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題名：DMH對於第一型與第二型糖尿病小鼠之治療效果
作者：林哲立
作者(外文)：Lin, Che-Li
校院名稱：國立體育大學
系所名稱：運動科學研究所
指導教授：黃啟彰
學位類別：博士
出版日期：2018
主題關鍵詞：糖尿病；血糖；db/db小鼠；STZ；diabetes；blood sugar；db/db mice；STZ
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如何有效幫助讓糖尿病患血糖濃度維持恆定，降低糖尿病合併症風險一直是全球中重要的議題。 本次研究案主要探討化合物DMH，是否對於第一型與第二型糖尿病具有長期調控血糖恆定的功能。而本研究案之動物模式可比照此原則誘發適當STZ的第一型糖尿病小鼠模式來進行測試藥物之功能性評估試驗以及動物模式為db/db之第二型糖尿病小鼠，此小鼠為leptin-receptor基因缺陷並具胰島素阻抗，因此具有類似第二型糖尿病之病理特徵來進行測試藥物之功能性評估試驗。利用多源基因體學與蛋白質體學之觀點探討相關血糖變化與調控機制，測量小鼠的各項功能性評估:生理數值測量、空腹血糖值測定、口服葡萄糖耐受試驗等，最後將各組動物組織臟器之病理切片進觀察。
本研究將小鼠各分為6組，STZ誘發小鼠分別為Normal、STZ、STZ-Met、STZ-0.5X DMH、STZ-1X DMH、STZ-2X DMH以及將db/db之第二型糖尿病小鼠分別為Normal、db/db-Met、db/db-0.5X DMH、db/db-1X DMH。於STZ的第一型糖尿病小鼠結果顯示，，在介入第3周時(3 Week)，Met與DMH不同劑量處理組別相較於STZ組別均顯著改善空腹血糖數值(P<0.05)，在連續六周投予試驗藥物後DMH-1X與DMH-2X組別在60與120分鐘上均顯著低於STZ組別(P<0.05)。利用軟體計算不同時間點葡萄糖耐受度曲線下面積以了解不同藥物與濃度介入下之藥物效果評估，連續投與藥物6周後(6 Week) 顯示DMH-1X與DMH-2X組別曲線下面積顯著低於STZ組別(P=0.02與P=0.04)，但在停藥6周(12 Week)均顯示STZ組別、Met組別與不同DMH濃度處理組別(STZ-DMH-0.5X/DMH-1X/DMH-2X) 血糖變化曲線下面積均無顯著差異。進一步瞭解STZ誘發糖尿病與藥物介入後，對於動物體內重要組織臟器影響:肝臟部分在STZ+DMH-1X組及STZ+DMH-2X組的動物肝臟組織，可觀察到上述組織型態學變化有緩解的趨勢，腎臟部分與胰臟部分無明顯差異性之觀察發現於副睪脂肪發現相對在STZ+DMH-1X組及STZ+DMH-2X組的脂肪細胞可見到有相對較多量的油滴蓄積於脂肪細胞中。另於db/db之第二型糖尿病小鼠研究結果顯示在第21周齡時(12Week)，相較於db/db組別而言DMH處理組均能顯著降低空腹血糖數值 (P＜0.05)；在第24周與27周齡時(15 Week與18 Week)，Normal組別顯著低於db/db各處理組 (P＜0.05)，在連續六周投予試驗藥物後，在DMH-1X與DMH-2X組別在15、30、60與120分鐘上均顯著低於db/db組別，相較於Met組別更具有改善葡萄糖耐受性之效果並於停止給予不同藥物的處理並於六周後(12 Week) ，其均顯著低於db/db組別，相較於Met組別更具有改善葡萄糖耐受性之效果。計算不同時間點葡萄糖耐受度曲線下面積以了解不同藥物與濃度介入下之藥物效果評估，連續投與藥物6周後(6 Week)顯示相較於db/db組別DMH給與後均能顯著減少曲線下面積；在停止給與藥物介入後的6周(12 Week)，DMH投予組別亦呈現顯著低於db/db組別。總結以上結果，DMH的連續投予能改善db/db糖尿病動物之空腹血糖數值與葡萄糖耐受性；在停止給藥後，該藥效能持續顯著減少葡萄糖曲線下面積達六周左右。
How to effectively help maintain a constant blood glucose concentration in diabetes, reducing the risk of diabetes complications has been an important issue in the world. This study focused on the compound DMH, which has a long-term regulation of blood glucose levels for type 1 and type 2 diabetes. The animal models of this study were be used to test the functional activities of DMH in the streptozotocin (STZ)-induced type 1 diabetic mouse model, as well as in the db/db mouse model of type 2 diabetes. The leptin-receptor gene is defective and has insulin resistance, so it has a pathological feature similar to that of type 2 diabetes for functional evaluation of test drugs. Using clinical biochemistry and proteomics approach to explore the relevant blood glucose changes and potential regulation mechanisms, measuring the functional evaluation of mice: physiological value measurement, fasting blood glucose measurement, oral glucose tolerance test, etc., and finally the pathological examinations of animal tissue organs were also observed.
In this study, mice were divided into 6 groups. STZ-induced mice were Normal, STZ, STZ-Met, STZ-0.5X DMH, STZ-1X DMH, STZ-2X DMH, and type 2 diabetes with db/db. The mice were Normal, db/db-Met, db/db-0.5X DMH, db/db-1X DMH, respectively. The results of type 1 diabetic mice in STZ showed that at the 3rd week of intervention (3 Week), the different doses of Met and DMH treated the group significantly improved the fasting blood glucose level compared with the STZ group (P<0.05). The DMH-1X and DMH-2X groups were significantly lower than the STZ group at 60 and 120 minutes after administration of the test drug for six consecutive weeks (P<0.05). The software was used to calculate the area under the glucose tolerance curve at different time points to understand the drug effect evaluation under different drug and concentration interventions. After 6 weeks of continuous drug administration (6 Week), the area under the DMH-1X and DMH-2X group curves was significantly lower than STZ. Groups (P=0.02 and P=0.04), but showed STZ group, Met group and different DMH concentration treatment groups (STZ-DMH-0.5X/DMH-1X/DMH-2X) blood glucose at 6 weeks (12 Week) There was no significant difference in the area under the curve of variation. To further understand the effects of STZ-induced diabetes and drug intervention on important organ organs in animals: liver tissue in the liver tissue of STZ+DMH-1X group and STZ+DMH-2X group, the trend of tissue type changes can be observed. There was no significant difference between the kidney part and the pancreas. It was found that in the fat cells of the STZ+DMH-1X group and the STZ+DMH-2X group, a relatively large amount of oil droplets were accumulated in the fat cells. In addition, the results of the second type of diabetic mice in db/db showed that at the 21st week (12Week), the DMH treatment group significantly reduced the fasting blood glucose level compared with the db/db group (P<0.05). At week 24 and 27 weeks (15 Week and 18 Week), the Normal group was significantly lower than the db/db treatment group (P<0.05), after administration of the test drug for six consecutive weeks, at DMH-1X and DMH-2X. The groups were significantly lower than the db/db group at 15, 30, 60 and 120 minutes, and had improved glucose tolerance compared with the Met group and stopped treatment with different drugs and after six weeks. (12 Week), which are significantly lower than the db/db group, have an effect of improving glucose tolerance compared to the Met group. The area under the glucose tolerance curve at different time points was calculated to understand the effect of drug intervention under different drug and concentration interventions. After 6 weeks of continuous drug administration (6 Week), it was shown that compared with db/db group DMH. The area under the curve was significantly reduced; the DMH administration group was also significantly lower than the db/db group at 6 weeks after stopping the drug intervention. Summarizing the above results, continuous administration of DMH can improve the fasting blood glucose level and glucose tolerance of db/db diabetic animals; after stopping the administration, the efficacy of the drug continues to significantly reduce the area under the glucose curve for about six weeks.
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