Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans
Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans
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DOI：
10.1111/j.1476-5381.2012.02184.x
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发表时间：
2013-01-01
影响因子：
7.3
通讯作者：
Ktorza, Alain
中科院分区：
文献类型：
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作者：
De Ceuninck, Frederic;Kargar, Catherine;Ktorza, Alain
背景和方法目前正在研究小分子葡萄糖激酶激活剂（GKA）作为治疗2型糖尿病（T2 D）的治疗选择。由于肝脏过度表达的葡萄糖激酶被认为是与改变脂质配置文件，这项研究的目的是在评估潜在的脂肪生成的风险与口服GKA administration.Experimental APPROACHNine GKA候选人资格为他们的能力，激活重组葡萄糖激酶和刺激糖原合成在大鼠肝细胞和胰岛素分泌在大鼠INS-1 E细胞。在啮齿动物中经口给药后，通过血糖和HbA 1c测量监测体内活性。通过测量肝脏和血浆甘油三酯和游离脂肪酸以及血浆转氨酶和碱性磷酸酶来评估风险相关效应。关键词TSGKA在高血糖db/db小鼠中有效降低急性条件下的高血糖和慢性给药后的HbA 1c水平的同时，是肝脂肪变性的强效诱导剂。该不良结局在每日口服药理学剂量后4天出现，并且不是一过性的。GKA处理类似地增加了糖尿病和正常血糖大鼠的肝脏甘油三酯，以及代谢表型模式，包括血浆甘油三酯、游离脂肪酸、丙氨酸和丙氨酸氨基转移酶以及碱性磷酸酶增加的不同组合。GKA属于三个不同的结构家庭诱导肝脂肪变性的db/db小鼠，主张在一个目标介导的，而不是化学类介导的，effect. CONCLITIONAND IMPLICATIONS鉴于与脂肪肝疾病的风险在一般人群中，而且在T2 D患者，这些研究结果代表了一个严重的警告GKA在人类中的使用。
BACKGROUND AND PURPOSESmall-molecule glucokinase activators (GKAs) are currently being investigated as therapeutic options for the treatment of type 2 diabetes (T2D). Because liver overexpression of glucokinase is thought to be associated with altered lipid profiles, this study aimed at assessing the potential lipogenic risks linked to oral GKA administration.EXPERIMENTAL APPROACHNine GKA candidates were qualified for their ability to activate recombinant glucokinase and to stimulate glycogen synthesis in rat hepatocytes and insulin secretion in rat INS-1E cells. In vivo activity was monitored by plasma glucose and HbA1c measurements after oral administration in rodents. Risk-associated effects were assessed by measuring hepatic and plasma triglycerides and free fatty acids, as well as plasma aminotransferases, and alkaline phosphatase.KEY RESULTSGKAs, while efficiently decreasing glycaemia in acute conditions and HbA1c levels after chronic administration in hyperglycemic db/db mice, were potent inducers of hepatic steatosis. This adverse outcome appeared as soon as 4 days after daily oral administration at pharmacological doses and was not transient. GKA treatment similarly increased hepatic triglycerides in diabetic and normoglycaemic rats, together with a pattern of metabolic phenotypes including different combinations of increased plasma triglycerides, free fatty acids, alanine and aspartyl aminotransferases, and alkaline phosphatase. GKAs belonging to three distinct structural families induced hepatic steatosis in db/db mice, arguing in favour of a target-mediated, rather than a chemical class-mediated, effect.CONCLUSION AND IMPLICATIONSGiven the risks associated with fatty liver disease in the general population and furthermore in patients with T2D, these findings represent a serious warning for the use of GKAs in humans.