咖啡酸對高脂飼料誘導高胰島素血症大鼠海馬迴及皮質醣類代謝之研究
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2013
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根據行政院衛生署統計，糖尿病 (diabetes mellitus; DM)為2012年國人十大死因第五位，其中又以第2型糖尿病 (Type 2 diabetes mellitus, Type 2 DM)為主，主因是胰島素阻抗 (insulin resistance)所造成的高胰島素血症 (hyperinsulinemia)。台灣逐漸步入高齡化社會，國人平均餘命逐漸增加，老人失智症愈趨受到重視。失智症 (dementia)以阿茲海默症 (alzheimer’s disease)佔最多數，研究指出高胰島素血症為阿茲海默症的重要影響因子。已有許多研究證實酚酸 (phenolic acids) 具有降血糖及保護神經細胞之生理活性。本研究先進行小鼠神經母瘤Neuro 2a細胞之細胞存活率 (cell viability) 試驗，結果顯示酚酸之最高安全使用劑量為2.5 μM，接著以胰島素阻抗細胞模式為平台篩選具改善胰島素阻抗潛力之酚酸樣品，選擇出改善胰島素阻抗細胞葡萄糖攝入能力最佳的咖啡酸 (caffeic acid)，之後進一步進行動物實驗，探討咖啡酸對高脂飼料誘導胰島素阻抗大鼠大腦海馬迴及皮質中胰島素阻抗與醣類代謝之影響。
動物試驗結果顯示，雄性SD大鼠以高脂飼料餵食同時每日餵食咖啡酸 (30mg/kg body weight) 30週後可顯著改善大鼠葡萄糖耐受能力、高內臟脂肪之效果。西方墨點法分析結果顯示，在醣類代謝部分，咖啡酸可以增加糖解作用相關酵素，包括 Hexokinase、 Phosphofructokinase與 Aldolase之蛋白質表現量。在胰島素訊息傳遞部分，咖啡酸可以增加海馬迴及皮質之胰島素受器 (insulin receptor, IR)、磷酸肌醇3激酶 (Phosphatidylinositol-3 kinase, PI3K)、 AKT/蛋白激酶B (AKT/Protein kinase B, AKT/PKB)、葡萄糖轉運蛋白-3 (glucose transporter-3, GLUT3) 及胰島素降解酵素 (insulin degrading enzyme, IDE)等蛋白質之表現量。另外也發現可增進瘦體素訊息傳遞蛋白瘦體素受器 (leptin receptor, LEPR)及pJAK2Tyr813/JAK2的表現量。被動迴避試驗結果也發現，咖啡酸具有顯著改善高脂飲食誘導之認知能力缺損的情況。
根據上述結果推測，咖啡酸可透過改善腦部醣類代謝、胰島素訊息傳遞及瘦體素訊息傳遞作用，因而具有保護高脂飼料餵食大鼠認知功能受損之效果。
According the statistics report of Department of Health in Taiwan, diabetes mellitus (DM) is the fifth among the top ten leading causes of death. Among them, 95% of diabetes patients are Type 2 DM, which is characterized by hyperinsulinemia resulted from insulin resistance. Taiwan is becoming to be an aging society and the life expectancy of people is increasing year by year. Thus, the dementia in elderly has been attached great importance to society country. Most dementia is Alzheimer’s disease (AD). The growing evidences indicate that high fat diet is the major risk factor of AD. Furthermore, the protective effect of phenolic acids on hypoglycermia and neuronal has been reported. The result from cell viability test revealed that the maxium safe dosage of phenolic acids is 12.5 μM on neuroblastoma Neuro 2a cells. The insulin resistant cell model was used as a platform for screening the anti-insulin resistance potential phenolic acids. Among the tested samples, caffeic acid exhibited the highest glucose uptake enhancing activity in insulin resistant cells. Then effect of caffeic acid on ameliorating carbohydrate metabolism, insulin resistance and memory impairment and learning ability in high fat diet (HFD)-induced hyperinsulinemic rats were investigated. The results show that orally administered with caffeic acid once a day at a dosage of 30mg/kg B.W. for 30 weeks significantly improved the glucose tolerance and abdominal fat in high-fat diet (HFD) fed male SD rats. The Western blot analysis reveals that caffeic acid increases the expression of glycolysis-associated enzymes, including hexokinase, phosphofructokinase and aldolase in hippocampus and cortex of HFD rats. Moreover, caffeic acid increases the protein expression of insulin signaling-associated proteins, including insulin receptor (IR), phosphatidylinositol-3-kinase (PI3K), AKT/Protein kinase B (AKT/ PKB), glucose transporter-3 (GLUT-3) and insulin degrading enzyme (IDE) in hippocampus and cortex of HFD rats. Additionally, caffeic acid increases the protein expression of leptin signaling-associated proteins, including leptin receptor (LEPR), pJAK2Tyr813/JAK2. The results from passive avoidance test also revealed that caffeic acid significantly improved the memory impairment in HFD rats. Above investigation elucidates that caffeic acid may alleviate brain insulin resistance and improve glucose metabolism thus ameliorate memory impairment and lraening ability in HFD rats.
According the statistics report of Department of Health in Taiwan, diabetes mellitus (DM) is the fifth among the top ten leading causes of death. Among them, 95% of diabetes patients are Type 2 DM, which is characterized by hyperinsulinemia resulted from insulin resistance. Taiwan is becoming to be an aging society and the life expectancy of people is increasing year by year. Thus, the dementia in elderly has been attached great importance to society country. Most dementia is Alzheimer’s disease (AD). The growing evidences indicate that high fat diet is the major risk factor of AD. Furthermore, the protective effect of phenolic acids on hypoglycermia and neuronal has been reported. The result from cell viability test revealed that the maxium safe dosage of phenolic acids is 12.5 μM on neuroblastoma Neuro 2a cells. The insulin resistant cell model was used as a platform for screening the anti-insulin resistance potential phenolic acids. Among the tested samples, caffeic acid exhibited the highest glucose uptake enhancing activity in insulin resistant cells. Then effect of caffeic acid on ameliorating carbohydrate metabolism, insulin resistance and memory impairment and learning ability in high fat diet (HFD)-induced hyperinsulinemic rats were investigated. The results show that orally administered with caffeic acid once a day at a dosage of 30mg/kg B.W. for 30 weeks significantly improved the glucose tolerance and abdominal fat in high-fat diet (HFD) fed male SD rats. The Western blot analysis reveals that caffeic acid increases the expression of glycolysis-associated enzymes, including hexokinase, phosphofructokinase and aldolase in hippocampus and cortex of HFD rats. Moreover, caffeic acid increases the protein expression of insulin signaling-associated proteins, including insulin receptor (IR), phosphatidylinositol-3-kinase (PI3K), AKT/Protein kinase B (AKT/ PKB), glucose transporter-3 (GLUT-3) and insulin degrading enzyme (IDE) in hippocampus and cortex of HFD rats. Additionally, caffeic acid increases the protein expression of leptin signaling-associated proteins, including leptin receptor (LEPR), pJAK2Tyr813/JAK2. The results from passive avoidance test also revealed that caffeic acid significantly improved the memory impairment in HFD rats. Above investigation elucidates that caffeic acid may alleviate brain insulin resistance and improve glucose metabolism thus ameliorate memory impairment and lraening ability in HFD rats.
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高胰島素血症, 神經細胞胰島素阻抗, 失智, 咖啡酸, hyperinsulinemia, neuronal insulin resistance, dementia, caffeic acid