Novel approaches to understand the mechanisms of insulin resistance in pregnancy

Summary

Maternal physiology undergoes extensive changes during pregnancy to ensure an adequate supply of nutrients to the fetus. One of these adaptations that occurs in later pregnancy is increased peripheral insulin resistance to mobilize glucose, amino acids and lipids for transfer to the growing fetus.

The development of maternal insulin resistance reduces glucose uptake and energy storage in maternal skeletal muscle, increases hepatic gluconeogenesis and increases lipolysis in adipose tissue. Consequently, lipids and glucose are made available for transfer to the fetus. In response to maternal insulin resistance, the capacity of maternal pancreatic cell 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 through the secretion of hormones and signalling factors into the maternal circulation.

However, the precise organ targets for these placental derived secreted factors, and the roles that they play in modifying organ physiology are largely unknown.

Project aims

The student will use newly developed mouse genetic tools to elucidate placental-to maternal communication during normal pregnancy and impaired insulin resistance pregnancy states.

Specifically, this project has 3 aims:

1. To in vivo label secreted placental proteins with biotin, using BirA*G3-ER trangenesis, in Igf2 mouse models of impaired insulin resistance (caused by placental endocrine dysfunction) and wild-type controls
2. To characterize the placental secretome in these mouse models and follow the trafficking of biotin-labelled proteins to maternal serum, liver, skeletal muscle, pancreas and adipose tissue (by performing streptavidin-biotin pulldowns followed by mass spectrometry quantification -Tandem Mass Tag proteomics, TMT)
3. To perform state-of-the-art whole body physiological assays to measure peripheral glucose/insulin handling (e.g.  euglycemic hyperinsulinemic clamps) in the mouse models and analyse genome-wide transcriptomic responses to placenta endocrine dysfunction by single-cell RNASeq.

This project is likely to identify novel biomarkers of insulin-resistance in pregnancy, which is highly relevant to pregnancy complications such as gestational diabetes, whilst elucidating the role of the placental factors in the control of glucose homeostasis during pregnancy, with potential therapeutic applications.

Contact details

Professor Miguel Constancia - jmasmc2@cam.ac.uk

Opportunities

This project is open to applicants who want to do a:

• PhD