Department of Medical Biology, Medical University of Bialystok, Bialystok, Poland.
Department of Physiology, Medical University of Bialystok, Bialystok, Poland.
Sci Rep. 2018 May 8;8(1):7249. doi: 10.1038/s41598-018-25397-6.
We sought to determine whether metformin treatment reverses a high-fat diet (HFD)-induced hepatic insulin resistance (IRes) and to identify lipid intermediates involved in induction of liver IRes. The experiments were conducted on male Wistar rats divided into three groups: 1. Control, 2. fed HFD and 3. fed HFD and treated with metformin. The animals were infused with a [U-C]palmitate to measure fractional lipid synthesis rate. This allowed for the calculation of fractional synthesis rate of signaling lipids (FSR) through the estimation of their isotopic enrichment. Liver ceramide (Cer), diacylglycerol (DAG) and acyl-carnitine concentration and enrichment were analyzed by LC/MS/MS. The content of proteins involved in lipid metabolism and insulin signaling were analyzed by Western Blot. HFD treatment increased the content and FSR of DAG and Cer in the liver which was accompanied by systemic insulin resistance and inhibition of hepatic insulin signaling pathway under insulin stimulation. Metformin treatment ameliorated systemic insulin resistance and augmented the hepatic insulin signaling cascade. It reduced both the concentration and FSR of Cer, DAG, and increased acyl-carnitine content and the expression of mitochondrial markers. We postulate, that in liver, the insulin sensitizing effect of metformin depends on augmentation of mitochondrial β-oxidation, which protects from hepatic accumulation of both the Cer and DAG and preserves insulin sensitivity under HFD consumption. Moreover, we showed that hepatic content of Cer and DAG corresponds with their respective FSR.
我们试图确定二甲双胍治疗是否能逆转高脂肪饮食（HFD）引起的肝胰岛素抵抗（IRes），并确定诱导肝 IRes 的脂质中间产物。该实验在雄性 Wistar 大鼠上进行，分为三组：1. 对照组，2. 喂食 HFD 组，3. 喂食 HFD 并接受二甲双胍治疗组。通过输注 [U-C]棕榈酸来测量信号脂质的部分合成率（FSR），通过估计其同位素丰度来计算 FS。通过 LC/MS/MS 分析肝脏神经酰胺（Cer）、二酰基甘油（DAG）和酰基辅酶 A 浓度和丰度。通过 Western Blot 分析参与脂质代谢和胰岛素信号通路的蛋白质含量。HFD 处理增加了肝脏中 DAG 和 Cer 的含量和 FSR，这伴随着全身胰岛素抵抗和胰岛素刺激下肝胰岛素信号通路的抑制。二甲双胍治疗改善了全身胰岛素抵抗并增强了肝胰岛素信号级联。它降低了 Cer、DAG 的浓度和 FSR，增加了酰基辅酶 A 含量和线粒体标志物的表达。我们推测，在肝脏中，二甲双胍的胰岛素增敏作用取决于增加线粒体β-氧化，这可以防止 Cer 和 DAG 在肝脏中的积累，并在 HFD 消耗下保持胰岛素敏感性。此外，我们表明肝脏 Cer 和 DAG 的含量与其各自的 FSR 相对应。
