Long-noncoding RNA HOXA transcript at the distal tip ameliorates the insulin resistance and hepatic gluconeogenesis in mice with gestational diabetes mellitus via the microRNA-423-5p/wingless-type MMTV integration site family member 7A axis

Long-noncoding RNA HOXA transcript at the distal tip (HOTTIP) has been probed to exert essential effects on diabetes progression, while its function in gestational diabetes mellitus (GDM) remains unclear. This study was committed to unravel the effects of HOTTIP on GDM progression via the microRNA (miR)-423-5p/wingless-type MMTV integration site family member 7A (WNT7A) axis. The GDM mouse model was established. HOTTIP, miR-423-5p and WNT7A levels in GDM mice were examined. The saline with dissolved various constructs altering HOTTIP, miR-423-5p and WNT7A expression was injected into GDM mice to detect the levels of GDM‐related biochemical indices, HOMA indices, liver gluconease: expression levels of phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G-6-Pase), glucose transporter 2 (GLUT2) and pathological changes of pancreatic tissues, and the apoptosis rate of pancreatic cells in GDM mice. The relations among HOTTIP, miR-423-5p and WNT7A were validated. HOTTIP and WNT7A levels were decreased while miR-423-5p was elevated in GDM mice. The enriched HOTTIP or silenced miR-423-5p alleviated the levels of GDM‐relatedbiochemical indices, enhanced the insulin homeostasis, elevated GLUT2 expression and decreased G-6-pase and PEPCK expression, mitigated the pathological changes of pancreatic tissues, and hindered the apoptosis of pancreatic cells. MiR-143-5p upregulation abrogated the effects of elevated HOTTIP on repressing GDM; whereas WNT7A deletion reversed the therapeutic effects of reduced miR-423-5p. HOTTIP sponged miR-423-5p that targeted WNT7A. HOTTIP ameliorates insulin resistance and hepatic gluconeogenesis in GDM mice via the modulation of the miR-423-5p/WNT7A axis. This study affords novel therapeutic modalities for GDM treatment.

远端同源盒A转录本长链非编码RNA（HOTTIP）已被证实可对糖尿病进程发挥关键调控作用，但其在妊娠期糖尿病（GDM）中的功能仍不明晰。本研究旨在阐明HOTTIP通过微小RNA（miR）-423-5p/无翅型MMTV整合位点家族成员7A（WNT7A）轴对GDM进程的影响。本研究构建了GDM小鼠模型，检测了GDM小鼠体内HOTTIP、miR-423-5p及WNT7A的表达水平。向GDM小鼠注射携带有可调控HOTTIP、miR-423-5p及WNT7A表达的各类重组构建体的生理盐水，以检测GDM相关生化指标水平、稳态模型评估（HOMA）指数、肝糖异生相关酶的表达水平（包括磷酸烯醇式丙酮酸羧激酶PEPCK、葡萄糖-6-磷酸酶G-6-Pase、葡萄糖转运蛋白2 GLUT2）、胰腺组织病理变化，以及GDM小鼠胰腺细胞的凋亡率，并验证了HOTTIP、miR-423-5p与WNT7A三者间的调控关系。实验结果显示，GDM小鼠体内HOTTIP与WNT7A的表达水平降低，而miR-423-5p的表达水平升高。过表达HOTTIP或沉默miR-423-5p可缓解GDM相关生化指标异常，改善胰岛素稳态，上调GLUT2的表达并下调G-6-Pase与PEPCK的表达，减轻胰腺组织病理损伤，同时抑制胰腺细胞凋亡。上调miR-143-5p可抵消过表达HOTTIP对GDM的抑制作用；而敲低WNT7A则可逆转沉默miR-423-5p所产生的治疗效应。机制验证表明，HOTTIP可通过海绵吸附作用结合miR-423-5p，而该微小RNA可靶向调控WNT7A的表达。综上，HOTTIP可通过调控miR-423-5p/WNT7A轴改善GDM小鼠的胰岛素抵抗与肝糖异生过程，本研究为GDM的临床治疗提供了全新的潜在治疗策略。