Inflammation is a major pathophysiological factor in development of type-2 diabetes mellitus (T2DM). Vitamin D (VITD) plays an imperative role in modulation of several inflammatory responses. The current study aimed to investigate the possible beneficial effects of coadministration of VITD with pioglitazone (PIO), a PPAR-γ agonist, in fructose/streptozotocin (F/STZ) T2DM model in male Wistar rats. T2DM was induced by maintaining rats on 10% (w/v) fructose in drinking water for 9 weeks with an intraperitoneal injection of sub-diabetogenic dose of STZ (35 mg/kg) by the end of the fourth week. One week after STZ injection, PIO (10 mg/kg/day) alone or with VITD (500 IU/kg/day) was administered orally to diabetic rats till the end of the experiment. Blood samples were collected, livers were homogenized to determine biochemical parameters, and samples of livers were fixed in 10% formalin in saline for histological examination. Administration of PIO alone improved diabetes-induced inflammatory and oxidative states besides controlling hyperglycemia and decreasing apoptosis. Coadministration of VIT D with PIO promoted additional improvement in glycemic and lipid profiles, provided further control on diabetic-induced hepatic inflammation evident by downregulating TLR2, TLR4, and IKK-β while upregulating IκB-α expression and reducing inflammatory cytokines namely; NF-κB, TNF-α, IL-6, and IL-1β, decreasing apoptosis and oxidative stress by hampering caspase-3 and MDA contents, respectively, and improved liver histology than PIO alone. These beneficial effects of VIT D may expand its use by diabetics combined with antidiabetic drugs due to its anti-inflammatory, antioxidant, and antiapoptotic properties.

Graphical Abstract

中文翻译：

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维生素 D 联合吡格列酮通过靶向炎症、细胞凋亡和氧化应激减轻 2 型糖尿病引起的肝损伤

炎症是 2 型糖尿病 (T2DM) 发展的主要病理生理因素。维生素 D (VITD) 在调节多种炎症反应中起着至关重要的作用。目前的研究旨在研究 VITD 与 PPAR-γ 激动剂吡格列酮 (PIO) 共同给药对男性Wistar果糖/链脲佐菌素 (F/STZ) T2DM 模型的可能有益影响老鼠。通过在第四周结束时腹膜内注射亚糖尿病剂量的 STZ (35 mg/kg) 将大鼠维持在饮用水中 10% (w/v) 果糖 9 周来诱导 T2DM。STZ注射一周后，给糖尿病大鼠口服PIO（10 mg/kg/天）或与VITD（500 IU/kg/天）一起口服直至实验结束。收集血样，将肝脏匀浆以确定生化参数，并将肝脏样品固定在含 10% 福尔马林的盐水中进行组织学检查。除了控制高血糖和减少细胞凋亡外，单独施用 PIO 还可以改善糖尿病引起的炎症和氧化状态。VIT D 与 PIO 的共同给药促进了血糖和血脂谱的进一步改善，通过下调 TLR2、TLR4 和 IKK-β，同时上调 IκB-α 表达和减少炎性细胞因子，进一步控制糖尿病引起的肝脏炎症；NF-κB、TNF-α、IL-6 和 IL-1β，分别通过阻碍 caspase-3 和 MDA 含量来减少细胞凋亡和氧化应激，并且比单独使用 PIO 改善肝脏组织学。由于 VIT D 的抗炎、抗氧化和抗细胞凋亡特性，维生素 D 的这些有益作用可能会扩大其在糖尿病患者与抗糖尿病药物联合用药中的应用。

图形概要