a Division of Diabetes, Endocrinology and Metabolism , Tokyo Medical University , 6-7-1Nishi-shinjuku, Shinjuku-ku , Tokyo 160-0023 , Japan.
b Department of Diabetes and Metabolic Diseases, Graduate School of Medicine , University of Tokyo , 7-3-1 Hongo, Bunkyo-ku , Tokyo 113-8655 , Japan.
Expert Opin Ther Targets. 2016;20(3):255-67. doi: 10.1517/14728222.2016.1098618. Epub 2015 Oct 12.
Type 2 diabetes (T2D) is a complex disease caused by an interaction between multiple genetic and environmental factors. T2D-associated loci identified by genome-wide association studies (GWAS) harbor the genes targeted by many clinically available drugs, supporting the idea that GWAS have the potential to discover novel genes for drug development.
This paper outlines, among the genes at those T2D-associated loci, the functional analysis of FTO, TCF7L2, SLC30A8, and MTNR1B, illustrating caveats we should be cautious about. This paper also reviews the current status of the compounds targeting the T2D-associated genes GCK, GKRP, ADIPOQ, and ADRA2A in clinical and preclinical phases.
Functional analysis of those loci has fallen too far behind identification of T2D-associated loci. It is mandatory to define the true causal gene at the T2D-associated loci by using a variety of experimental techniques. The biggest challenge lies in the limited access to human tissues relevant to the pathogenesis of T2D. The ultimate goal of human genetic study is enabling personalized medicine based on the genetic information of individuals. More research will be needed to achieve this goal.
2 型糖尿病(T2D)是一种由多种遗传和环境因素相互作用引起的复杂疾病。全基因组关联研究(GWAS)鉴定的 T2D 相关位点包含许多临床可用药物的靶点基因,这支持了 GWAS 有可能发现新的药物开发基因的观点。
本文概述了 T2D 相关位点的基因中,FTO、TCF7L2、SLC30A8 和 MTNR1B 的功能分析,并说明了我们应该谨慎对待的注意事项。本文还回顾了目前针对 GCK、GKRP、ADIPOQ 和 ADRA2A 等 T2D 相关基因的化合物在临床前和临床阶段的现状。
这些位点的功能分析已经远远落后于 T2D 相关位点的鉴定。必须通过各种实验技术来确定 T2D 相关位点的真正因果基因。最大的挑战在于获得与 T2D 发病机制相关的人类组织的机会有限。人类遗传学研究的最终目标是根据个体的遗传信息实现个性化医疗。要实现这一目标,还需要进行更多的研究。