De Ceuninck Frédéric, Kargar Catherine, Charton Yves, Goldstein Solo, Perron-Sierra Françoise, Ilic Catherine, Caliez Audrey, Rolin Jean-Olivier, Sadlo Marjorie, Harley Elizabeth, Vinson Cédric, Ktorza Alain
Department of Metabolic Diseases, Institut de Recherches Servier, Suresnes, France.
Br J Pharmacol. 2013 Jul;169(5):999-1010. doi: 10.1111/bph.12172.
Small molecule glucokinase activators (GKAs) have been associated with potent antidiabetic efficacy and hepatic steatosis in rodents. This study reports the discovery of S 50131 and S 51434, two novel GKAs with an original scaffold and an atypical pharmacological profile.
Activity of the compounds was assessed in vitro by measuring activation of recombinant glucokinase, stimulation of glycogen synthesis in rat hepatocytes and increased insulin secretion from rat pancreatic islets of Langerhans. Efficacy and safety in vivo were evaluated after oral administration in db/db mice by measuring glycaemia, HbA1c and dyslipidaemia-associated events.
S 50131 and S 51434 activated GK and stimulated glycogen synthesis in hepatocytes and insulin secretion from pancreatic islets. Unexpectedly, while both compounds effectively lowered glycaemia after acute oral administration, they did not decrease HbA1c after a 4-week treatment in db/db mice. This lack of antidiabetic efficacy was associated with increased plasma free fatty acids (FFAs), contrasting with the effect of GKA50 and N00236460, two GKAs with sustained HbA1c lowering activity but neutral regarding plasma FFAs. S 50131, but not S 51434, also induced hepatic steatosis, as did GKA50 and N00236460. However, a shorter, 4-day treatment resulted in increased hepatic triglycerides without changing the plasma FFA levels, demonstrating dynamic alterations in the lipid profile over time.
In addition to confirming the occurrence of dyslipidaemia with GKAs, these findings provide new insights into understanding how such compounds may sustain or lose efficacy over time.
小分子葡萄糖激酶激活剂（GKAs）已被证明在啮齿动物中具有强大的抗糖尿病功效和改善肝脂肪变性的作用。本研究报告了两种新型GKAs，即S 50131和S 51434的发现，它们具有独特的骨架和非典型的药理特性。
通过测量重组葡萄糖激酶的激活、大鼠肝细胞中糖原合成的刺激以及大鼠胰岛中胰岛素分泌的增加，在体外评估化合物的活性。通过测量血糖、糖化血红蛋白（HbA1c）和血脂异常相关指标，评估db/db小鼠口服给药后的体内疗效和安全性。
S 50131和S 51434激活葡萄糖激酶，并刺激肝细胞中的糖原合成以及胰岛中的胰岛素分泌。出乎意料的是，虽然两种化合物在急性口服给药后均能有效降低血糖，但在db/db小鼠中进行4周治疗后，它们并未降低HbA1c。这种缺乏抗糖尿病功效的情况与血浆游离脂肪酸（FFA）增加有关，这与GKA50和N00236460的作用形成对比，后两者具有持续降低HbA1c的活性，但对血浆FFA无影响。S 50131（而非S 51434）还诱导了肝脂肪变性，GKA50和N00236460也是如此。然而，为期4天的较短治疗导致肝脏甘油三酯增加，而血浆FFA水平未改变，这表明脂质谱随时间发生动态变化。
除了证实GKAs会引发血脂异常外，这些发现为理解此类化合物如何随时间维持或丧失疗效提供了新的见解。
