Knobler H, Weiss Y, Peled M, Groner Y
Division of Endocrinology, Kaplan Hospital Rehovot, Israel.
Diabetes. 1997 Sep;46(9):1414-8. doi: 10.2337/diab.46.9.1414.
The selective impairment of glucose-induced insulin secretion in NIDDM can be attributed to defects in the glucose-signaling system. An alteration in the activity of phosphofructokinase (PFK), a key enzyme in the glycolytic pathway, may play a role in the abnormal glucose-induced insulin secretion. In this study, we evaluated insulin secretion in transgenic (Tg) mice overexpressing the liver-type subunit of phosphofructokinase (PFKL). Three independently derived Tg-PFKL lines showed random and postprandial hyperglycemia with diminished acute insulin response following intravenous glucose tolerance load. Isolated islets of Tg-PFKL mice exhibited a shift to the right of the glucose insulin dose curve. However, the maximal insulin secretory capacity, as well as the potentiation effect by arginine, were retained. PFK activity in Tg-PFKL islets was increased by 30-70%, because of the overexpression of PFKL. Conceivably, a selective overexpression of the PFKL isoform in Tg-PFKL mice altered the enzymatic properties of the tetrameric PFK and thereby affected glucose metabolism. A similar phenomenon was previously observed in transfected PC12-PFKL cells. The data show that overexpression of PFKL in transgenic mice was associated with diminished glucose-induced insulin response and suggest a mechanism to explain the role of beta-cell PFK activity in glucose-induced insulin secretion.
非胰岛素依赖型糖尿病（NIDDM）中葡萄糖诱导的胰岛素分泌的选择性损害可归因于葡萄糖信号系统的缺陷。磷酸果糖激酶（PFK）是糖酵解途径中的关键酶，其活性改变可能在异常的葡萄糖诱导的胰岛素分泌中起作用。在本研究中，我们评估了过表达磷酸果糖激酶肝脏型亚基（PFKL）的转基因（Tg）小鼠的胰岛素分泌情况。三个独立衍生的Tg-PFKL品系表现出随机和餐后高血糖，静脉注射葡萄糖耐量负荷后急性胰岛素反应减弱。Tg-PFKL小鼠分离的胰岛显示葡萄糖-胰岛素剂量曲线向右移动。然而，最大胰岛素分泌能力以及精氨酸的增强作用得以保留。由于PFKL的过表达，Tg-PFKL胰岛中的PFK活性增加了30%-70%。可以想象，Tg-PFKL小鼠中PFKL同工型的选择性过表达改变了四聚体PFK的酶学性质，从而影响了葡萄糖代谢。先前在转染的PC12-PFKL细胞中也观察到类似现象。数据表明，转基因小鼠中PFKL的过表达与葡萄糖诱导的胰岛素反应减弱有关，并提示了一种机制来解释β细胞PFK活性在葡萄糖诱导的胰岛素分泌中的作用。
