Tutwiler G F, Kirsch T, Mohrbacher R J, Ho W
Metabolism. 1978 Oct;27(10):1539-56. doi: 10.1016/s0026-0495(78)80027-4.
A specific inhibitor of fatty acid oxidation, methyl 2-tetradecylglycidate (McN-3716) has been found to produce a dose dependent hypoglycemic effect when administered orally to rats, mice, and dogs. In addition to being more potent than other inhibitors of fatty acid oxidation, McN-3716 was also found to be 15--20 times more potent than tolbutamide in lowering the blood glucose of fasting rats. Furthermore, evidence is presented that McN-3716 produces hypoglycemia by a mechanism which differs from that of other oral hypoglycemic agents, the biguanides and the sulfonylureas. As predicted by the Randle glucose-fatty acid cycle, McN-3716 lowered glucose concentrations only under conditions where fatty acids were being used as the major energy substrates (fasting, diabetes, and feeding of high fat diets) but not under conditions where energy was derived mainly from carbohydrate (fed state or following hypophysectomy). Administration of McN-3716 produced a remarkable lowering of the plasma glucose and the glycosuria of depancreatized dogs but did not result in complete normalization of glucose, especially the excursions of blood glucose following feeding. It did, however, produce virtually complete reversal of the ketoacidosis of alloxan diabetic rats and depancreatized dogs without worsening the plasma lipid profile. Thus, McN-3716 may have potential utility as an oral therapeutic agent for the treatment of ketosis-prone juvenile or maturity-onset diabetes.
已发现一种脂肪酸氧化的特异性抑制剂，2-十四烷基缩水甘油酸甲酯（McN-3716），当对大鼠、小鼠和狗口服给药时，会产生剂量依赖性的降血糖作用。除了比其他脂肪酸氧化抑制剂更有效外，还发现McN-3716在降低禁食大鼠血糖方面比甲苯磺丁脲强15至20倍。此外，有证据表明，McN-3716产生低血糖的机制与其他口服降糖药（双胍类和磺脲类）不同。正如兰德尔葡萄糖-脂肪酸循环所预测的那样，McN-3716仅在脂肪酸被用作主要能量底物的情况下（禁食、糖尿病和高脂饮食喂养）降低葡萄糖浓度，而在能量主要来自碳水化合物的情况下（进食状态或垂体切除术后）则不会。给予McN-3716可显著降低胰腺切除狗的血糖和糖尿，但并未使血糖完全恢复正常，尤其是进食后的血糖波动。然而，它确实几乎完全逆转了四氧嘧啶糖尿病大鼠和胰腺切除狗的酮症酸中毒，且没有使血浆脂质谱恶化。因此，McN-3716作为治疗易发生酮症的青少年或成年型糖尿病的口服治疗剂可能具有潜在用途。
