糖尿病，乃因胰島素作用的失常所引致高血糖的一種新陳代謝疾病;有85%以上的患者主要是因胰島素受器或其相關訊息分子異常所引起。本研究欲探討臨床第二型糖尿病用藥Metformin改善胰島素抗性的作用機轉。
　　首先，利用果糖誘發的胰島素抗性老鼠進行葡萄糖耐受試驗，以Glucose-insulin index為評估指標，發現給予Metformin可降低該指標，但會因給予Naloxone阻斷而使該指標回升；在基因型胰島素抗性的Zucker老鼠也得到相同的結果。另外，由Hyperinsulinemic- euglycemic clamp的結果也顯示Naloxone或Naloxonazine會阻斷因Metformin而改善的胰島素抗性相關指標。進一步以餵食果糖的嗎啡型接受體剔除的小鼠進行測試，發現Metformin改善胰島素抗性的能力消失。此外，在西方點墨法也看到Metformin所活化的Akt會被Naloxonazine所抑制。由此可知，嗎啡型受體對Metformin改善胰島素抗性的重要性。
　　接著，藉由Enzyme- linked immunosorbent assay (ELISA)得知，Metformin會以劑量相關的方式增加果糖老鼠血中-endorphin的含量。由於-endorphin的釋放可能來自腎上腺，因此，將果糖大白鼠的兩側腎上腺摘除，發現胰島素抗性就無法被Metformin所改善。另外，Metformin在第一型糖尿病老鼠會透過抑制COMT活性刺激-endorphin釋放而達到降血糖的效果。因此，也測試了第二型糖尿病老鼠，發現給予 Metformin會使catecholamines增加，COMT的活性減少；在給予1受體阻斷劑Prazosin後，會抑制COMT的阻斷劑Encatapone對胰島素抗性的改善效果。
　　藉由西方點墨法測試，看到於離體骨骼肌的檢體，-endorphin會增加AMPK的磷酸化。此外，已知AMPK活化會增加體內脂肪酸的氧化作用，本研究也證實不論是Metformin或是型受體作用劑Loperamide都有此一現象。
　　綜合以上結果，Metformin藉由抑制COMT活性而刺激腎上腺釋放-endorphin，進一步活化嗎啡型受體，再透過增加Akt磷酸化來改善胰島素抗性。另外，Metformin也會活化AMPK，改善血中游離脂肪酸；此現象和改善胰島素抗性也有關。

　　Diabetes mellitus (DM) is the metabolic disorder caused by abnormalities of insulin action, and 85% patients result from dysregulation of insulin receptor or its signaling pathway. In the present study, effect of metformin on insulin resistance is investigated.
　　Metformin causes the lowering of glucose-insulin index in fructose-fed rats in the glucose tolerance test. This lowering effect on glucose-insulin index by metformin is abolished by pretreatment of naloxone. In addition, the response was also observed in Zucker-diabetic fatty rats. Also, the improvement of insulin resistance indicator by metformin is inhibited by naloxone or naloxonazine in the hyperinsulinemic-euglycemic clamp. Furthermore, in the fructose-fed knockout -receptor mice metformin loses the ability to improve insulin resistance. In the Western blot, phosphorylation of Akt by metformin is inhibited by naloxonazine. It is indicated that opioid- receptors play a role in the effect of metformin on insulin resistance.
　　From the enzyme-linked immunosorbent assay (ELISA), metformin dose dependently increase the plasma -endorphin level in fructose-fed rats. In general, plasma -endorphin is mostly secreted from the adrenal gland. In bilateral adrenalectomized fructose-fed rats, the ability of improving insulin resistance caused by metformin is abolished. As described previously, metformin increased the plasma -endorphin to lower plasma glucose through inhibition of COMT activity in type І diabetic rats. In type П diabetic rats, metformin increase catecholamines and inhibit COMT activity. Also, prazosin abolishes the insulin resistance improving action of COMT inhibitor, encatapone.
　　In present study, we present the data that -endorphin also increases phosphorylation of AMPK in vitro. In the animal study, fatty acid oxidation was increased by AMPK. Also, metformin and loperamide reduce free fatty acid.
　　In conclusion, metformin can increase -endorphin secrete from adrenal gland via inhibition of COMT activity. Then, -endorphin activates opioid  receptor to increase phosphorylation of Akt, for improvement of insulin resistance. Moreover, metformin can activate AMPK directly to increase fatty acid oxidation that may involve in the improvement of insulin resistance.

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