Gene-environment interaction in islet serotonin metabolism and impacts on maternal glucose homeostasis

摘要 妊娠期糖尿病的特征是妊娠期慢性高血糖。 糖尿病的诊断。这是一种非常常见的产科并发症，全球约有10%-25%的孕妇受到影响。 因为患有妊娠期糖尿病的妇女更有可能有其他妊娠并发症，所以 对于妊娠或早产儿，并发展为II型糖尿病，妊娠期糖尿病构成严重威胁。 为母婴健康干杯。尽管已经定义了一些风险因素，但潜在的机制 是复杂的，确切的病因还知之甚少。最近的研究表明，胰腺5-羟色胺 信号转导在母体葡萄糖动态平衡中起着关键作用。胰腺中5-羟色胺合成增加 胰岛是一个促进β细胞增殖和增加胰岛素分泌的关键事件，这是 预防孕期母体高血糖。降低胰岛5-羟色胺的饮食和遗传因素 合成与小鼠的妊娠期糖尿病有因果关系。我们的初步研究表明，低剂量 暴露于全氟辛酸(PFOA)与5-羟色胺丰度降低及其危害性有关 妊娠C57BL/6小鼠胰腺中的辅因子维生素B6。这些结果与 流行病学研究发现，孕妇接触全氟辛烷磺酸与母亲高血糖、胰岛素有关 抵抗力和葡萄糖耐受性。有趣的是，暴露于全氟辛酸的DBA/2J小鼠不会发生妊娠 糖尿病。C57BL/6和DBA/2J小鼠代谢维生素B6的能力不同，这是由于 碱性磷酸酶(ALP)活性。这些结果表明，环境暴露导致 妊娠期糖尿病受遗传背景的调节，较高的内源性维生素B6水平给予 保护。总体假设是怀孕小鼠暴露于全氟辛烷磺酸与妊娠有关。 干扰母系胰岛5-羟色胺代谢的糖尿病机制及其影响 受维生素B6生物利用度遗传差异的影响。我们建议研究β细胞 对照组和全氟辛酸暴露孕鼠的增殖和5-羟色胺丰度的测定 妊娠期糖尿病是否与β细胞扩张减少和胰岛素减少有关 分泌物。我们还希望研究在DBA/2J怀孕小鼠中使用碱性磷酸酶抑制剂是否会 减少胰岛中的维生素B6，导致对妊娠期糖尿病失去保护。最后，为了 确定怀孕和妊娠期糖尿病如何影响胰岛编程，我们将进行RNA 靶和标记下的测序和切割，然后测序以研究细胞的变化 转录组和表观基因组对生理变化和疾病的反应。拟议的研究将 提供有关妊娠期糖尿病潜在机制的知识，使公众健康受益。

ABSTRACT Gestational diabetes is characterized by chronic maternal hyperglycemia during pregnancy without a prior diagnosis of diabetes. It is a very common obstetric complication affecting ~10-25% pregnant women globally. Because women with gestational diabetes are more likely to have other pregnancy complications, deliver large for gestational or premature babies, and develop type II diabetes, gestational diabetes poses a serious threat to the health of mother and baby. Although some risk factors have been defined, the underlying mechanisms are complex and the precise etiologies are poorly understood. Recent studies show that pancreatic serotonin signaling plays a critical role in maternal glucose homeostasis. Increased serotonin synthesis in the pancreatic islet is a critical event that promotes beta cell proliferation and increased insulin secretion that are needed to prevent maternal hyperglycemia during pregnancy. Dietary and genetic factors that reduce islet serotonin synthesis are causatively linked to gestational diabetes in mice. Our preliminary studies show that low dose exposure to perfluorooctanoic acid (PFOA) is associated with reduced abundance of serotonin and its critical cofactor vitamin B6 in the pancreas from pregnant C57BL/6 mouse. These results are consistent with epidemiological findings that PFOA exposure in pregnant women is linked to maternal hyperglycemia, insulin resistance, and glucose intolerance. Interestingly, DBA/2J mice exposed to PFOA do not develop gestational diabetes. The C57BL/6 and DBA/2J mice differ in their abilities to metabolize vitamin B6 due to differences in activities of alkaline phosphatase (ALP). These results suggest that environmental exposure-induced gestational diabetes is modulated by genetic background and higher endogenous vitamin B6 level confers a protection. The overall hypothesis is that PFOA exposure in pregnant mice is causatively linked to gestational diabetes through mechanisms that perturb serotonin metabolism in maternal pancreatic islets and the effects are modulated by genetic differences in vitamin B6 bioavailability. We propose to investigate beta cell proliferation and serotonin abundance in control and PFOA-exposed pregnant C57BL/6 mice to determine whether the gestational diabetes is causatively linked to reduced beta cell expansion and reduced insulin secretion. We also wish to investigate whether treatment with an ALP inhibitor in the DBA/2J pregnant mice will reduce vitamin B6 in pancreatic islets and result in loss of protection to gestational diabetes. Finally, to determine how pregnancy and gestational diabetes influence islet programming, we will perform RNA sequencing and Cleavage Under Targets and Tagmentation followed by sequencing to study changes in the transcriptome and epigenome in response to physiological changes and disease. The proposed research will provide knowledge on mechanisms underlying gestational diabetes that benefit public health.