Pregnant glycaemic control and its effects on healthy development and aging: a role for kisspeptin

在正常的健康妊娠期间，母亲的胰岛素敏感性降低，并且作为响应，胰岛中的胰岛素分泌β细胞释放更多的胰岛素并且数量增加以维持正常的血糖水平。临床上，当母亲不能充分增加胰岛素释放以补偿胰岛素抵抗时，可能发生妊娠糖尿病，尽管目前对所涉及的机制知之甚少。然而，即使妊娠期糖尿病没有发展，怀孕期间仍然是一个关键时期，此时β细胞处于压力之下，血糖水平控制受损。Kisspeptin是一种最近发现的分子，沿着其受体，存在于人体的几个区域-大脑的下丘脑区域，胎盘和内分泌胰腺。在正常情况下，血液中kisspeptin的水平很低，但在怀孕期间，由于胎盘大量释放，这些水平会大大增加。我们以前已经表明，胎盘kisspeptin在调节妊娠期间β细胞功能的适应方面起着重要作用，如果没有它，β细胞就不能科普妊娠的要求。我们在小鼠模型中产生的数据表明，循环kisspeptin参与了妊娠期间胰岛素释放增加和妊娠期间β细胞增殖增加。此外，我们最近完成了一项翻译研究，以检查血浆kisspeptin水平和孕妇血糖控制受损之间的相关性。这项研究的初步数据表明，妊娠期间的血浆kisspeptin水平与口服葡萄糖耐量试验中葡萄糖刺激的胰岛素反应程度呈正相关，这表明kisspeptin在人类胰岛适应妊娠中的作用。在怀孕期间发生的β细胞功能的变化，以及它们的长期影响，由于后代出生之外的几个原因，具有很大的潜在利益。已经确定，葡萄糖耐受不良和妊娠期糖尿病是母亲在以后生活中葡萄糖稳态受损和潜在的2型糖尿病的强烈标志物，尽管尚不清楚这是否代表因果关系，并且潜在的机制尚不清楚。因此，怀孕期间胰岛的健康是一个关键的生命事件，对胰岛的健康老化有潜在的长期影响。同样，许多先前的研究已经描述了妊娠期间母体葡萄糖控制改变与成年后代代谢功能障碍和糖尿病的后续发展之间的联系。因此，怀孕显然是母亲和子女生活中的一个主要生理事件。了解确保健康怀孕所涉及的信号对于确保胰岛能够科普以后生活中的压力也非常重要。本研究旨在研究妊娠期间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本身是维持妊娠期间正常葡萄糖稳态的重要信号，那么它在通过预防妊娠期间葡萄糖耐受不良的发展来确保母亲和后代在以后的生活中β细胞的持续健康方面也可能同样重要。这将通过两个主要目标来完成：（1）研究胎盘kisspeptin在健康母体衰老中的作用。(2)研究胎盘kisspeptin在后代健康贫血控制中的作用。

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.