- 學位論文
大麻素受體經由降低葡萄糖轉運子4之表現而抑制肌肉細胞之葡萄糖攝取
Cannabinoid receptor type 1 regulates glucose uptake by reducing GLUT4 expression in C2C12 skeletal muscle cells
摘要
Rimonabant (SR141716) 為減肥及治療糖尿病的有效藥物，但由於會造成憂鬱及自殺傾向的副作用，因此已被禁止使用。過去有許多研究指出，rimonabant不只是可以通過血腦障壁 (blood brain barrier) 進到腦部抑制中樞神經的食慾中樞，還可以作用在周邊組織，促進肌肉細胞葡萄糖攝取、減少脂肪組織的油脂堆積。若能修飾rimonabant，使其無法通過血腦障壁，則藥物就不會到達腦部而造成憂鬱自殺的副作用，且仍然可以作用在周邊組織，有改善醣類及脂肪代謝的作用。肌肉組織為代謝消耗醣類的主要組織，若肌肉組織產生胰島素抗性，則很有可能造成第二型糖尿病，本研究主要探討CB1 receptor的agonist anandamide (AEA) 是否會抑制胰島素所促進的肌肉細胞葡萄糖攝取，而rimonabant (SR141716) 及其修飾物compound A、compound B、compound C以及compound D是否有恢復胰島素刺激肌肉細胞攝取葡萄糖的效果。我們發現在前處理AEA (100 nM) 後，會抑制胰島素所促進的肌肉細胞葡萄糖攝取，加入rimonabant之後，則會有恢復胰島素作用的效果。我們經由本研究發現，AEA會經由抑制肌肉細胞的GLUT4表現量進而造成肌肉細胞葡萄糖攝取量降低，我們的實驗也證實，rimonabant的修飾物compound A、compound B、compound C以及compound D與rimonabant一樣，有恢復肌肉細胞葡萄糖攝取的效果，同時我們也發現，AEA可能會經由抑制肌肉細胞p38的活性來抑制GLUT4的內生性活性。
並列摘要
Rimonabant is an CB1 receptor reverse agonist that has been shown to lower body weight and improves metabolic abnormalities in type 2 diabetes patients. However, marketing for rimonabant has been terminated because of serious neuropsychiatric effects, including anxiety, depression and concern about suicides in individual receiving rimonabant. Rimonabant exerts these neuropsychiatric effects by passing through the blood brain barrier. However, in addition to the central effects, rimonabant may also act on peripheral tissues. For example, rimonabant stimulates glucose uptake into muscle cells and reduces lipogenesis in adipose tissue and liver. Thus an attractive hypothesis is to develop rimonabant derivatives that do not pass through the blood brain barrier. Skeletal muscle plays an important role in glucose homeostasis. In the present study, anandamide (AEA), an endogenous cannabinoid neurotransmitter, was used to study glucose uptake in C2C12 myotubes. Our data showed that treatment with AEA (100 nM) for 24 hrs inhibited insulin stimulated glucose uptake in C2C12 myotubes. Pretreatment of C2C12 myotubes with rimonabant (100 nM) for 30 minutes abolished the inhibition of AEA on insulin stimulated glucose uptake through regulating GLUT4 expression. We have tested the rimonababt derivatives do not cross BBB, and our data demonstrated that these rimonabant derivatives compound A, compound B, compound C and compound D exert rimonabant-like effects. These data suggest that rimonabant derivatives are equally effective compare to rimonabant, but may avoid the adverse effects on CNS. Furthermore, we have found 100 nM AEA inhibited p-38 phosphorylation which might be related to GLUT4 intrinsic activity.