非诺贝特改善老年高脂喂养C57小鼠胰岛β细胞功能及其作用机制研究

Fenofibrate improves β cell function by regulating pancreatic activities of ATPase and Ca^(2+) release in high-fat diet induced Aged-C57 obese mice

目的考察非诺贝特对老年高脂喂养C57(Aged-C57)小鼠胰岛β细胞功能的影响并探讨可能的作用机制。方法老年高脂喂养C57小鼠(n=28),随机分为老年动物模型组和非诺贝特组(100 mg·kg-1d-1),连续灌胃给药8周。另取正常雄性C57小鼠14只,作为正常组。考察其对血糖、血脂、胰岛素敏感性及β细胞功能的影响。结果非诺贝特给药约5周,可显著改善Aged-C57小鼠胰岛素耐量血糖-时间曲线下面积(P<0.01);给药7周,能显著降低Aged-C57小鼠的空腹血糖(P<0.01)及空腹血胰岛素水平(P<0.05);亦可显著降低其血清三酰甘油水平(P<0.05);非诺贝特可显著增加高血糖钳夹葡萄糖刺激后5min和10 min的胰岛素分泌(P<0.01,P<0.05),增加稳态葡萄糖输注速率(P<0.05);非诺贝特可明增加其胰腺中Ca2+含量(P<0.05)及胰腺线粒体ATPase活性(P<0.01);与模型组相比,非诺贝特可显著上调胰腺中胰岛素合成和信号通路中INS1、PDX1、IRS2和PKB的mRNA表达水平(P<0.01),显著上调钙离子释放相关蛋白RYR3及SERCA2的基因表达水平(P<0.001,P<0.01)。结论长期给予非诺贝特显著改善老年高脂喂养C57(Aged-C57)小鼠的糖脂代谢紊乱状态,其作用机制可能与通过上调胰腺PDX1、INS1及细胞钙库Ca2+释放相关因子的表达有关。

Objective To evaluate the effects of the fenofibrate on glu-cose and lipids metabolism and beta cell function in high -fat diet in-duced Aged-C57 obese mice.Methods Male high-fat diet induced Aged-C57 obese mice selected by insulin tolerance test （ ITT） were di-vided into two groups , model group was orally administered by gavage with water , fenofibrate group at a dose of 100 mg· kg -1· d-1 for about 8 weeks.The C57 healthy mice was as normal group （ n =14 ） .Fasting plasma lipids , glucose , insulin levels were detected at the end of treat-ment.ITT and hyperglycemic clamp were determined .Pancreas morpho-logy changes and βcell mass were evaluated by hematoxylin -eosin and Gomori stainnings.The changes of mRNA expression in the pancreas were also analyzed by Real -time PCR.Results Fenofibrate signifi-cantly improved insulin sensitivity in high -fat diet induced Aged -C57 obese mice.Fasting plasma glucose , triglyceride and insulin levels were decreased increased after 50 days fenofibrate treatment （ P 〈0.01 ,P〈0.05, P〈0.05）.In addition, pancreatic Ca2＋levels （P〈0.05） and activities of ATPase （P〈0.01） were also significantly increased after fenofibrate treatment .It was shown that fenofibrate up -regulated the pancreatic mRNA ex-pression of PDX1, INS1 and PKB （P〈0.01, P〈0.05, P〈0.01）.Moreover, the mRNA expression of RYR3 and SERCA2 associated with calcium ions release were increased in fenofibrate group （P〈0.001, P〈0.01）.Conclusion These results indicated that chronic administration of fenofibrate improved dyslipidemia and glucose homeostasis in high-fat diet induced Aged-C57 obese mice , which is related to up-regulation of the pancreatic expression of some factors, which involved in insulin biosynthesis and calcium release .