美国西奈山伊坎医学院Paul J. Kenny研究团队近日取得一项新成果。他们发现缰核区域的TCF7L2基因表达将尼古丁成瘾与糖尿病联系起来。这一研究成果2019年10月16日发表在国际学术期刊《自然》上。

研究人员发现与糖尿病相关的基因Tcf7l2在啮齿动物大脑的内侧缰核（mHb）区域中密集表达，在该区域调节烟碱型乙酰胆碱受体的功能。在mHb中抑制TCF7L2信号传导会增加小鼠和大鼠的尼古丁摄入量。尼古丁通过mHb的TCF7L2依赖性刺激来增加血糖水平。病毒追踪实验确定了从mHb到胰腺的多突触连接，具有尼古丁摄入史的野生型大鼠显示胰高血糖素和胰岛素的循环水平增加，以及血糖稳态的糖尿病样失调。相比之下，突变的Tcf712大鼠对尼古丁的这些作用具有抗性。

这项研究结果表明，TCF7L2调节尼古丁在缰核-胰腺信号轴上的刺激作用，其将尼古丁的成瘾性与其促进糖尿病的作用联系起来。

据悉，糖尿病在吸烟者中比非吸烟者更为普遍，但潜在的机制尚不清楚。

附：英文原文

Title: Habenular TCF7L2 links nicotine addiction to diabetes

Author: Alexander Duncan, Mary P. Heyer, Masago Ishikawa, Stephanie P. B. Caligiuri, Xin-an Liu, Zuxin Chen, Maria Vittoria Micioni Di Bonaventura, Karim S. Elayouby, Jessica L. Ables, William M. Howe, Purva Bali, Clementine Fillinger, Maya Williams, Richard M. OConnor, Zichen Wang, Qun Lu, Theodore M. Kamenecka, Avi Maayan, Heidi C. ONeill, Ines Ibanez-Tallon, Aron M. Geurts, Paul J. Kenny

Issue&Volume: 2019-10-16

Abstract: 

Diabetes is far more prevalent in smokers than non-smokers, but the underlying mechanisms of vulnerability are unknown. Here we show that the diabetes-associated gene Tcf7l2 is densely expressed in the medial habenula (mHb) region of the rodent brain, where it regulates the function of nicotinic acetylcholine receptors. Inhibition of TCF7L2 signalling in the mHb increases nicotine intake in mice and rats. Nicotine increases levels of blood glucose by TCF7L2-dependent stimulation of the mHb. Virus-tracing experiments identify a polysynaptic connection from the mHb to the pancreas, and wild-type rats with a history of nicotine consumption show increased circulating levels of glucagon and insulin, and diabetes-like dysregulation of blood glucose homeostasis. By contrast, mutant Tcf7l2 rats are resistant to these actions of nicotine. Our findings suggest that TCF7L2 regulates the stimulatory actions of nicotine on a habenula–pancreas axis that links the addictive properties of nicotine to its diabetes-promoting actions.

DOI: 10.1038/s41586-019-1653-x

Source:https://www.nature.com/articles/s41586-019-1653-x