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

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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.