2型糖尿病是一种常见的代谢性疾病，目前临床上仍然缺乏有效的治疗药物。葡萄糖激酶（Glucokinase，GCK）是调节体内葡萄糖代谢和参与血糖动态平衡的主要调节者。早在20世纪90年代葡萄糖激酶作为一个潜在的药物作用靶点已引起科技人员高度的关注。葡萄糖激酶活化剂(又称葡萄糖激酶激动剂，Glucokinase activators，GKAs)是直接作用于葡萄糖激酶且代表一类富有希望和前景的抗2型糖尿病(T2DM)药物。糖尿病动物模型和T2DM患者的短期给药研究已显示TKA能降低血糖和糖化血红蛋白水平，但与此同时，胰腺胰岛β-细胞GCK活化后产生低血糖的风险也日益受到关注，虽然当时学者们普遍认为GKAs对肝脏可能没有明显的不良反应。但在《英国药理学杂志》刊登的文章中，De Ceunick等报告了以GKA进行短期和长期治疗血糖水平正常和高血糖的啮齿动物却导致三酰甘油在肝脏明显的沉积，表明GCK活化后引起的肝脏葡萄糖吸收和抑制肝脏内源性葡萄糖生成作用可能会带来显著的不良反应，GKA可引发肝脏脂肪变性，这就指出了关于GKA药物的重大安全问题。因此，这些GKAs小分子化合物所引起的血浆和肝脏三酰甘油水平的升高在将来研究中应值得密切的关注。另外，最近完成的几个Ⅱ期临床试验结果很令人失望，在T2DM患者治疗时，发现GKA用药几个月后逐渐失去疗效，在一些或一定比例患者治疗时产生高血脂和高血压。这些结果已使人们对GKAs药物的疗效和安全产生怀疑。因此，在将来的临床研究中，强烈建议对GKAs这一类药物的有效性和安全性进行重新评价。%Type 2 diabetes is a common metabolic disease, currently it still lack clinically of effective therapeutic agents. Glucokinase (GCK) is a main regulator of glucose metabolism and glucose homeostasis in vivo. As a potential target for drug action, glucokinase has caused much attention of researchers early since the last century 90's.Glucokinase activators (GKAs) are the drugs against the type 2 diabetes which will effect directly on glucokinase and represent a class full of hope and promise agents. Studies with animal models of diabetes and T2DM patients with short-term administration have shown that GKAs can reduce the blood glucose and glycated hemoglobin levels, but at the same time, there exists a big concern that the GCK activation in pancreatic islet cells-risk could induce hypoglycemia, although scientists at that time believe generally that it may have no obvious side-effects of GKAs on the liver. But De Ceunick reported byan article which was published in British Journal of Pharmacology that short and long term treatment with GKA can cause obviously deposition and accumulation of triglyceridein rodent liver with normal blood glucose level and hyperglycemia animal models, which showed that activation of GCK prohibits hepatic glucose uptake and endogenous glucose production in liver, this may bring significant side-effects of GKA treatment such as hepatic steatosis, triglyceride elevation, and may raise security problems in management of the T2DM patients. Therefore, triglyceride level changes caused by GKA in plasma and in liver should be monitored carefully in future studies. In addition, the results of several recent phase II trials completed were quite disappointing because patients developed hyperlipidemia and vascular hypertension, and the drug lost efficacy within several months. These results have raised doubts and brought a puzzle about the efficacy and safety of GKA, and it’s strongly suggested that it’s necessary of re-evaluation of the efficacy, and especially safety of GKAs in future clinical studies.
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