Oxford Centre for Diabetes Endocrinology & Metabolism, University of Oxford, Oxford, UK.
Br J Pharmacol. 2013 Jan;168(2):335-8. doi: 10.1111/j.1476-5381.2012.02201.x.
Glucokinase activators (GKAs) represent one of the leading hopes for the next generation of type 2 diabetes (T2D) therapeutics, showing efficacy in reducing blood glucose and HbA1c levels in animal models of T2D and short-term human trials. While the hypoglycaemic risks of GCK activation in pancreatic beta-cells have long been appreciated, the hepatic effects of GKAs have generally been perceived to be without significant side effect. In this issue of the British Journal of Pharmacology, De Ceuninck et al. report that acute and chronic GKA treatment of normoglycaemic and hyperglycaemic rodent models results in significant accumulation of triglycerides in the liver. This suggests GKA-mediated activation of hepatic glucose uptake and suppression of endogenous glucose production may come at a significant cost; namely, the development of hepatic steatosis. This raises important questions regarding the safety of GKAs and emphasizes that both plasma and hepatic lipid profiles should be carefully monitored in on-going and future studies of these molecules.
This article is a commentary on De Ceuninck et al., pp. 339-353 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2012.02184.x.
葡萄糖激酶激活剂（GKAs）是下一代 2 型糖尿病（T2D）治疗方法的主要希望之一，在 T2D 动物模型和短期人体试验中显示出降低血糖和 HbA1c 水平的功效。虽然人们早就认识到胰腺β细胞中 GCK 激活的低血糖风险，但一般认为 GKAs 的肝脏作用没有明显的副作用。在本期英国药理学杂志上，De Ceuninck 等人报告说，正常血糖和高血糖啮齿动物模型的急性和慢性 GKA 治疗会导致肝脏甘油三酯的大量积累。这表明 GKA 介导的肝葡萄糖摄取激活和内源性葡萄糖产生抑制可能会带来重大代价；即肝脂肪变性的发展。这就提出了关于 GKAs 安全性的重要问题，并强调在这些分子的正在进行和未来的研究中，应仔细监测血浆和肝脂质谱。
本文是 De Ceuninck 等人对本期杂志第 339-353 页的评论。要查看本文，请访问 http://dx.doi.org/10.1111/j.1476-5381.2012.02184.x。
