Umbelliferone ameliorates oxidative stress and testicular injury, improves steroidogenesis and upregulates peroxisome proliferator-activated receptor gamma in type 2 diabetic rats

Abstract

Objectives Diabetes mellitus (DM) is a chronic disease associated with serious complications, including male infertility. Umbelliferone (UMB) is a coumarin with promising antioxidant, anti-inflammatory and other beneficial effects. This study investigated the ameliorative effect of UMB against testicular injury, oxidative stress and altered steroidogenesis in rats with type 2 DM. Methods Rats received a high fat diet for 4 weeks followed by a single injection of streptozotocin. Diabetic rats were treated with UMB or pioglitazone (PIO) for 6 weeks and samples were collected for analysis. Key findings Diabetic rats exhibited hyperglycemia, insulin resistance and dyslipidemia associated with increased serum pro-inflammatory cytokines, and decreased gonadotropins and testosterone. UMB significantly ameliorated metabolic alterations, decreased pro-inflammatory cytokines, and increased gonadotropins and testosterone levels. UMB prevented testicular injury, suppressed lipid peroxidation and nitric oxide and increased antioxidants in diabetic rats. In addition, UMB upregulated testicular gonadotropins receptors, steroidogenesis markers (steroidogenic acute regulatory protein, cytochrome P450 family 17 subfamily A member 1 [CYP17A1], 3β-hydroxysteroid dehydrogenase [3ß-HSD] and 17ß-hydroxysteroid dehydrogenase [17ß-HSD]), and peroxisome proliferator-activated receptor gamma (PPARγ) expression. Conclusions UMB prevents testicular injury by preventing metabolic alterations, suppressing oxidative damage and inflammation, and boosting antioxidant defenses in diabetic rats. UMB enhanced pituitary-gonadal axis and steroidogenesis and upregulated testicular PPARγ in diabetic rats. Thus, UMB may represent a protective agent against testicular injury and sexual dysfunction associated with chronic hyperglycemia.

The Effects of Separate and Combined Treatment of Male Rats with Type 2 Diabetes with Metformin and Orthosteric and Allosteric Agonists of Luteinizing Hormone Receptor on Steroidogenesis and Spermatogenesis

“…In the diabetic testes, gene expression and LH/hCG-R content were reduced (Figures 3, 4, 7 and 8), which is consistent with previously obtained data on a decrease in the expression of LH/hCG-R in the testicular cells of diabetic animals with T2DM and T1DM [38,43,64,70]. A decrease in LH/hCG-R expression should result in a weakening of the steroidogenic response of Leydig cells to endogenous gonadotropins and, we believe, is one of the key causes of androgen deficiency in T2DM male rats.…”

“…A histochemical analysis of the diabetic testes showed a decrease in the thickness of the seminiferous epithelium and the number of spermatogonia and pachytene spermatocytes (Figure 6; Table 6). Earlier, we and other authors have also demonstrated a decrease in the level of androgens, and an impaired spermatogenesis in rats with different models of T2DM [43,[63][64][65]. In the testes of diabetic rats, the structural disruption and atrophy of the seminiferous tubules, the reduced number of spermatogenic cells and their degeneration and disorganization and the disappearance of spermatids in the lumen of the seminiferous tubules were shown [43,63,65].…”

“…Only a tendency towards weakening of the expression of gene for cholesterol-transporting protein StAR, which is responsible for the first, rate-limiting stage of steroidogenesis, was shown ( Figure 3 and Figure 4 ). Other authors also demonstrated a decrease in the expression of the StAR gene in the testes of rats with T2DM and HFD-induced obesity [ 64 , 77 , 78 , 79 , 80 ]. Despite a significant decrease in testosterone production in T2DM, we showed an increase in the gene expression for CYP17A1 cytochrome responsible for the synthesis of 17-OH-progesterone and androstenedione ( Figure 3 and Figure 4 ).…”

“…Long-term T2DM in male patients often lead to dysfunctions of the hypothalamic-pituitary-gonadal axis, a decrease in testosterone production and a decrease in fertility, which has been demonstrated both in human [ 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ] and on experimental models of these metabolic diseases in rodents [ 43 , 61 , 62 , 63 , 64 , 65 ]. The main causes of functional changes in the male reproductive system in T2DM are postprandial hyperglycemia, insulin and leptin resistance, inflammation, elevated production of the reactive oxygen and nitrogen species, oxidative stress and lipotoxicity [ 65 , 66 , 67 , 68 ].…”

Naturally Based Nano Formulation in Metabolic and Reproductive Disorders: A Review

“…Several studies have shown that oxidative stress plays a role in the development of diabetic reproductive system damage and that antioxidants can help. According to the evidence, oxidative stress was the primary cause of the testicular malfunction, which resulted in male hypogonadism and infertility (Allam et al 2021). Hyperglycemia boosted mitochondrial glucose oxidation by releasing a large amount of superoxide and other free radicals into the cytoplasm, according to a study.…”