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ZFAND3 Overexpression in the Mouse Liver Improves Glucose Tolerance and Hepatic Insulin Resistance
Experimental and Clinical Endocrinology & Diabetes ( IF 1.8 ) Pub Date : 2021-03-29 , DOI: 10.1055/a-1400-2656
Kahori Shimizu 1 , Yuya Ogiya 1 , Kaede Yoshinaga 1 , Hajime Kimura 1 , Shotaro Michinaga 2 , Moe Ono 3 , Ayako Taketomi 1 , Tomoyuki Terada 1 , Fuminori Sakurai 4 , Hiroyuki Mizuguchi 4, 5, 6, 7 , Koji Tomita 3 , Toru Nishinaka 1
Affiliation  

Genome-wide association studies have identified more than 300 loci associated with type 2 diabetes mellitus; however, the mechanisms underlying their role in type 2 diabetes mellitus susceptibility remain largely unknown. Zinc finger AN1-type domain 3 (ZFAND3), known as testis-expressed sequence 27, is a type 2 diabetes mellitus-susceptibility gene. Limited information is available regarding the physiological role of ZFAND3 in vivo. This study aimed to investigate the association between ZFAND3 and type 2 diabetes mellitus. ZFAND3 was significantly upregulated in the liver of diabetic mice compared to wild-type mice. To overexpress ZFAND3, we generated a ZFAND3-expressing adenovirus (Ad) vector using an improved Ad vector exhibiting significantly lower hepatotoxicity (Ad-ZFAND3). Glucose tolerance was significantly improved in Ad-ZFAND3-treated mice compared to the control Ad-treated mice. ZFAND3 overexpression in the mouse liver also improved insulin resistance. Furthermore, gluconeogenic gene expression was significantly lower in primary mouse hepatocytes transduced with Ad-ZFAND3 than those transduced with the control Ad vector. The present results suggest that ZFAND3 improves glucose tolerance by improving insulin resistance and suppressing gluconeogenesis, serving as a potential novel therapeutic target for type 2 diabetes mellitus.

中文翻译:

小鼠肝脏中的 ZFAND3 过表达可提高葡萄糖耐量和肝胰岛素抵抗

全基因组关联研究已经确定了 300 多个与 2 型糖尿病相关的位点;然而,它们在 2 型糖尿病易感性中的作用的潜在机制仍然很大程度上未知。锌指 AN1 型结构域 3 (ZFAND3),称为睾丸表达序列 27,是一种 2 型糖尿病易感基因。关于 ZFAND3 在体内的生理作用的信息有限。本研究旨在探讨 ZFAND3 与 2 型糖尿病之间的关联。与野生型小鼠相比,糖尿病小鼠肝脏中的 ZFAND3 显着上调。为了过表达 ZFAND3,我们使用表现出显着降低肝毒性的改进的 Ad 载体 (Ad-ZFAND3) 生成了表达 ZFAND3 的腺病毒 (Ad) 载体。与对照 Ad 处理的小鼠相比,Ad-ZFAND3 处理的小鼠的葡萄糖耐量显着提高。ZFAND3 在小鼠肝脏中的过度表达也改善了胰岛素抵抗。此外,用 Ad-ZFAND3 转导的原代小鼠肝细胞中的糖异生基因表达显着低于用对照 Ad 载体转导的那些。目前的结果表明,ZFAND3 通过改善胰岛素抵抗和抑制糖异生来改善葡萄糖耐量,作为 2 型糖尿病的潜在新治疗靶点。
更新日期:2021-03-30
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