School of Exercise and Nutrition Sciences, Deakin University, Geelong, Australia.
Metabolism. 2010 Jul;59(7):1057-64. doi: 10.1016/j.metabol.2009.11.002. Epub 2009 Dec 31.
The human Abelson helper integration site-1 (AHI1) gene is associated with both neurologic and hematologic disorders; however, it is also located in a chromosomal region linked to metabolic syndrome phenotypes and was identified as a type 2 diabetes mellitus susceptibility gene from a genomewide association study. To further define a possible role in type 2 diabetes mellitus development, AHI1 messenger RNA expression levels were investigated in a range of tissues and found to be highly expressed in skeletal muscle as well as displaying elevated levels in brain regions and gonad tissues. Further analysis in a rodent polygenic animal model of obesity and type 2 diabetes mellitus identified increased Ahi-1 messenger RNA levels in red gastrocnemius muscle from fasted impaired glucose-tolerant and diabetic rodents compared with healthy animals (P < .002). Moreover, elevated gene expression levels were confirmed in skeletal muscle from fasted obese and type 2 diabetes mellitus human subjects (P < .02). RNAi-mediated suppression of Ahi-1 resulted in increased glucose transport in rat L6 myotubes in both the basal and insulin-stimulated states (P < .01). Finally, single nucleotide polymorphism association studies identified 2 novel AHI1 genetic variants linked with fasting blood glucose levels in Mexican American subjects (P < .037). These findings indicate a novel role for AHI1 in skeletal muscle and identify additional genetic links with metabolic syndrome phenotypes suggesting an involvement of AHI1 in the maintenance of glucose homeostasis and type 2 diabetes mellitus progression.
人类 Abelson 辅助整合位点 1（AHI1）基因与神经和血液疾病有关；然而，它也位于与代谢综合征表型相关的染色体区域，并且从全基因组关联研究中被鉴定为 2 型糖尿病易感性基因。为了进一步确定其在 2 型糖尿病发展中的可能作用，研究了 AHI1 信使 RNA 在多种组织中的表达水平，结果发现其在骨骼肌中高度表达，并且在大脑区域和性腺组织中表达水平升高。在肥胖和 2 型糖尿病的啮齿动物多基因动物模型中的进一步分析表明，与健康动物相比，禁食糖耐量受损和糖尿病啮齿动物的红色比目鱼肌中 Ahi-1 信使 RNA 水平升高（P <.002）。此外，在禁食肥胖和 2 型糖尿病的人类受试者的骨骼肌中也证实了基因表达水平的升高（P <.02）。RNAi 介导的 Ahi-1 抑制导致大鼠 L6 肌管在基础和胰岛素刺激状态下葡萄糖转运增加（P <.01）。最后，单核苷酸多态性关联研究鉴定出 2 种与墨西哥裔美国人空腹血糖水平相关的新型 AHI1 遗传变异（P <.037）。这些发现表明 AHI1 在骨骼肌中具有新的作用，并确定了与代谢综合征表型的其他遗传联系，表明 AHI1 参与了葡萄糖稳态的维持和 2 型糖尿病的进展。
