State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No,1 Xiannongtan Street, Beijing 100050, PR China.
J Transl Med. 2011 Oct 14;9:176. doi: 10.1186/1479-5876-9-176.
Fenofibrate, a PPAR alpha agonist, has been widely used in clinics as lipid-regulating agent. PPAR alpha is known to be expressed in many organs including pancreatic beta cells and regulate genes involved in fatty acid metabolism. Some reports based on cell lines or animals have provided evidences that PPAR alpha agonists may affect (increased or suppressed) beta cell insulin secretion, and several studies are producing interesting but still debated results.
In this research, we investigated the long term effects of fenofibrate on beta cell function in a metabolic syndrome animal model, monosodium glutamate (MSG) induced obese rats. Obese MSG rats were administered by gavage with fenofibrate at a dose of 100 mg/kg for 12 weeks. Oral glucose tolerance and insulin tolerance tests were performed to evaluate glucose metabolism and insulin sensitivity. We have used the hyperglycemic clamp technique to evaluate the capacity of beta cell insulin secretion. This technique provides an unbiased approach to understand the beta cell function in vivo. The changes of gene and protein expression in the pancreas and islets were also analyzed by Real-Time-PCR, Western blot and immunostaining.
Fenofibrate reduced the plasma lipid levels within a few days, and showed no beneficial effects on glucose homeostasis or insulin sensitivity in obese MSG rats. But the animals treated with fenofibrate exhibited significantly decreased fasting plasma insulin and impaired insulin secretory response to glucose stimulation. Further studies confirmed that fenofibrate increased MDA level and decreased total ATPase activity in pancreatic mitochondrion, accompanied by the upregulation of iNOS and NF-kappa B and TNF alpha expression in pancreatic islets of obese MSG rats.
Long-term fenofibrate treatment disrupted beta cell function, and impaired glucose-stimulated insulin secretion in obese MSG rats, perhaps to some extent associated with the activated inflammatory pathway and increased formation of oxidative products, especially the up-regulation of NF-kappa B and iNOS expression in islets.
非诺贝特是一种过氧化物酶体增殖物激活受体α（PPARα）激动剂，被广泛应用于临床调脂治疗。已知 PPARα在许多组织中表达，包括胰岛β细胞，并调节脂肪酸代谢相关基因的表达。一些基于细胞系或动物的研究报告提供了证据，表明 PPARα 激动剂可能影响（增加或抑制）β细胞胰岛素分泌，而一些研究则产生了有趣但仍存在争议的结果。
本研究通过给予谷氨酸单钠（MSG）诱导的肥胖大鼠非诺贝特灌胃（剂量为 100mg/kg）12 周，来研究非诺贝特对代谢综合征动物模型（肥胖 MSG 大鼠）β细胞功能的长期影响。进行口服葡萄糖耐量和胰岛素耐量试验，以评估葡萄糖代谢和胰岛素敏感性。我们采用高血糖钳夹技术评估β细胞胰岛素分泌能力。该技术为了解体内β细胞功能提供了一种无偏倚的方法。还通过实时 PCR、Western blot 和免疫染色分析了胰腺和胰岛中基因和蛋白表达的变化。
非诺贝特在几天内降低了血浆脂质水平，但对肥胖 MSG 大鼠的葡萄糖稳态或胰岛素敏感性没有有益作用。然而，用非诺贝特处理的动物表现出空腹血浆胰岛素显著降低，并且对葡萄糖刺激的胰岛素分泌反应受损。进一步的研究证实，非诺贝特增加了肥胖 MSG 大鼠胰腺线粒体 MDA 水平和总 ATP 酶活性降低，同时胰岛中 iNOS 和 NF-κB 以及 TNFα表达上调。
长期非诺贝特治疗破坏了肥胖 MSG 大鼠的β细胞功能，并损害了葡萄糖刺激的胰岛素分泌，这在某种程度上可能与激活的炎症途径和氧化产物形成增加有关，尤其是 NF-κB 和 iNOS 在胰岛中的表达上调。
