Hypoglycemia with enhanced hepatic glycogen synthesis in recombinant mice lacking hexose-6Phosphate dehydrogenase
Hypoglycemia with enhanced hepatic glycogen synthesis in recombinant mice lacking hexose-6Phosphate dehydrogenase
复制标题
DOI：
10.1210/en.2007-0963
复制
发表时间：
2007-12-01
期刊：
影响因子：
4.8
通讯作者：
Stewart, Paul M.
中科院分区：
文献类型：
--
作者：
Lavery, Gareth G.;Hauton, David;Stewart, Paul M.
己糖-6-磷酸脱氢酶（H6PDH）敲除（KO）小鼠内质网内烟酰胺腺嘌呤二核苷酸磷酸（还原）的生成减少。因此，11 β-羟基类固醇脱氢酶1型酶活性从还原酶转换为脱氢酶，导致糖皮质激素失活。11 β-羟基类固醇脱氢酶1型已成为调节肝脏葡萄糖输出的重要因素;因此，我们研究了KO小鼠葡萄糖稳态的各个方面。与野生型小鼠相比，KO小鼠体重增加减少，表现出外周空腹低血糖，葡萄糖耐量改善，血浆皮质酮浓度升高。进食和禁食KO小鼠的血浆胰岛素水平正常;然而，禁食动物再进食后4小时胰岛素和血糖水平降低，表明胰岛素敏感性改善。在禁食KO小鼠中，糖皮质激素响应性促凋亡酶磷酸烯醇丙酮酸羧激酶和葡萄糖-6-磷酸酶的诱导和活性得以保留。进食KO肝脏中糖原储存升高，KO小鼠中进食糖原生成速率增加。乳酸盐通过再生作用以血浆葡萄糖的形式恢复，同时乳酸盐衍生的糖原增加。这些数据表明，在肝脏水平的糖皮质激素敏感性的部分保留。因此，我们推测，增加糖原合成可能反映了增加的流量葡萄糖-6-磷酸（H6PDH底物）通过糖原在H6PDH介导的代谢的情况下。
Hexose-6-phosphate dehydrogenase (H6PDH) knockout ( KO) mice have reduced generation of nicotinamide adenine dinucleotide phosphate ( reduced) within the endoplasmic reticulum. As a consequence, 11 beta-hydroxysteroid dehydrogenase type 1 enzyme activity switches from a reductase to a dehydrogenase leading to glucocorticoid inactivation. 11 beta-Hydroxysteroid dehydrogenase type 1 has emerged as an important factor in regulating hepatic glucose output; therefore, we examined aspects of glucose homeostasis in KO mice. Compared with wild-type mice, KO mice reduced weight gain, displayed peripheral fasting hypoglycemia, improved glucose tolerance, and elevated plasma corticosterone concentrations. Plasma insulin levels in fed and fasted KO mice are normal; however, insulin and plasma glucose levels are reduced 4 h after fasted animals are refed, indicating improved insulin sensitivity. There is preserved induction and activity of the glucocorticoid-responsive gluconeogenic enzymes phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in fasted KO mice. Glycogen storage is elevated in fed KO liver, with fed glycogenesis rates increased in KO mice. There is normal flux of lactate through gluconeogenesis recovered as plasma glucose, coupled with increased glycogen derived from lactate. These data suggest partial retention of glucocorticoid sensitivity at the level of the liver. We therefore postulate that increased glycogen synthesis may reflect increased flux of glucose-6-phosphate(H6PDHsubstrate) through to glycogen in the absence of H6PDH mediated metabolism.