臺灣博碩士論文加值系統

為了要發展新的藥物來治療糖尿病，我們使用自從天然植物中所萃取出來的物質去篩選具
有降血糖活性的物質。本項工作使用三種糖尿病的老鼠來研究；一種是利用streptozotoc
in所誘發的糖尿病老鼠，一種是遺傳性的糖尿病老鼠(B.B. rats)，這是類似糖尿病第一
型「胰島素依賴型(insulin-dependent DM, IDDM)」病人的動物，另一種則是類似糖尿病
第二型「非胰島素依賴型(non-insulin dependent DM, NIDDM)」病人的老鼠。赤芍素(Pa
eoniflorin) 是從Paeoniae Radix所分離出來具有作用的天然物，本實驗的主要目的是想
去瞭解和探討這項降血糖的作用機轉。赤芍素的作用時間為靜脈注射5 mg/kg約25分鐘後
可達最大降血糖作用，經由葡萄糖挑戰試驗(glucose challenge test) ，證實這種降低
血糖的作用是經由增加葡萄糖的利用率。在離體(in vitro)的脂肪細胞，赤芍素會依濃度
的遞增性(dose-dependent)來增加[14C] 2-deoxy-glucose的進入細胞。而赤芍素的類似
物8-debenzoylpaeoniflorin也有類似的作用，只是效果不及赤芍素(Paeoniflorin)。另
外，在骨骼肌方面，例如:比目魚肌(soleus muscle)，赤芍素對於肝醣的合成有顯著的效
果。投予赤芍素直接刺激脂肪細胞，可使得蛋白激脢C (protein kinase C, PKC-β)從細
胞質移轉到細胞膜上，並使葡萄糖運輸物(glucose transporter 4)從細胞內的原漿微粒(
intracellular microsomal pool) 移轉到漿膜 (plasma membrane)上。在離體(in vitro
)的脂肪細胞，預先以一種磷脂質(PLC)的抑制劑U73122 (0.33-3.3 μM 10分鐘) 處理，再
與赤芍素反應30分鐘，發現U73122 (3.3 μM)幾乎可以完全抑制赤芍素的作用使得葡萄糖
之攝取改變。可是，U73343，U73122的類似物，卻無法抑制赤芍素的作用；即使在同樣的
高濃度之下。另一方面，我們也使用A1 (Adenosine) 接受器的拮抗劑：DPCPX (10 μM -
0.1 μM)，來探討它的作用是否在接受器上。發現DPCPX在10 mM就可抑制赤芍素引致使PKC
-β和GLUT4從細胞質移轉到細胞膜的作用。總之，在糖尿病老鼠方面，赤芍素的降血糖作
用主要是增進葡萄糖的利用率，同時蛋白激脢C (protein kinase C, PKC-β) 和葡萄糖運
輸物 (glucose transporter, GLUT4)在赤芍素的降血糖作用機轉上扮演了極為重要的角
色。

In an attempt to develop the new compounds for the treatment of diabetes mel
litus (DM), screen of antihyperglycemic activity is carried out from the extra
cts of natural plants in three types of diabetic rats; the streptozotocin (STZ
)-induced one and the genetic one (B.B. rats) which is similar to the patients
with insulin-dependent DM (IDDM) and the NIDDM (non-insulin-dependent DM rats
) one . Paeoniflorin, the compound isolated from Paeoniae Radix, was found to
have most effective antihyperglycemic action. The present study
is designed to u
nderstand the mechanisms for antihyperglycemic action. Paeoniflorin induced t
he maximal response at 25 min later of intravenous (i.v.) injection to produce
a dose-dependent antihyperglycemic action. This compound lowered the blood gl
ucose level in rats received glucose challenge indicating the increase of gluc
ose utilization. In the isolated adipocytes, paeoniflorin reduced the uptake
of [14C]2-deoxy-glucose (2-DG) in a dose-dependent manner where 8-debenzoylpae
oniflorin produced a similar but lower effect. Also, paeoniflorin influenced t
he glycogen synthesis slightly in soleus muscle of rats. These actions seem re
sponsible for the antihyperglycemic action. Moreover, stimulatory effects of
paeoniflorin on the translocation of protein kinase C (PKC-β) from cytosol to
membrane and glucose transporter (GLUT4) from the intracellular microsomal po
ol to plasma membrane were observed. Pretreatment of adipocytes with U73122
(0.33, 1, 3.3 μM for 10 min) , one of the PLC (phospholipid C) inhibitors, inh
ibited the action of paeoniflorin (8 μMfor 30 min). A complete inhibition was
observed in 3.3 μM U73122-treated samples. In contrast, U73343, an ineffectiv
e analog of U73122, failed to block the paeoniflorin-increased adipocytes upta
ke. In adipose tissue where the adenosine A receptors enhance insulin action a
nd inhibit adenylyl cyclase. In the presence of A1 adenosine receptors antagon
ist, DPCPX at 10 μM∼0.1 μM, mimics the action of
paeoniflorin for translocat
ion of PKC-β and GLUT4 to rat adipocyte membranes. In conclusion, paeoniflo
rin possesses the ability to lower blood glucose in diabetic rats through the
utilization of glucose. The obtained results suggest that protein kinase C (PK
C-β) and GLUT4 play important roles in antihyperglycemic action of paeoniflori
n.