Pregnant glycaemic control and its effects on healthy development and aging: a role for kisspeptin
妊娠血糖控制及其对健康发育和衰老的影响:Kisspeptin 的作用
基本信息
- 批准号:BB/N00616X/1
- 负责人:
- 金额:$ 47.08万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2016
- 资助国家:英国
- 起止时间:2016 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
During normal healthy pregnancy insulin sensitivity in the mother decreases and in response the insulin-secreting beta-cells in the islets of Langerhans release more insulin and increase in number to maintain normal blood glucose levels. Clinically gestational diabetes can occur when the mother is unable to increase insulin release sufficiently to compensate for the insulin resistance, though the mechanisms involved are currently poorly understood. However, even if gestational diabetes does not develop, pregnancy can still be a critical period when the beta-cells are placed under stress and there is impaired control of blood glucose levels.Kisspeptin is a recently-discovered molecule that is found, along with its receptor, in a few areas of the human body - the hypothalamic area of the brain, the placenta and the endocrine pancreas. Under normal conditions the levels of kisspeptin found in the blood are very low, but these levels increase greatly during pregnancy due to massive release from the placenta. We have previously shown that placental kisspeptin plays an important role in regulating the adaptation of beta-cell function both during pregnancy, and without it the beta-cells are less able to cope with the demands of pregnancy. We have generated data in mouse models indicating that circulating kisspeptin is involved in both increased insulin release during pregnancy and the increase in beta-cell proliferation during pregnancy. Furthermore we have recently completed a translational study to examine correlations between plasma kisspeptin levels and impaired glycaemic control in pregnant women. Preliminary data from this study indicates that there is a positive correlation between plasma kisspeptin levels during pregnancy and the extent of the insulin response to a glucose challenge as part of an oral glucose tolerance test, suggesting a role for kisspeptin in the adaptation of islets to pregnancy in humans.However, maintaining normal control of blood glucose during pregnancy is important not just for the duration of pregnancy itself. The changes in beta-cell function that occur during pregnancy, and their long-term effects, are of great potential interest for several reasons beyond the birth of the offspring. It is well established that glucose intolerance and gestational diabetes is a strong marker for impaired glucose homeostasis and potentially type 2 diabetes in the mother in later life, although it is not known whether this represents a causative link, and the underlying mechanisms are unclear. As such the health of the pancreatic islets during pregnancy represents a critical life event with potential long term consequences on the healthy aging of the islets. Similarly, numerous previous studies have described the links between altered maternal glucose control during pregnancy and the subsequent development of metabolic dysfunction and diabetes in the adult offspring. Thus pregnancy is clearly a major physiological event in the life of both mother and offspring. An understanding of the signals involved in ensuring a healthy pregnancy is also hugely important in ensuring that the islets are able to cope with stresses later in life. The present study aims to investigate the longer-term effects of kisspeptin signalling during pregnancy on healthy beta-cell function in both the mother and offspring after pregnancy. If kisspeptin is an important signal for maintaining normal glucose homeostasis during pregnancy per se, it may also be equally important in ensuring the continued health of the beta-cells in both the mother and the offspring in later life through preventing the development of glucose intolerance during pregnancy. This will be done through two main objectives: (1) investigating the role of placental kisspeptin in healthy maternal aging. (2) investigating the role of placental kisspeptin in healthy glycaemic control in offspring.
在正常健康的怀孕期间,母亲的胰岛素敏感性降低,作为反应,朗格汉斯岛分泌胰岛素的β细胞释放更多的胰岛素,并增加数量以维持正常的血糖水平。临床妊娠期糖尿病可能发生在母亲不能充分增加胰岛素释放以补偿胰岛素抵抗的情况下,尽管其机制目前尚不清楚。然而,即使妊娠期糖尿病没有发生,妊娠期仍然是一个关键时期,此时β细胞处于压力之下,血糖水平的控制受到损害。Kisspeptin是最近发现的一种分子,它和它的受体一起存在于人体的几个部位——大脑的下丘脑区、胎盘和内分泌胰腺。在正常情况下,血液中的kisspeptin水平很低,但在怀孕期间,由于胎盘大量释放,kisspeptin水平会大幅上升。我们之前已经证明胎盘kisspeptin在怀孕期间调节β细胞功能的适应方面起着重要作用,没有它,β细胞就无法应对怀孕的需求。我们在小鼠模型中获得的数据表明,循环kisspeptin参与了妊娠期间胰岛素释放的增加和妊娠期间β细胞增殖的增加。此外,我们最近完成了一项转化研究,以检查孕妇血浆kisspeptin水平与血糖控制受损之间的相关性。本研究的初步数据表明,妊娠期间血浆kisspeptin水平与胰岛素对葡萄糖挑战的反应程度呈正相关,这是口服葡萄糖耐量试验的一部分,表明kisspeptin在人类胰岛对妊娠的适应中起着重要作用。然而,在怀孕期间保持正常的血糖控制不仅对怀孕本身很重要。怀孕期间发生的β细胞功能的变化及其长期影响,除了后代的出生之外,还有几个原因引起了人们极大的潜在兴趣。葡萄糖耐受不良和妊娠期糖尿病是葡萄糖稳态受损和母亲晚年可能患2型糖尿病的重要标志,尽管尚不清楚这是否代表一种致病联系,其潜在机制也不清楚。因此,怀孕期间胰岛的健康是一个重要的生活事件,对胰岛的健康衰老有潜在的长期影响。同样,许多先前的研究已经描述了怀孕期间母亲血糖控制的改变与成年后代随后代谢功能障碍和糖尿病的发展之间的联系。因此,怀孕显然是母亲和子女一生中一个重大的生理事件。了解确保健康怀孕所涉及的信号对于确保胰岛能够在以后的生活中应对压力也非常重要。本研究旨在探讨妊娠期间kisspeptin信号传导对妊娠后母亲和后代健康β细胞功能的长期影响。如果kisspeptin在妊娠期间本身是维持正常葡萄糖稳态的重要信号,那么它也可能同样重要,通过防止妊娠期间葡萄糖耐受不良的发展,确保母亲和后代的β细胞在以后的生活中持续健康。这将通过两个主要目标来完成:(1)调查胎盘kisspeptin在健康母亲衰老中的作用。(2)探讨胎盘kisspeptin在子代健康血糖控制中的作用。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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James Bowe其他文献
Nrf2 activator Sulforaphane improves maternal glucose tolerance and vascular function in obese pregnancy
Nrf2 激活剂萝卜硫素改善肥胖妊娠的母体葡萄糖耐量和血管功能
- DOI:
10.1016/j.freeradbiomed.2022.12.059 - 发表时间:
2023-03-01 - 期刊:
- 影响因子:8.200
- 作者:
Jessica Morris;Paraskevi;Maria Psefteli;Luigi Gnudi;James Bowe;Paul Taylor;Manasi Nandi;Sarah Chapple - 通讯作者:
Sarah Chapple
James Bowe的其他文献
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