Sánchez-Gutiérrez J C, Sánchez-Arias J A, Lechuga C G, Valle J C, Samper B, Felíu J E
Servicio de Endocrinología Experimental, Hospital Puerta de Hierro, Universidad Autónoma de Madrid, Spain.
Endocrinology. 1994 Apr;134(4):1868-73. doi: 10.1210/endo.134.4.8137754.
In vivo studies have demonstrated that hepatic glucose production is poorly responsive to insulin in genetically obese Zucker rats. In this work, we have investigated the modulation by insulin of basal gluconeogenesis, fructose 2,6-bisphosphate levels, and pyruvate kinase and 6-phosphofructo 2-kinase activities in hepatocytes isolated from fed obese (fa/fa) or lean (Fa/-) rats. Gluconeogenesis was estimated by the conversion of a mixture of [14C]lactate-pyruvate to [14C]glucose. Basal gluconeogenesis was significantly reduced in hepatocytes isolated from obese rats compared to that measured in hepatocytes from lean animals (0.63 +/- 0.09 vs. 1.47 +/- 0.05 mumol lactate converted to glucose/g cells.20 min; n = 3-4; P < 0.001). In hepatocytes isolated from lean rats, insulin, without affecting the cellular cAMP concentration, caused a dose-dependent inhibition of the rate of gluconeogenesis, which was accompanied by a significant increase in fructose 2,6-bisphosphate levels and activation of both pyruvate kinase and 6-phosphofructo 2-kinase. In contrast, in hepatocytes isolated from obese (fa/fa) rats, neither basal gluconeogenesis nor any of the other metabolic parameters mentioned were significantly modified by insulin, even when assayed at high hormonal concentrations (10 nM). These results demonstrate a lack of responsiveness of hepatic gluconeogenesis to short term insulin action in genetically obese (fa/fa) rats.
体内研究表明，在遗传性肥胖的 Zucker 大鼠中，肝脏葡萄糖生成对胰岛素的反应较差。在本研究中，我们研究了胰岛素对从喂食的肥胖（fa/fa）或瘦（Fa/-）大鼠分离的肝细胞中基础糖异生、果糖 2,6-二磷酸水平、丙酮酸激酶和 6-磷酸果糖 2-激酶活性的调节作用。糖异生通过将 [14C]乳酸-丙酮酸混合物转化为 [14C]葡萄糖来估计。与瘦动物肝细胞中测得的相比，肥胖大鼠分离的肝细胞中基础糖异生显著降低（0.63±0.09 对 1.47±0.05 μmol 乳酸转化为葡萄糖/g 细胞·20 分钟；n = 3-4；P < 0.001）。在从瘦大鼠分离的肝细胞中，胰岛素在不影响细胞 cAMP 浓度的情况下，引起糖异生速率的剂量依赖性抑制，同时果糖 2,6-二磷酸水平显著增加，丙酮酸激酶和 6-磷酸果糖 2-激酶均被激活。相反，在从肥胖（fa/fa）大鼠分离的肝细胞中，即使在高激素浓度（10 nM）下测定，基础糖异生和上述任何其他代谢参数均未被胰岛素显著改变。这些结果表明，遗传性肥胖（fa/fa）大鼠的肝脏糖异生对短期胰岛素作用缺乏反应性。
