大多数动物，包括人类，在其一生中都不断经历进食和饥饿的周期循环。进食后以葡萄糖为主的血糖急速上升，而血糖得不到及时的控制则是糖尿病最主要的特征，同时餐后的高血糖也是糖尿病病人罹患心血管并发症的主要原因。机体有多种机制参与了餐后血糖的调控，其中最主要的途径是通过胰岛细胞分泌胰岛素，增加机体外周组织对血糖的吸收，从而降低血糖。
肝脏是机体最重要的代谢器官，同时也是一个血糖的感受器官。多年前的动物实验表明，进食后约三分之一的血糖能够转化为肝糖原，从而储备过多的葡萄糖。但目前尚不清楚肝脏的糖原合成如何与进食和饥饿的循环周期相协调，以维持餐后血糖的稳定。
中科院上海生命科学院营养科学研究所陈雁课题组的博士生罗小琳等人发现，饥饿能在小鼠肝脏中诱导一个基因的表达，名为PPP1R3G，而进食后该基因表达则下降。进一步的研究表明PPP1R3G是一个蛋白磷酸酶的调节亚基，PPP1R3G的功能是把该蛋白磷酸酶锚定在糖原上，增加糖原合成酶的活性，进而增加糖原合成。在小鼠实验中，罗小琳等人发现过度表达PPP1R3G后，进食后血糖清除率明显提高。若在小鼠中降低PPP1R3G的表达，进食后的血糖清除速度则显著延迟。因此，这一研究发现了肝脏PPP1R3G在餐后血糖的调控中发挥了至关重要的功能，而尤其有意义的是，这一功能与机体的进食和饥饿周期紧密相扣。机体在饥饿时PPP1R3G增加，进食后的短时间内，PPP1R3G可以介导肝糖原的快速合成，从而快速降低血糖。
该工作近日在国际糖尿病研究领域权威杂志Diabetes在线发表。血糖调控异常是糖尿病的一个最根本因素，而糖尿病的发病率在我国以及世界范围内呈现急剧上升的趋势。该研究揭示了一个全新的调控餐后血糖的新机制，对于糖尿病血糖失衡的理解和未来控制血糖的策略提供了一个全新的思路。
该工作得到了中科院、国家基金委和科技部的资助。（生物谷Bioon.com）
生物谷推荐原文出处：
Diabetes doi: 10.2337/db10-1663
Fasting-Induced Protein Phosphatase 1 Regulatory Subunit Contributes to Postprandial Blood Glucose Homeostasis via Regulation on Hepatic Glycogenesis
Xiaolin Luo, Yongxian Zhang, Xiangbo Ruan, Xiaomeng Jiang, Lu Zhu, Xiao Wang, Qiurong Ding, Weizhong Liu, Yi Pan, Zhenzhen Wang and Yan Chen
Abstract
OBJECTIVE Most animals experience fasting–feeding cycles throughout their lives. It is well known that the liver plays a central role in regulating glycogen metabolism. However, how hepatic glycogenesis is coordinated with the fasting–feeding cycle to control postprandial glucose homeostasis remains largely unknown. This study determines the molecular mechanism underlying the coupling of hepatic glycogenesis with the fasting–feeding cycle.
RESEARCH DESIGN AND METHODS Through a series of molecular, cellular, and animal studies, we investigated how PPP1R3G, a glycogen-targeting regulatory subunit of protein phosphatase 1 (PP1), is implicated in regulating hepatic glycogenesis and glucose homeostasis in a manner tightly orchestrated with the fasting–feeding cycle.
RESULTS PPP1R3G in the liver is upregulated during fasting and downregulated after feeding. PPP1R3G associates with glycogen pellet, interacts with the catalytic subunit of PP1, and regulates glycogen synthase (GS) activity. Fasting glucose level is reduced when PPP1R3G is overexpressed in the liver. Hepatic knockdown of PPP1R3G reduces postprandial elevation of GS activity, decreases postprandial accumulation of liver glycogen, and decelerates postprandial clearance of blood glucose. Other glycogen-targeting regulatory subunits of PP1, such as PPP1R3B, PPP1R3C, and PPP1R3D, are downregulated by fasting and increased by feeding in the liver.
CONCLUSIONS We propose that the opposite expression pattern of PPP1R3G versus other PP1 regulatory subunits comprise an intricate regulatory machinery to control hepatic glycogenesis during the fasting–feeding cycle. Because of its unique expression pattern, PPP1R3G plays a major role to control postprandial glucose homeostasis during the fasting–feeding transition via its regulation on liver glycogenesis.
