Hypoglycemic effects of a novel fatty acid oxidation inhibitor in rats and monkeys
Hypoglycemic effects of a novel fatty acid oxidation inhibitor in rats and monkeys
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DOI：
10.1152/ajpregu.1998.274.2.r524
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发表时间：
1998-02-01
影响因子：
2.8
通讯作者：
Foley, JE
中科院分区：
文献类型：
--
作者：
Deems, RO;Anderson, RC;Foley, JE
脂肪酸氧化增加导致非胰岛素依赖型糖尿病患者出现高血糖。为了改善这些患者的葡萄糖稳态，我们设计了一种新型可逆肉碱棕榈酰转移酶 I (CPT I) 抑制剂，可有效抑制脂肪酸氧化。 SDZ-CPI-975 显着降低正常禁食 18 小时的非人灵长类动物和大鼠的血糖水平。在大鼠中，通过β-羟基丁酸（β-氧化的最终产物）水平测量，降低葡萄糖需要大于或等于70%的脂肪酸氧化抑制。在食蟹猴中，通过更适度地降低β-羟基丁酸水平，实现了相当的血糖降低。 SDZ-CPI-975 不会增加心肌对葡萄糖的利用，表明用 SDZ-CPI-975 抑制 CPT I 不会诱导心脏肥大。这与不可逆的 CPT I 抑制剂依托莫克相比。这些结果表明，SDZ-CPI-975 有效抑制两个物种的脂肪酸氧化并降低血糖水平。因此，CPT I的可逆抑制剂代表了一类新型降血糖药，其抑制脂肪酸氧化而不诱导心脏肥大。
Increased fatty acid oxidation contributes to hyperglycemia in patients With non-insulin-dependent diabetes mellitus. To improve glucose homeostasis in these patients, we have designed a novel, reversible inhibitor of carnitine palmitoyltransferase I (CPT I) that potently inhibits fatty acid oxidation. SDZ-CPI-975 significantly lowered glucose levels in normal 18-h-fasted nonhuman primates and rats. In rats, glucose lowering required fatty acid oxidation inhibition of greater than or equal to 70%, as measured by beta-hydroxybutyrate levels, the end product of beta-oxidation. In cynomolgus monkeys, comparable glucose lowering was achieved with more modest lowering of beta-hydroxybutyrate levels. SDZ-CPI-975 did not increase glucose utilization by heart muscle, suggesting that CPT I inhibition with SDZ-CPI-975 would not induce cardiac hypertrophy. This was in contrast to the irreversible CPT I inhibitor etomoxir. These results demonstrate that SDZ-CPI-975 effectively inhibited fatty acid oxidation and lowered blood glucose levels in two species. Thus reversible inhibitors of CPT I represent a class of novel hypoglycemic agents that inhibit fatty acid oxidation without inducing cardiac hypertrophy.