Lechuga C G, Carrillo J J, Sánchez-Gutiérrez J C, Felíu J E
Servicio de Endocrinología Experimental, Clínica Puerta de Hierro, and Universidad Autónoma de Madrid, Spain.
Life Sci. 2001 Feb 23;68(14):1617-28. doi: 10.1016/s0024-3205(01)00965-1.
The influence of the hypoglycemic agent glipizide (0-100 microM) on the rate of gluconeogenesis from lactate, as well as on the levels of fructose 2,6-bisphosphate, has been investigated in hepatocytes isolated from genetically obese (fa/fa) Zucker rats and from their corresponding lean (Fa/-) littermates. As compared to lean rat hepatocytes, liver cells isolated from obese animals showed a lower rate of basal gluconeogenesis (0.9 +/- 0.2 vs 5.4 +/- 0.5 micromol of lactate converted to glucose/g cell x 30 min, n=4) and higher levels of fructose 2,6-bisphosphate (11.5 +/- 1.0 vs 5.9 +/- 0.4 nmol/g cell, n=8-9). In lean rat hepatocytes, the presence of glipizide in the incubation medium caused a dose-dependent inhibition of the rate of lactate conversion to glucose (maximal inhibition=46%; EC50 value=26 microM), and simultaneously raised the cellular content of fructose-2,6-bisphosphate (maximal increment=40%; EC50 value=10 microM). In contrast, in hepatocytes isolated from obese rats, the inhibition of gluconeogenesis and the increment in fructose-2,6-bisphosphate levels elicited by glipizide were significantly reduced (maximal effects of 22 and 13%, respectively). Similarly, the activation of glycogen phosphorylase and the increase in hexose 6-phosphate levels in response to glipizide were less marked in obese rat hepatocytes than in liver cells isolated from lean animals. These results demonstrate that the efficacy of sulfonylureas as inhibitors of hepatic gluconeogenesis is reduced in the genetically obese (fa/fa) Zucker rat.
已研究降糖药格列吡嗪（0 - 100微摩尔）对从遗传性肥胖（fa/fa） Zucker大鼠及其相应的瘦（Fa/-）同窝仔鼠分离的肝细胞中乳酸糖异生速率以及果糖2,6 - 二磷酸水平的影响。与瘦大鼠肝细胞相比，从肥胖动物分离的肝细胞显示基础糖异生速率较低（0.9±0.2对5.4±0.5微摩尔乳酸转化为葡萄糖/克细胞×30分钟，n = 4），果糖2,6 - 二磷酸水平较高（11.5±1.0对5.9±0.4纳摩尔/克细胞，n = 8 - 9）。在瘦大鼠肝细胞中，孵育培养基中存在格列吡嗪会导致乳酸转化为葡萄糖的速率呈剂量依赖性抑制（最大抑制率 = 46%；EC50值 = 26微摩尔），同时提高果糖 - 2,6 - 二磷酸的细胞含量（最大增量 = 40%；EC50值 = 10微摩尔）。相反，在从肥胖大鼠分离的肝细胞中，格列吡嗪引起的糖异生抑制和果糖 - 2,6 - 二磷酸水平的增加显著降低（分别为最大效应的22%和13%）。同样，肥胖大鼠肝细胞中糖原磷酸化酶的激活以及对格列吡嗪反应的6 - 磷酸己糖水平的增加不如从瘦动物分离的肝细胞明显。这些结果表明，在遗传性肥胖（fa/fa） Zucker大鼠中，磺脲类药物作为肝糖异生抑制剂的功效降低。
