Pancreatic alpha-cells and Maternal metabolic Adaptation

总结 在怀孕期间，母体的新陈代谢经历了一系列的适应，以满足恒定的 营养需求从胎儿室和准备哺乳。母体代谢适应失败 导致妊娠期糖尿病（GDM）和其他并发症。胰岛细胞数量显著增加， 质量和胰岛素生产在正常怀孕期间。胰腺α-细胞是第二主要的 胰高血糖素是胰岛内分泌细胞的重要组成部分，主要通过胰高血糖素的内分泌作用调节葡萄糖代谢。 虽然有研究报道，怀孕可能会增加α-细胞质量和母体血胰高血糖素 浓度，有一个知识缺口α细胞在控制母体代谢适应的作用。 我们最近的研究表明，α-细胞在母体胰岛素产生中的重要作用， 怀孕首先，我们使用诱导遗传方法消融成年小鼠的α细胞。尽管没有显著 空腹和随机进食血糖浓度的变化，α细胞消融改善了葡萄糖耐量 在非妊娠小鼠中。与此相反，血糖浓度显著升高和低胰岛素 在α-null母鼠中观察到分泌。第二，我们用胰高血糖素受体抗体治疗怀孕的小鼠， 以确定胰高血糖素在母体代谢适应中的作用。令人惊奇的是， 胰高血糖素受体拮抗作用不改变母体血糖和胰岛素水平。除胰高血糖素外，α- 细胞还分泌胰高血糖素样蛋白1（GLP-1）。众所周知，胰岛内GLP-1在调节胰岛素抵抗中起重要作用。 在代谢应激条件下增加葡萄糖诱导的胰岛素产生。我们的研究表明， GLP-1受体激动剂恢复了α无效母体的胰岛素产生和葡萄糖代谢。所以我们 假设α-细胞通过胰岛内分泌在调节母体代谢适应中起重要作用， 旁分泌对胰岛素产生的影响。我们将使用α细胞特异性Pcsk 1基因，它指导GLP-1 生产、敲除母鼠和胰高血糖素或GLP-1重建来验证该假设。小鼠模型 将采用α细胞特异性催乳素受体（Prlr）基因敲除来验证PL/PRLR在 调节α-细胞对妊娠的适应和胰岛内GLP-1的产生。我们将使用RNAseq方法， 比较来自妊娠小鼠和经胰岛素治疗的人类胰岛的分选α细胞的基因表达谱， 确定α细胞如何适应怀孕。这个项目的成功将揭示一个新的潜在机制 母亲的新陈代谢适应。它将对生殖医学和 GDM。

SUMMARY During pregnancy, maternal metabolism goes through a series of adaptations to meet the constant nutrient demand from the fetal compartment and prepare lactation. Failure of maternal metabolic adaptation causes gestational diabetes mellitus (GDM) and other complications. There is a significant increase in islet mass and insulin production during normal pregnancy. The pancreatic α-cells are the second primary endocrine cells in islets and regulate glucose metabolism mainly through the endocrine effects of glucagon. Although studies have reported that pregnancy may increase α-cell mass and maternal blood glucagon concentrations, there is a knowledge gap about the role of α-cells in controlling maternal metabolic adaptation. Our most recent study demonstrated the essential role of α-cells in maternal insulin production during pregnancy. First, we ablated α-cells in adult mice using an inducible genetic approach. Despite no significant change in fasting and randomly fed blood glucose concentrations, α-cell ablation improved glucose tolerance in non-pregnant mice. In contrast, a significant elevation of blood glucose concentrations and low insulin secretion were observed in α-null dams. Second, we treated pregnant mice with a glucagon receptor antibody during pregnancy to determine the contribution of glucagon in maternal metabolic adaptation. Surprisingly, glucagon receptor antagonism did not alter maternal blood glucose and insulin levels. Besides glucagon, α- cells also secret glucagon-like protein 1 (GLP-1). It is known that intraislet GLP-1 plays an important role in augmenting glucose-induced insulin production under metabolic stress conditions. Our study showed that GLP-1 receptor agonist restored insulin production and glucose metabolism in α-null dams. Therefore, we hypothesize that α-cells play a vital role in regulating maternal metabolic adaptation through the intraislet paracrine effects on insulin production. We will use the α cell-specific Pcsk1 gene, which directs GLP-1 production, knockout dams, and glucagon or GLP-1 reconstitution to verify this hypothesis. Mouse models with α cell-specific prolactin receptor (Prlr) gene knockout will be employed to verify the role of PL/PRLR in regulating α-cell adaptation to pregnancy and intraislet GLP-1 production. We will use the RNAseq approach to compare gene expression profiles in sorted α-cells from pregnant mice and hormone-treated human islets to determine how α-cell adapt to pregnancy. The success of this project will reveal a new underlying mechanism of maternal metabolic adaptation. It will significantly impact the research of both reproductive medicine and GDM.