Community Research and Development Information Service - CORDIS

Molecular insight into gestational metabolic changes

Millions of women of reproductive age worldwide are at high risk of developing gestational diabetes mellitus (GDM). Understanding the underlying aetiology should help scientists develop appropriate interventions.
Molecular insight into gestational metabolic changes
During pregnancy, the maternal metabolism undergoes substantial changes including a marked increase in insulin resistance. In certain predisposed women, insulin cannot control glucose levels and may lead to the development of GDM in the third trimester. Although in the majority of cases, GDM disappears after the baby is born, these women are more likely to develop type 2 diabetes later in life. Moreover, the nutritional environment in the womb can impact the developing baby and its propensity to develop diabetes later in life.

Intrahepatic cholestasis of pregnancy (ICP) is a metabolic complication caused by an interruption in the bile flow from the liver and is associated with adverse pregnancy outcomes. Similar to GDM, ICP in the mother has been linked to an increased risk of subsequent obesity and increased blood lipids in the child. Furthermore, ICP women have increased susceptibility to GDM but the reasons are not fully understood.

The scope of the EU-funded GDMICP (Gestational signal and bile acid role in the enteroinsular axis) project was to shed light on the association between GDM and ICP. Previous work had identified an involvement of the receptors FXR and TGR5 in the regulation of liver bile acid and glucose metabolism. During GDMICP, researchers worked under the hypothesis that ICP interfered with FXR and TGR5, leading to the development of GDM.

Researchers discovered that women with GDM had lower levels of progesterone metabolites during pregnancy, which directly influenced pancreatic islet function and insulin secretion. This indicated the presence of a feedback mechanism that works to meet the higher insulin demand required for the adaptation to the gestational increase in maternal food intake and fat deposition. Furthermore, it underscored the potential of using progesterone metabolites as a useful biomarker to identify women with a higher risk of developing GDM later during pregnancy.

Mice lacking FXR presented with severe maternal glucose intolerance caused by increased insulin resistance and an islet inability to expand. This indicated that FXR has an important role in the association between ICP and GDM. Moreover, GLP-1 seemed to be an important contributor in this pathology, suggesting that ursodeoxycholic acid treatment in ICP women could help restore glucagon-like peptide 1 levels and trigger insulin release.

Collectively, the findings of the GDMICP study provide fundamental insight into the mechanism that links the two most common gestational metabolic conditions, GDM and ICP. This knowledge could be exploited clinically to restore metabolic homeostasis during pregnancy and hopefully avoid potential complications later in life.

Related information


Gestational diabetes mellitus, insulin resistance, intrahepatic cholestasis of pregnancy, bile, FXR, TGR5, progesterone
Follow us on: RSS Facebook Twitter YouTube Managed by the EU Publications Office Top