Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
Department of Endocrinology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
Front Endocrinol (Lausanne). 2022 May 4;13:852149. doi: 10.3389/fendo.2022.852149. eCollection 2022.
Pregnancy is a dynamic state involving multiple metabolic adaptions in various tissues including the endocrine pancreas. However, a detailed characterization of the maternal islet metabolome in relation to islet function and the ambient circulating metabolome during pregnancy has not been established.
A timed-pregnancy mouse model was studied, and age-matched non-pregnant mice were used as controls. Targeted metabolomics was applied to fasting plasma and purified islets during each trimester of pregnancy. Glucose homeostasis and islet function was assessed. Bioinformatic analyses were performed to reveal the metabolic adaptive changes in plasma and islets, and to identify key metabolic pathways associated with pregnancy.
Fasting glucose and insulin were found to be significantly lower in pregnant mice compared to non-pregnant controls, throughout the gestational period. Additionally, pregnant mice had superior glucose excursions and greater insulin response to an oral glucose tolerance test. Interestingly, both alpha and beta cell proliferation were significantly enhanced in early to mid-pregnancy, leading to significantly increased islet size seen in mid to late gestation. When comparing the plasma metabolome of pregnant and non-pregnant mice, phospholipid and fatty acid metabolism pathways were found to be upregulated throughout pregnancy, whereas amino acid metabolism initially decreased in early through mid pregnancy, but then increased in late pregnancy. Conversely, in islets, amino acid metabolism was consistently enriched throughout pregnancy, with glycerophospholid and fatty acid metabolism was only upregulated in late pregnancy. Specific amino acids (glutamate, valine) and lipids (acyl-alkyl-PC, diacyl-PC, and sphingomyelin) were found to be significantly differentially expressed in islets of the pregnant mice compared to controls, which was possibly linked to enhanced insulin secretion and islet proliferation.
Beta cell proliferation and function are elevated during pregnancy, and this is coupled to the enrichment of islet metabolites and metabolic pathways primarily associated with amino acid and glycerophospholipid metabolism. This study provides insight into metabolic adaptive changes in glucose homeostasis and islet function seen during pregnancy, which will provide a molecular rationale to further explore the regulation of maternal metabolism to avoid the onset of pregnancy disorders, including gestational diabetes.
妊娠是一种动态状态，涉及包括内分泌胰腺在内的各种组织的多种代谢适应。然而，母体胰岛代谢组与胰岛功能以及妊娠期间周围循环代谢组之间的详细特征尚未建立。
研究了定时妊娠小鼠模型，并将年龄匹配的非妊娠小鼠用作对照。在妊娠的每个三个月期间，应用靶向代谢组学对空腹血浆和纯化胰岛进行分析。评估葡萄糖稳态和胰岛功能。进行生物信息学分析，以揭示血浆和胰岛中的代谢适应性变化，并确定与妊娠相关的关键代谢途径。
与非妊娠对照组相比，整个妊娠期妊娠小鼠的空腹血糖和胰岛素水平明显降低。此外，妊娠小鼠的葡萄糖波动更大，口服葡萄糖耐量试验时的胰岛素反应更强。有趣的是，早期至中期妊娠时，α和β细胞增殖均显著增强，导致中晚期妊娠时胰岛大小明显增加。比较妊娠和非妊娠小鼠的血浆代谢组学，发现整个妊娠期间磷脂和脂肪酸代谢途径上调，而氨基酸代谢在早期至中期妊娠时最初降低，但随后在晚期妊娠时增加。相反，在胰岛中，整个妊娠期间氨基酸代谢始终丰富，而甘油磷酸脂和脂肪酸代谢仅在晚期妊娠时上调。与对照组相比，在妊娠小鼠的胰岛中发现特定的氨基酸（谷氨酸，缬氨酸）和脂质（酰基-烷基-PC、二酰基-PC 和神经鞘磷脂）的表达显著不同，这可能与增强的胰岛素分泌和胰岛增殖有关。
妊娠期间β细胞增殖和功能升高，这与胰岛代谢物和代谢途径的富集有关，这些途径主要与氨基酸和甘油磷酯代谢有关。这项研究提供了对妊娠期间葡萄糖稳态和胰岛功能的代谢适应性变化的深入了解，为进一步探索母体代谢的调节以避免妊娠疾病（包括妊娠糖尿病）的发生提供了分子依据。
