Liu Tong-Yan, Shi Chang-Xiang, Gao Run, Sun Hai-Jian, Xiong Xiao-Qing, Ding Lei, Chen Qi, Li Yue-Hua, Wang Jue-Jin, Kang Yu-Ming, Zhu Guo-Qing
Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China.
Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu, China.
Clin Sci (Lond). 2015 Nov;129(10):839-50. doi: 10.1042/CS20150009. Epub 2015 Jul 13.
Increased glucose production and reduced hepatic glycogen storage contribute to metabolic abnormalities in diabetes. Irisin, a newly identified myokine, induces the browning of white adipose tissue, but its effects on gluconeogenesis and glycogenesis are unknown. In the present study, we investigated the effects and underlying mechanisms of irisin on gluconeogenesis and glycogenesis in hepatocytes with insulin resistance, and its therapeutic role in type 2 diabetic mice. Insulin resistance was induced by glucosamine (GlcN) or palmitate in human hepatocellular carcinoma (HepG2) cells and mouse primary hepatocytes. Type 2 diabetes was induced by streptozotocin/high-fat diet (STZ/HFD) in mice. In HepG2 cells, irisin ameliorated the GlcN-induced increases in glucose production, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) expression, and glycogen synthase (GS) phosphorylation; it prevented GlcN-induced decreases in glycogen content and the phosphoinositide 3-kinase (PI3K) p110α subunit level, and the phosphorylation of Akt/protein kinase B, forkhead box transcription factor O1 (FOXO1) and glycogen synthase kinase-3 (GSK3). These effects of irisin were abolished by the inhibition of PI3K or Akt. The effects of irisin were confirmed in mouse primary hepatocytes with GlcN-induced insulin resistance and in human HepG2 cells with palmitate-induced insulin resistance. In diabetic mice, persistent subcutaneous perfusion of irisin improved the insulin sensitivity, reduced fasting blood glucose, increased GSK3 and Akt phosphorylation, glycogen content and irisin level, and suppressed GS phosphorylation and PEPCK and G6Pase expression in the liver. Irisin improves glucose homoeostasis by reducing gluconeogenesis via PI3K/Akt/FOXO1-mediated PEPCK and G6Pase down-regulation and increasing glycogenesis via PI3K/Akt/GSK3-mediated GS activation. Irisin may be regarded as a novel therapeutic strategy for insulin resistance and type 2 diabetes.
葡萄糖生成增加和肝糖原储存减少导致糖尿病的代谢异常。鸢尾素是一种新发现的肌动蛋白，可诱导白色脂肪组织褐变，但其对糖异生和糖原生成的影响尚不清楚。在本研究中，我们研究了鸢尾素对胰岛素抵抗的肝细胞中糖异生和糖原生成的影响及潜在机制，以及其在2型糖尿病小鼠中的治疗作用。通过氨基葡萄糖（GlcN）或棕榈酸酯在人肝癌（HepG2）细胞和小鼠原代肝细胞中诱导胰岛素抵抗。通过链脲佐菌素/高脂饮食（STZ/HFD）诱导小鼠患2型糖尿病。在HepG2细胞中，鸢尾素改善了GlcN诱导的葡萄糖生成增加、磷酸烯醇丙酮酸羧激酶（PEPCK）和葡萄糖-6-磷酸酶（G6Pase）表达增加，以及糖原合酶（GS）磷酸化增加；它防止了GlcN诱导的糖原含量降低、磷酸肌醇3激酶（PI3K）p110α亚基水平降低，以及Akt/蛋白激酶B、叉头框转录因子O1（FOXO1）和糖原合酶激酶-3（GSK3）的磷酸化降低。抑制PI3K或Akt可消除鸢尾素的这些作用。鸢尾素的作用在GlcN诱导的胰岛素抵抗的小鼠原代肝细胞和棕榈酸酯诱导的胰岛素抵抗的人HepG2细胞中得到证实。在糖尿病小鼠中，持续皮下灌注鸢尾素可改善胰岛素敏感性，降低空腹血糖，增加GSK3和Akt磷酸化、糖原含量和鸢尾素水平，并抑制肝脏中GS磷酸化以及PEPCK和G6Pase表达。鸢尾素通过PI3K/Akt/FOXO1介导的PEPCK和G6Pase下调减少糖异生，并通过PI3K/Akt/GSK3介导的GS激活增加糖原生成，从而改善葡萄糖稳态。鸢尾素可被视为治疗胰岛素抵抗和2型糖尿病的一种新策略。
