Developing precision medicine for gestational diabetes

Researchers at the Harvard Pilgrim Health Care Institute have identified a potential risk factor for the development of gestational diabetes, finding that a deficit in the placental expression of the gene insulin-like growth factor 1 (IGFBP1) and low IGFBP1 circulating levels are associated with insulin resistance during pregnancy.

Gestational diabetes, the most common pregnancy metabolic complication, can lead to several pregnancy and delivery complications  Although previous research has demonstrated that excess insulin resistance in pregnancy contributes to gestational diabetes, the exact causes of this resistance remain unclear.

Lead author of the study Dr Marie-France Hivert, Harvard Medical School associate professor of population medicine at the Harvard Pilgrim Health Care Institute, explained: “The placenta – the major driver of changes in insulin physiology in pregnancy – is likely a key source of hormones involved in the development of gestational diabetes…Our goal was to discover novel placental factors that are implicated in gestational diabetes, by studying all proteins expressed in placenta tissues, across the human genome. We identified placental insulin-like growth factor 1 (IGFBP1) as a secreted placental factor that is likely implicated in regulation of glucose in human pregnancy.”

This research adds to Dr Hivert’s extensive exploration into the determinants of gestational diabetes using genetics and other omics approaches, and their interaction with lifestyle and environmental factors. In the new study, the team conducted genome-wide RNA sequencing on maternal-facing placental tissue samples. They measured identified proteins in blood collected in multiple pregnancy cohorts with diverse backgrounds.

The team detected 14 genes whose placental RNA expression levels were associated with insulin resistance, finding the strongest association with gene IGFBP1. They found that IGFBP1 levels increase over the course of pregnancy and are five times higher in pregnant people compared to outside of pregnancy, by measuring the IGFBP1 protein levels in circulation. This suggests that the placenta is one of the major sources of this protein during pregnancy.

Low levels of circulating IGFBP1 in early pregnancy could predict who is likely to develop gestational diabetes in late second trimester of pregnancy. Also, the researchers discovered that the trajectory of IGFBP1 levels across pregnancy differs in people who have a subtype of gestational diabetes characterised by insulin resistance previously shown more likely to develop pregnancy complications.

“Identifying a novel protein that characterises a subtype of gestational diabetes is one additional step towards developing precision medicine for gestational diabetes,” concluded Dr Hivert. “It’s possible that measuring IGFBP1 in the first trimester could help identify people at risk of developing gestational diabetes early in pregnancy, potentially offering a window for prevention. We hope to conduct future research to address whether this protein plays a causal role in gestational glycaemic regulation.”

This study was published in Nature Medicine.