Novel approaches to understand the mechanisms of insulin resistance in pregnancy

Supervised by: Prof. Miguel Constancia (jmasmc2@medschl.cam.ac.uk) and Prof. Sue Ozanne (seo10@cam.ac.uk)

Project Title: Metabolic determinants of early placental development

Project description 

Maternal physiology undergoes extensive changes during pregnancy to ensure an adequate supply of nutrients to the fetus. One of these adaptations, occurring in late pregnancy, is increased insulin resistance (i.e. decreased sensitivity of maternal organs to insulin-mediated glucose uptake). The development of maternal insulin resistance reduces glucose uptake and energy storage in maternal skeletal muscle, increases hepatic gluconeogenesis and increases lipolysis in the adipose tissue. This promotes glucose, amino acids and lipid transfer to the growing fetus. In response to maternal insulin resistance, the capacity of maternal pancreatic cells to produce insulin is increased (e.g. through beta-cell mass expansion).

It is thought that maternal peripheral insulin resistance is largely orchestrated by the placenta, a specialized organ at the interface between the mother and the fetus, and the site for maternal-fetal exchange. It is well established that the placenta regulates maternal physiological adaptations, including development of insulin resistance, through the secretion of hormones and signalling factors into the maternal circulation. However, the complete profile of these placental-derived secreted factors, the precise organ they target and the mechanisms by which they modify organ physiology, e.g. insulin sensitivity, are largely unknown.

The student will use newly developed mouse genetic tools to elucidate placental-to-maternal communication during normal and complicated pregnancies. 

Specifically, this project has 3 aims:

1. to in vivo label secreted placental proteins with biotin, using BirA*G3-ER transgenesis, in Igf2 mouse models of impaired insulin sensitivity (caused by placental endocrine dysfunction) and wild-type controls
2. to characterize the placental secretome in these mouse models and follow the trafficking of placentally-derived biotinylated proteins to key metabolic maternal organs such as the skeletal muscle, liver, pancreas and adipose tissue. Trafficking will be determined by performing streptavidin-biotin pulldowns followed by mass spectrometry quantification -Tandem Mass Tag proteomics, TMT- in target organs.
3. to perform state-of-the-art whole body physiological assays to measure peripheral glucose/insulin handling (e.g.  euglycemic hyperinsulinemic clamps - EHCs) and analyse the transcriptomic responses by single-cell RNA-Seq in these mouse models during pregnancy, of placenta endocrine dysfunction

This project is likely to identify novel biomarkers of insulin sensitivity/resistance in pregnancy, which is highly relevant to pregnancy complications such as gestational diabetes, that affects 1 in 7 pregnancies globally. In addition, it will define the role of the placental factors in the control of glucose homeostasis during pregnancy, with potential therapeutic applications.

References

1. PMID: 19794064
2. PMID: 37437545
3. PMID: 26740602
4. PMID: 35946312