Zhou Jun, Wang Deng, Luo XiaoHong, Jia Xu, Li MaoXing, Laudon Moshe, Zhang RuXue, Jia ZhengPing
College of Pharmacy, Lanzhou University, Lanzhou, PR China (J.Z., M.X.L, R.X.Z, Z.P.J.); Xi'an Daxing Hospital, Shaanxi, PR China (D.W.); Lanzhou General Hospital of PLA, Lanzhou, PR China (J.Z., X.L., M.X.L, R.X.Z, Z.P.J.); Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China (X.J.); and Drug Discovery, Neurim Pharmaceuticals Ltd., Tel-Aviv, Israel (M.L.).
College of Pharmacy, Lanzhou University, Lanzhou, PR China (J.Z., M.X.L, R.X.Z, Z.P.J.); Xi'an Daxing Hospital, Shaanxi, PR China (D.W.); Lanzhou General Hospital of PLA, Lanzhou, PR China (J.Z., X.L., M.X.L, R.X.Z, Z.P.J.); Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China (X.J.); and Drug Discovery, Neurim Pharmaceuticals Ltd., Tel-Aviv, Israel (M.L.)
J Pharmacol Exp Ther. 2018 Jan;364(1):55-69. doi: 10.1124/jpet.117.243998. Epub 2017 Oct 12.
Modern lifestyle factors (high-caloric food rich in fat) and daily chronic stress are important risk factors for metabolic disturbances. Increased hypothalamic-pituitary-adrenal (HPA) axis activity and the subsequent excess production of glucocorticoids (GCs) in response to chronic stress (CS) leads to increases in metabolic complications, such as type 2 diabetes and insulin resistance (IR). Melatonin (MLT), which protects several regulatory components of the HPA axis from GC-induced deterioration, might improve glucose homeostasis. Piromelatine is a melatonin receptor-1/melatonin receptor-2 (MT1/MT2) agonist with high affinity for MLT receptors and a longer duration of action than MLT. The objective of the present study was to explore the potential effects of piromelatine on glucose and lipid metabolism and insulin sensitivity in rats with IR induced by a high-fat diet combined with CS (CF). The results showed that piromelatine prevented the suppression of body weight gain and energy intake induced by CF and normalized CF-induced hyperglycemia and homeostasis model assessment-IR index, which suggests that piromelatine prevented whole-body IR. Piromelatine also prevented CF-induced dysregulation of genes involved in glucose and lipid metabolism, including proinflammatory cytokines, in adipose tissue. In addition, piromelatine also attenuated CF-induced excess free corticosterone release, increased glucocorticoid receptor expression, and decreased 11-hydroxysteroid dehydrogenase-1 expression, suggesting that piromelatine might ameliorate impaired glucose metabolism and prevent IR by normalizing HPA-axis functions. In conclusion, piromelatine might be a novel therapeutic agent for glucose intolerance and IR.
现代生活方式因素（富含脂肪的高热量食物）和日常慢性应激是代谢紊乱的重要危险因素。下丘脑 - 垂体 - 肾上腺（HPA）轴活性增加以及随后因慢性应激（CS）导致的糖皮质激素（GCs）过量产生会导致代谢并发症增加，如2型糖尿病和胰岛素抵抗（IR）。褪黑素（MLT）可保护HPA轴的几个调节成分免受GC诱导的退化，可能改善葡萄糖稳态。匹罗美拉汀是一种褪黑素受体 -1/褪黑素受体 -2（MT1/MT2）激动剂，对MLT受体具有高亲和力，且作用持续时间比MLT长。本研究的目的是探讨匹罗美拉汀对高脂饮食联合CS（CF）诱导的IR大鼠的葡萄糖和脂质代谢以及胰岛素敏感性的潜在影响。结果表明，匹罗美拉汀可防止CF诱导的体重增加和能量摄入抑制，并使CF诱导的高血糖和稳态模型评估 - IR指数正常化，这表明匹罗美拉汀可预防全身IR。匹罗美拉汀还可防止CF诱导的脂肪组织中参与葡萄糖和脂质代谢的基因失调，包括促炎细胞因子。此外，匹罗美拉汀还可减轻CF诱导的游离皮质酮释放过多，增加糖皮质激素受体表达，并降低11 - 羟基类固醇脱氢酶 -1表达，表明匹罗美拉汀可能通过使HPA轴功能正常化来改善葡萄糖代谢受损并预防IR。总之，匹罗美拉汀可能是一种治疗葡萄糖不耐受和IR的新型治疗药物。
