Department of Internal Medicine, Division of Endocrinology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands.
Department of Internal Medicine, Division of Endocrinology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands.
Trends Mol Med. 2015 Oct;21(10):583-594. doi: 10.1016/j.molmed.2015.08.004.
The continuous search for drugs targeting type 2 diabetes mellitus (T2DM) has led to the identification of small molecules that disrupt the binding between glucokinase and glucokinase regulatory protein (GKRP). Although mice studies are encouraging, it will take years before these disruptors can be introduced to T2DM patients. Recently, genome-wide association studies (GWASs) have shown that variants in the gene encoding GKRP protect against T2DM and kidney disease but predispose to gout, nonalcoholic fatty liver disease, and dyslipidemia. These genetic data, together with previous experience with systemic and hepatospecific glucokinase activators, provide insight into the anticipated efficacy and safety of small-molecule disruptors in humans. Interestingly, they suggest that the opposite--enhanced GKRP-glucokinase binding--could be beneficial in selected patients.
针对 2 型糖尿病（T2DM）的药物的持续探索导致了小分子的发现，这些小分子可以破坏葡萄糖激酶与葡萄糖激酶调节蛋白（GKRP）之间的结合。尽管小鼠研究令人鼓舞，但这些抑制剂要引入 T2DM 患者还需要数年时间。最近，全基因组关联研究（GWAS）表明，编码 GKRP 的基因中的变异可以预防 T2DM 和肾脏疾病，但易患痛风、非酒精性脂肪性肝病和血脂异常。这些遗传数据，以及以前对全身和肝特异性葡萄糖激酶激活剂的经验，为小分子抑制剂在人类中的预期疗效和安全性提供了深入了解。有趣的是，它们表明相反的情况——增强的 GKRP-葡萄糖激酶结合——在某些患者中可能是有益的。
