Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 2215 Garland Ave., Nashville, TN 37232-0615, USA.
J Pharmacol Exp Ther. 2011 Jun;337(3):610-20. doi: 10.1124/jpet.110.177899. Epub 2011 Mar 1.
The effects of a glycogen phosphorylase inhibitor (GPI) and metformin (MT) on hepatic glucose fluxes (μmol · kg(-1) · min(-1)) in the presence of basal and 4-fold basal levels of plasma glucagon were investigated in 18-h fasted conscious dogs. Compared with the vehicle treatment, GPI infusion suppressed net hepatic glucose output (NHGO) completely (-3.8 ± 1.3 versus 9.9 ± 2.8) despite increased glucose 6-phosphate (G-6-P) neogenesis from gluconeogenic precursors (8.1 ± 1.1 versus 5.5 ± 1.1). MT infusion did not alter those parameters. In response to a 4-fold rise in plasma glucagon levels, in the vehicle group, plasma glucose levels were increased 2-fold, and NHGO was increased (43.9 ± 5.7 at 10 min and 22.7 ± 3.4 at steady state) without altering G-6-P neogenesis (3.7 ± 1.5 and 5.5 ± 0.5, respectively). In the GPI group, there was no increase in NHGO due to decreased glucose-6-phosphatase flux associated with reduced G-6-P concentration. A lower G-6-P concentration was the result of increased net glycogenesis without altering G-6-P neogenesis. In the MT group, the increment in NHGO (22.2 ± 4.4 at 10 min and 12.1 ± 3.6 at steady state) was approximately half of that of the vehicle group. The lesser NHGO was associated with reduced glucose-6-phosphatase flux but a rise in G-6-P concentration and only a small incorporation of plasma glucose into glycogen. In conclusion, the inhibition of glycogen phosphorylase a activity decreases basal and glucagon-induced NHGO via redirecting glucose 6-phosphate flux from glucose toward glycogen, and MT decreases glucagon-induced NHGO by inhibiting glucose-6-phosphatase flux and thereby reducing glycogen breakdown.
在 18 小时禁食清醒犬中，研究了糖原磷酸化酶抑制剂 (GPI) 和二甲双胍 (MT) 对基础和基础水平 4 倍的血浆胰高血糖素存在下肝葡萄糖通量 (μmol · kg(-1) · min(-1)) 的影响。与载体处理相比，GPI 输注完全抑制净肝葡萄糖输出 (NHGO) (-3.8 ± 1.3 对 9.9 ± 2.8)，尽管来自糖异生前体的葡萄糖 6-磷酸 (G-6-P) 新生增加 (8.1 ± 1.1 对 5.5 ± 1.1)。MT 输注没有改变这些参数。在对血浆胰高血糖素水平升高 4 倍的情况下，在载体组中，血浆葡萄糖水平增加了 2 倍，NHGO 增加（10 分钟时增加 2 倍，稳定状态时增加 22.7 ± 3.4），而 G-6-P 新生没有改变（分别为 3.7 ± 1.5 和 5.5 ± 0.5）。在 GPI 组中，由于与 G-6-P 浓度降低相关的葡萄糖-6-磷酸酶通量减少，NHGO 没有增加。较低的 G-6-P 浓度是由于净糖生成增加而没有改变 G-6-P 新生的结果。在 MT 组中，NHGO 的增加（10 分钟时增加 22.2 ± 4.4，稳定状态时增加 12.1 ± 3.6）约为载体组的一半。NHGO 减少与葡萄糖-6-磷酸酶通量减少有关，但 G-6-P 浓度升高，仅少量血浆葡萄糖掺入糖原。总之，糖原磷酸化酶 a 活性的抑制通过将葡萄糖 6-磷酸通量从葡萄糖重新定向到糖原，降低基础和胰高血糖素诱导的 NHGO，而 MT 通过抑制葡萄糖-6-磷酸酶通量并减少糖原分解来降低胰高血糖素诱导的 NHGO。
