Pitchaimani Vigneshwaran, Arumugam Somasundaram, Thandavarayan Rajarajan Amirthalingam, Karuppagounder Vengadeshprabhu, Afrin Mst Rejina, Sreedhar Remya, Harima Meilei, Suzuki Hiroshi, Miyashita Shizuka, Suzuki Kenji, Nakamura Masahiko, Ueno Kazuyuki, Watanabe Kenichi
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan.
Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX 77030, USA.
Life Sci. 2016 May 15;153:118-23. doi: 10.1016/j.lfs.2016.04.006. Epub 2016 Apr 12.
Sustained glucagon infusion increases hepatic glucose production, but this effect is transient due to hypothalamic glucagon signaling. In hypoglycemia, glucagon acts as a major defense to sustain the blood glucose level and this raises the question regarding glucagon signaling associated glucose production in prolonged fasting hypoglycemia. In this study, we investigated the proteins associated with hypothalamic glucagon signaling and liver gluconeogenesis during fasting hypoglycemia.
8-9week old, male C57BL6/J mice were fasted for 4, 8, 12, 18, 24, 30, 36 or 42h. In the hypothalamus, we investigated glucagon signaling by analyzing the glucagon receptor and its downstream protein, peroxisome proliferator-activated receptor-gamma coactivator 1 (PGC-1) expression. In the liver, we investigated gluconeogenesis by analyzing p-protein kinase A (PKA)(Ser/Thr) substrate and phosphoenolpyruvate carboxykinase - cytosolic (PEPCK-C) expression using the western blotting technique.
The elevated or trended higher hypothalamic glucagon receptor and PGC-1 expressions at 18 and 42h were correlated with the attenuated liver p-PKA(Ser/Thr) substrate expression. The attenuated hypothalamic glucagon receptor and PGC-1 expressions at 12, 24, 30 and 36h were correlated with the elevated or trended higher liver p-PKA(Ser/Thr) substrate expression.
The hypothalamic glucagon signaling during fasting hypoglycemia might have been modulated by circadian rhythm and this possibly attenuates the liver p-PKA(Ser/Thr) substrate to modify the gluconeogenesis pathway. This mechanism will help to understand the hyperglucagonemia associated complications in diabetes.
持续输注胰高血糖素可增加肝脏葡萄糖生成，但由于下丘脑胰高血糖素信号传导，这种作用是短暂的。在低血糖症中，胰高血糖素是维持血糖水平的主要防御机制，这就提出了一个问题，即在长期禁食低血糖症中，与胰高血糖素信号传导相关的葡萄糖生成情况如何。在本研究中，我们调查了禁食低血糖症期间与下丘脑胰高血糖素信号传导和肝脏糖异生相关的蛋白质。
将8-9周龄的雄性C57BL6/J小鼠禁食4、8、12、18、24、30、36或42小时。在下丘脑中，我们通过分析胰高血糖素受体及其下游蛋白过氧化物酶体增殖物激活受体γ共激活因子1（PGC-1）的表达来研究胰高血糖素信号传导。在肝脏中，我们使用蛋白质印迹技术通过分析p-蛋白激酶A（PKA）（丝氨酸/苏氨酸）底物和磷酸烯醇式丙酮酸羧激酶-胞质（PEPCK-C）的表达来研究糖异生。
在18小时和42小时时，下丘脑胰高血糖素受体和PGC-1表达升高或呈上升趋势，这与肝脏p-PKA（丝氨酸/苏氨酸）底物表达减弱相关。在12、24、30和36小时时，下丘脑胰高血糖素受体和PGC-1表达减弱，这与肝脏p-PKA（丝氨酸/苏氨酸）底物表达升高或呈上升趋势相关。
禁食低血糖症期间的下丘脑胰高血糖素信号传导可能受昼夜节律调节，这可能会减弱肝脏p-PKA（丝氨酸/苏氨酸）底物，从而改变糖异生途径。这一机制将有助于理解糖尿病中与高胰高血糖素血症相关的并发症。
