Department of Endocrinology, Guangzhou Red Cross Hospital Affiliated to Jinan University, Guangzhou, China; Medical Care Center, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China.
Department of Endocrinology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China.
Biochem Biophys Res Commun. 2024 May 21;709:149844. doi: 10.1016/j.bbrc.2024.149844. Epub 2024 Mar 28.
We aimed to investigate the effects and mechanisms of the ghrelin-regulated endoplasmic reticulum stress (ERS) signalling pathway in gestational diabetes mellitus (GDM).
Pregnant female C57BL/6 mice were randomly divided into a normal group, GDM group (high-fat diet + STZ), GDM + ghrelin group (acyl ghrelin), and GDM + ghrelin + ghrelin inhibitor group ([D-lys3]-GHRP-6). We measured body weight, the intake of water and food, glucose, cholesterol, triglyceride and fasting insulin levels in each group. HE staining was used to observe the morphological changes in the pancreas. The TUNEL method was used to detect the apoptosis rate of islet cells. qPCR and Western boltting were performed to detect the relative expression levels of PERK, ATF6, IREIα, GRP78, CHOP and caspase-12, which are related to the ERS signalling pathway in the pancreas. Then, NIT-1 cells were cultured to verify whether ghrelin regulates ERS under high-glucose or tunicamycin conditions.
Compared with the GDM group, the GDM + ghrelin group showed improved physical conditions and significantly decreased the fasting blood glucose, glucose tolerance, cholesterol, triglyceride and fasting insulin levels. Damaged islet areas were inhibited by ghrelin in the GDM group. The GDM + ghrelin group showed reduced β-cell apoptosis compared to the GDM and GDM + ghrelin + ghrelin inhibitor groups. ERS-associated factors (PERK, ATF6, IREIα, GRP78, CHOP and caspase-12) mRNA and protein levels were obviously lower in the GDM + ghrelin group than in the GDM group, while expression levels were restored in the inhibitor group. Ghrelin treatment improved the high-glucose or tunicamycin-induced apoptosis, increased insulin levels and upregulation of GRP78, CHOP and caspase-12 in NIT-1 cells.
Ghrelin suppressed ERS signalling and apoptosis in GDM mice and in NIT-1 cells. This study established a link between ghrelin and GDM, and the targeting of ERS with ghrelin represents a promising therapeutic strategy for GDM.
本研究旨在探讨胃饥饿素调节的内质网应激（ERS）信号通路在妊娠期糖尿病（GDM）中的作用及机制。
将妊娠雌性 C57BL/6 小鼠随机分为正常组、GDM 组（高脂饮食+STZ）、GDM+胃饥饿素组（酰基胃饥饿素）和 GDM+胃饥饿素+胃饥饿素抑制剂组（[D-lys3]-GHRP-6）。检测各组小鼠的体重、水和食物摄入量、血糖、胆固醇、甘油三酯和空腹胰岛素水平。HE 染色观察胰腺形态学变化。TUNEL 法检测胰岛细胞凋亡率。qPCR 和 Western blot 检测胰腺中与 ERS 信号通路相关的 PERK、ATF6、IREIα、GRP78、CHOP 和 caspase-12 的相对表达水平。然后，培养 NIT-1 细胞，验证胃饥饿素是否在高糖或衣霉素条件下调节 ERS。
与 GDM 组相比，GDM+胃饥饿素组的一般情况得到改善，空腹血糖、葡萄糖耐量、胆固醇、甘油三酯和空腹胰岛素水平显著降低。胃饥饿素抑制了 GDM 组胰岛区域的损伤。与 GDM 组和 GDM+胃饥饿素+胃饥饿素抑制剂组相比，GDM+胃饥饿素组的β细胞凋亡减少。GDM+胃饥饿素组的 ERS 相关因子（PERK、ATF6、IREIα、GRP78、CHOP 和 caspase-12）mRNA 和蛋白水平明显低于 GDM 组，而在抑制剂组中则恢复表达。胃饥饿素处理改善了高糖或衣霉素诱导的 NIT-1 细胞凋亡，增加了胰岛素水平，并上调了 GRP78、CHOP 和 caspase-12。
胃饥饿素抑制 GDM 小鼠和 NIT-1 细胞中的 ERS 信号和细胞凋亡。本研究建立了胃饥饿素与 GDM 之间的联系，用胃饥饿素靶向 ERS 可能为 GDM 提供一种有前途的治疗策略。
