Department of Obstetrics and Gynecology, Baylor College of Medicine/Texas Children's Hospital, Houston, Texas, United States of America.
PLoS One. 2022 Mar 24;17(3):e0265890. doi: 10.1371/journal.pone.0265890. eCollection 2022.
Gestational diabetes mellitus (GDM) is associated with defective pancreatic β-cell adaptation in pregnancy, but the underlying mechanism remains obscure. Our previous studies demonstrated that GDM women display increased plasma adrenomedullin (ADM) levels, and non-obese GDM mice show decreased serum concentrations of insulin and the number of β-cells in pancreas islets. The aims of this study is to examine if ADM and its receptors are expressed in female mouse pancreas, and if so, whether insulin secretion is regulated by ADM in mouse β-cell line, NIT-1 cells and isolated mouse pancreatic islets. Present study shows that ADM and its receptor components CRLR, RAMPs are present in mouse pancreatic islets and co-localized with insulin. The expressions of ADM, CRLR and RAMP2 in islets from pregnant mice are reduced compared to that of non-pregnant mice. NIT-1-β cells express ADM and its receptor mRNA, and glucose dose-dependently stimulates expressions. Furthermore, ADM inhibits NIT-1-β cell growth, and this inhibition is reversed by ADM antagonist, ADM22-52. The glucose-induced insulin secretion was suppressed by ADM in NIT-1-β cells and isolated pancreatic islets from pregnant mice. These inhibitory effects are accompanied by upregulation of endoplasmic reticulum (ER) stress biomarker genes in NIT-1-β cells. This study unveils that reduced ADM and its receptors may play a role in β-cell adaptation during pregnancy, while increased plasma ADM in GDM may contribute to the β-cells dysfunction, and blockade of ADM may reverse β-cell insulin production.
妊娠期糖尿病（GDM）与妊娠期间胰腺β细胞适应性缺陷有关，但潜在机制尚不清楚。我们之前的研究表明，GDM 女性表现出血浆肾上腺髓质素（ADM）水平升高，非肥胖 GDM 小鼠表现出血清胰岛素浓度降低和胰腺胰岛β细胞数量减少。本研究旨在研究 ADM 及其受体是否在雌性小鼠胰腺中表达，如果是，ADM 是否调节 NIT-1 细胞和分离的小鼠胰岛中的小鼠β细胞胰岛素分泌。本研究表明，ADM 及其受体成分 CRLR、RAMP 在胰岛中存在，并与胰岛素共定位。与非妊娠小鼠相比，孕鼠胰岛中的 ADM、CRLR 和 RAMP2 表达减少。NIT-1-β 细胞表达 ADM 和其受体 mRNA，并且葡萄糖呈剂量依赖性地刺激表达。此外，ADM 抑制 NIT-1-β 细胞生长，而 ADM 拮抗剂 ADM22-52 可逆转这种抑制作用。ADM 在 NIT-1-β 细胞和来自孕鼠的分离胰岛中抑制葡萄糖诱导的胰岛素分泌。这些抑制作用伴随着 NIT-1-β 细胞中内质网（ER）应激生物标志物基因的上调。这项研究揭示了 ADM 和其受体的减少可能在妊娠期间β细胞适应性中发挥作用，而 GDM 中增加的血浆 ADM 可能导致β细胞功能障碍，并且 ADM 的阻断可能逆转β细胞胰岛素产生。
