Present status of clinical deployment of glucokinase activators.
Present status of clinical deployment of glucokinase activators.
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DOI：
10.1111/jdi.12294
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发表时间：
2015-03
影响因子：
3.2
通讯作者：
Terauchi Y
中科院分区：
文献类型：
--
作者：
Nakamura A;Terauchi Y
葡萄糖激酶是己糖激酶家族的四个成员之一。其表达仅限于被认为在葡萄糖传感中具有综合作用的主要器官（如胰腺、肝脏、脑和胃肠道）。在肝脏中，葡萄糖激酶对葡萄糖的磷酸化促进糖原合成，而在β细胞中，它导致胰岛素释放。对葡萄糖激酶连锁的基因修饰小鼠和人类突变的研究已经说明了葡萄糖激酶在全身葡萄糖稳态中发挥的重要作用，并表明使用增强葡萄糖激酶活性的药理学药物可能代表2型糖尿病患者的可行治疗策略。自2003年以来，已经开发了许多葡萄糖激酶激活剂（GKA），并且已经在几种2型糖尿病动物模型中显示了它们降低血糖的能力。此外，我们和其他人已经在小鼠模型中表明，GKA也具有刺激β细胞增殖的作用。然而，最近的II期试验结果表明，GKA在使用几个月内失去疗效，并且其使用与低血糖的高发生率相关;此外，接受GKA治疗的患者经常发生血脂异常。需要更好地理解葡萄糖激酶在代谢效应中的作用，以解决临床试验中发现的几个问题。
Glucokinase is one of four members of the hexokinase family of enzymes. Its expression is limited to the major organs (such as the pancreas, liver, brain and the gastrointestinal tract) that are thought to have an integrated role in glucose sensing. In the liver, phosphorylation of glucose by glucokinase promotes glycogen synthesis, whereas in the β-cells, it results in insulin release. Studies of glucokinase-linked genetically-modified mice and mutations in humans have illustrated the important roles played by glucokinase in whole-body glucose homeostasis, and suggest that the use of pharmacological agents that augment glucokinase activity could represent a viable treatment strategy in patients with type 2 diabetes. Since 2003, many glucokinase activators (GKAs) have been developed, and their ability to lower the blood glucose has been shown in several animal models of type 2 diabetes. Also, we and others have shown in mouse models that GKAs also have the effect of stimulating the proliferation of β-cells. However, the results of recent phase II trials have shown that GKAs lose their efficacy within several months of use, and that their use is associated with a high incidence of hypoglycemia; furthermore, patients treated with GKAs frequently developed dyslipidemia. A better understanding of the role of glucokinase in metabolic effects is required to resolve several issues identified in clinical trials.
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影响因子：
56.9
作者：
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通讯作者：
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作者：
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