水飛薊 (Silymarin)對高血糖症之影響

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1 水飛薊 (Silymarin)對高血糖症之影響
糖尿病一全球普遍性的慢性疾病。在94年台灣十大死因中排名第四。由我們過去分析92年度台灣健保資料結果顯示，同時罹患肝臟疾病之糖尿病患人數則排名第三，僅次於心血管疾病和高血脂症。因此本研究將針對臨床常用保肝藥silymarin (SB) 對高血糖症之影響，並分別利用糖尿病動物模式以及某醫學中心糖尿病患為研究對象，並以血糖值為血糖控制指標進行分析。動物實驗發現口服投與SB 100 mg/kg至似青年期發作的成人型糖尿病MODY-like (pancreas-reactivated HNF 1α-knockout mice) 糖尿病小鼠，在藥物投與後第2、4小時血糖值分別較未投藥前下降42.5%、17.5%；而經口投與SB (0、10、30、100、300、500 mg/kg ) 對第二代抗精神病劑quetiapine (Q) (20 mg/kg ip) 所誘發的 (Q-induced) 高血糖症，經統計分析結果發現SB不同劑量組之第二小時血糖值則分別為投藥前之1.6、2.1、1.7、1.6、1.8、1.8 倍。在病患用藥分析部份：本實驗室則以回溯性病歷回顧方法來評估SB對糖尿病患血糖控制之影響，血糖控制的依據分別以HbA1c/ 飯前/飯後血糖為評估指標。結果顯示連續服用SB 3個月之病患 (n=176)，平均年齡為55.0 ±11.2歲、男女比為1.6，有50.0%病人 (n=88) 在服用SB時間區間裡血糖控制較未服用的時間區段佳 [HbA1c 8.4 vs 6.9, p<0.001 (n=16); AC vs p<0.001 (n=68); PC vs p=0.028 (n=4) ]，並具統計上意義；而未使用SB的糖尿病患 (n=118)，平均年齡為60.3±11.9歲、男女比為1.4，血糖控制指標有改善之病患佔22.0% (n=26) [HbA1c 7.8 vs 7.3, p=0.423 (n=7); AC vs 149.0, p=0.270 (n=12); PC vs 165.3, p=0.055 (n=7) ]，但改善指標數值不具統計意義。由上述基礎與臨床研究結果顯示，100 mg/kg SB可以改善MODY-like 糖尿病動物模式高血糖症，對接受口服降血糖藥治療之糖尿病患之血糖控制亦有輔助作用。所以SB可以改善大部分糖尿病合併有肝疾患的血糖控制。但由於SB不會改善Q所誘發的高血糖症。因此臨床上糖尿病患使用第二代抗精神病劑在使用SB仍需仔細評估藥物交互作用和其安全性。

2 Effects of Silymarin on Hyperglycemia
Diabetes is becoming a worldwide epidemic. In Taiwan, diabetes was reported by the government to be the fourth leading cause of death and its mortality increased more than 10% in Chronic hepatitis was also reported to be the third leading concurrent disease in the year 2002 database of diabetes outpatients by our laboratory. In current study, we used two mouse models of diabetes and the drug utilization with blood parameters (HbA1c and blood glucose) of diabetic outpatients were collected in order to investigate effects of silymarin (SB) on the glycemic control. In MODY-like (pancreas-reactivated HNF 1α-knockout mice) model, the mean blood glucose decreased 42.5%, 17.5% (n=4) at 2, 4 hours, respectively, following SB (100 mg/kg) oral administration. In quetiapine (Q; 20 mg/kg)-induced hyperglycemia model, mean blood glucose values increased to 1.6, 2.1, 1.7, 1.6, 1.8, 1.8 fold following various concentrations (0, 10, 30, 100, 300, 500 mg/kg) of SB compared to the baseline. Among 650 screened diabetes patients, there were 176 patients (55.0±11.2 y/o; male/female=1.6) who were continuously prescribed with SB (286.5  85.4 mg per day) for 3 months, and there was a statistically significant decrease in HbA1c, fasting blood glucose (FBG) or postprandial blood glucose (PBG) in 88 patients of this population (50%) while SB was added to the therapy regimen for 3-month continuously [HbA1c 8.4 vs 6.9, p<0.001 (n=16); FBG vs 137.0, p<0.001 (n=68); PBG vs 190.3, p=0.028 (n=4)]. Among the diabetic patients without taking SB (n=118; 60.3±11.9 y/o; male/female=1.4), the glycemic control of 26 patients (22% of this group) was improved [HbA1c 7.8 vs 7.3, p=0.423 (n=7); FBG vs 149.0, p=0.270 (n=12); PBG vs 165.3, p=0.055 (n=7)], though there was no significant difference. Here we demonstrated that SB at 100 mg/kg improved hyperglycemia in MODY-like diabetic animal model, and there was a synergistic effect of SB to oral hypoglycemic drugs in patients. However, SB didn’t improve Q-induced hyperglycemia model so drug safety issues should be more concerned in the diabetic patients using the secondary generation of antipsychotics.