysfunction [3][4][5][6][7][8]. Diabetes mellitus has also been found to alter glucose metabolism in Sertoli cells, decrease spermatogenesis, damage testicular structure, and reduce testosterone levels [8][9][10][11][12][13].…”

Anti-diabetic effect of betulinic acid on streptozotocin-nicotinamide induced diabetic male mouse model

“…Consistent with our study, treatment with betulin improved insulin sensitivity (Tang et al, 2011). However, in the administration of BA as an anti-diabetic agent, side effects such as those on the reproductive system should be considered (Ahangarpour et al, 2016c).…”

“…BA has a preventive effect on diabetic nephropathy during diabetic situations (Ahangarpour et al, 2016b). In contrast, administration of BA in STZ-NA diabetic treated mice can induce a worse outcome in the male reproductive system (Ahangarpour et al, 2016c). BA can be useful for treatment and prevention of early atherosclerosis (Yoon et al, 2017).…”