| 摘要: | 研究目的：糖尿病（Diabetes mellitus）是體內胰島素不足或細胞產生胰島素抗性而導致血糖濃度無法降低，造成高血糖症的發生。
目前臨床治療糖尿病的策略，大多是使用注射胰島素或口服降血糖藥物等方法控制血糖。然而在糖尿病長程的病程發展過程中，除了血糖的控制外，還須留意糖尿病併發症的發生，如：低血糖症、酮酸中毒、心血管疾病、慢性腎衰竭、視網膜病變等，這些併發症往往造成死亡率及醫療費用的攀升。許多研究認為這些併發症高度關聯到醣化血色素（HbA1c），因此若能控制HbA1c就可能減緩或降低併發症的發生。 研究方法：本研究經由臨床治療經驗分析可能具控制HbA1c之中醫藥方劑，再透過基礎實驗驗證中醫方劑在控制HbA1c的療效，進一步探究其調控HbA1c是否可減緩或降低糖尿病併發症的發生。 結果與討論：我們以中央健保局所推動「全民健保論質計酬計劃」中的糖尿病病患（ICD-9-CM250）為研究對象，為能使「全民健保論質計酬計劃」發揮效果，我們納入的準則為加入計劃後滿一年內，有持續定期接受追蹤者。統計結果符合定義的人數共有9,973人，曾經使用過中藥的糖尿病患者有529人。而由中央健保局所推動的「全民健保論質計酬計劃」中的糖尿病病患統計分析中，發現以六味地黃丸、玉泉丸、白虎加參湯、知柏地黃丸、濟生腎氣丸、杞菊地黃丸、甘露飲、白虎湯、竹葉石膏湯、八味地黃丸等中醫方劑較常使用。在分析中醫方劑改善HbA1c的情形後，發現TCM-DM可以明顯地降低病患的HbA1c值，進一步將TCM-DM以人體劑量餵食小鼠後，再於葡萄糖攻擊後不同時間測定血糖。結果顯示與對照組相比，TCM-DM呈現明顯調降血糖的功效，而且調降血糖的效應呈現劑量反應，這些結果代表TCM-DM具有調整血糖的活體效應。接著取上述動物與葡萄糖調控有關的肌肉組織樣品，萃取RNA，再利用DNA微陣列進行分析，將表現有差異的基因進行訊息傳導路徑的分析，結果顯示TCM-DM會明顯地影響與糖類或脂肪代謝有關的訊息傳導路徑，包括citrate cycle、PPAR signaling pathway、fatty acid metabolism、FFA signaling pathway等，也會影響胰島素訊息傳導路徑，這些結果代表TCM-DM可能可以藉由影響與糖類或脂肪代謝有關的訊息傳導路徑，而達到調整血糖的活體功效。利用高效液相層析儀（HPLC）進行分析TCM-DM的組成分，除了可以將HPLC指紋圖譜作為日後TCM-DM品管的標準外，也發現在沖提5分鐘及17.5分鐘時所出現的波峰可能含有TCM-DM的特定物質，值得進一步分析及追蹤。本研究透過physiological （HbA1c、血糖）、biochemical（血清生化）及pharmacogenomic （DNA微陣列）等方式進行特定中醫方劑基礎研究的驗證，期望將臨床觀察到的現象利用科學驗證證實其功效，確定其最適用病程、投與時間及劑量等細節，未來再推向臨床試驗。
Aim: Diabetes mellitus (DM) refers to a group of common metabolic disorders that share the phenotype of hyperglycemia. Administration of glucose-lowering agents, such as insulin, and insulin secretagogues, such as tolbutamide, has been used for the glycemic management of DM. In addition to hyperglycemia, DM leads to several complications, including retinopathy, nephropathy, and neuropathy. Clinical studies showed that reductions in glycated hemoglobin A1c (HbA1c) directly reflect improvements in glycemic control and diabetic complications. Therefore, the specific aims of this study are to find the Chinese medicinal formula with HbA1c-lowering potential and to further elucidate the molecular mechanism and therapeutic effect of this formula on the DM and diabetic complications. Method: Chinese medicinal formulae with HbA1c-lowering potentials were further analyzed for their therapeutic effects and mechanisms by glucose tolerance test and DNA microarray. Results & Discussion: By surveying the National Health Insurance Database for the DM patients who administer both Chinese medicinal formula and clinical agents, we found that TCM-DM significantly lowered the HbA1c level in patients. Oral administration of TCM-DM decreased the blood glucose levels in mice, and the decrease was dose dependent. DNA microarray further showed that TCM-DM significantly affected several pathways involved in glucose and lipid metabolism, including citrate cycle, PPAR signaling pathway, fatty acid metabolism, FFA signaling pathway, and insulin signaling pathway. These findings suggested that TCM-DM might regulate the blood glucose by affecting the pathways associated with glucose and lipid metabolism. The components of TCM-DM were analyzed by HPLC. Data showed that HPLC fingerprinting map could be the standard for quality control of TCM-DM. Moreover, the major components of TCM-DM might be present in the fractions eluted at 5 min and 17.5 min. In conclusion, the physiological investigations (HbA1C and blood glucose level), biochemical investigations (serum biochemical parameters), and pharmacogenomic investigations (microarray analysis) will be further performed to elucidate the molecular mechanisms of TCM-DM on DM. Additionally, this project is a translational medicine study that connects the basic molecular studies and clinical studies of TCM-DM. |
