Cardio/Repro-metabolic and Microbiome Research Unit, Department of Physiology, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, 360101, Nigeria; School of Laboratory Medicine & Medical Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Private Bag X54001, Congella 4013, Westville, Durban, South Africa.
Cardio/Repro-metabolic and Microbiome Research Unit, Department of Physiology, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, 360101, Nigeria.
Reprod Toxicol. 2021 Dec;106:69-81. doi: 10.1016/j.reprotox.2021.10.008. Epub 2021 Oct 14.
Type 2 diabetes mellitus (T2DM) accounts for 90-95 % of worldwide diabetes cases and is primarily characterized by insulin resistance. Its progression as a chronic metabolic disease has been largely associated with female reproductive abnormalities, including ovarian dysfunction with consequent infertility. Epigenetic modifications have been suggested as a possible link to metabolic comorbidities. We therefore hypothesized that short chain fatty acids, acetate (ACA), a potential histone deacetylase inhibitor (HDAC) ameliorates hypothalamic-pituitary-ovarian (HPO) dysfunction in T2DM. Female Wistar rats weighing 160-190 g were allotted into three groups (n = 6/group): Control (vehicle; po), T2D and T2D + ACA (200 mg/kg; po). T2DM was induced by fructose administration (10 %; w/v) for 6 weeks and single dose of streptozotocin (35 mg/kg; ip). The present data showed that in addition to insulin resistance, increased fasting blood glucose and insulin, T2DM induced elevated plasma, hypothalamic and ovarian triglyceride, lipid peroxidation, TNF-α and glutathione depletion. Aside, T2DM also led to increased plasma lactate production and γ-Glutamyl transferase as well as decreased gonadotropins/17β-estradiol. Histologically, hypothalamus, pituitary and ovaries revealed disrupted neuronal cells/moderate hemorrhage, altered morphology/vascular congestions, and degenerated antral follicle/graafian follicle with mild fibrosis and infiltrated inflammatory cells respectively in T2D animals. Interestingly, these alterations were accompanied by elevated plasma/hypothalamic HDAC5 and attenuated when treated with acetate. The present results demonstrate that T2DM induces HPO dysfunction, which is accompanied by elevated circulating/hypothalamic HDAC5. The results in addition suggest that acetate restores HPO function in T2DM by suppression of HDAC5 and enhancement of insulin sensitivity.
2 型糖尿病（T2DM）占全球糖尿病病例的 90-95%，其主要特征是胰岛素抵抗。作为一种慢性代谢性疾病，其进展与女性生殖异常密切相关，包括卵巢功能障碍导致的不孕。表观遗传修饰被认为是与代谢合并症相关的一个可能的联系。因此，我们假设短链脂肪酸、醋酸盐（ACA），一种潜在的组蛋白去乙酰化酶抑制剂（HDAC），可以改善 T2DM 患者的下丘脑-垂体-卵巢（HPO）功能障碍。体重为 160-190g 的雌性 Wistar 大鼠被分为三组（每组 6 只）：对照组（载体；po）、T2D 组和 T2D+ACA 组（200mg/kg；po）。T2DM 通过给予果糖（10%；w/v）6 周和单次链脲佐菌素（35mg/kg；ip）诱导。目前的数据表明，除了胰岛素抵抗、空腹血糖和胰岛素升高外，T2DM 还导致血浆、下丘脑和卵巢甘油三酯、脂质过氧化、TNF-α 和谷胱甘肽耗竭增加。此外，T2DM 还导致血浆乳酸生成和γ-谷氨酰转移酶增加以及促性腺激素/17β-雌二醇减少。组织学上，下丘脑、垂体和卵巢显示神经元细胞破坏/中度出血、形态改变/血管充血以及退化的窦前卵泡/格拉夫卵泡，伴有轻度纤维化和浸润的炎性细胞，这些改变在 T2D 动物中分别存在。有趣的是，这些改变伴随着血浆/下丘脑 HDAC5 的升高，而用醋酸盐治疗后则减弱。本研究结果表明，T2DM 引起 HPO 功能障碍，同时伴有循环/下丘脑 HDAC5 升高。此外，结果表明，醋酸盐通过抑制 HDAC5 和增强胰岛素敏感性来恢复 T2DM 中的 HPO 功能。
