Progression from gestational diabetes to type 2 diabetes can be predicted: study

A pair of studies from the University of Toronto is advancing precision medicine for people with a history of gestational diabetes.

Studying women who recently experienced gestational diabetes, researchers discovered genetic and metabolic markers associated with future type 2 diabetes onset. The findings uncover new clues about the development of type 2 diabetes after gestational diabetes and why some people are at greater risk than others.

Gestational diabetes is a form of diabetes that occurs in approximately 10 to 20 per cent of pregnancies. While most people recover from the condition after giving birth, they remain at significantly higher risk of having type 2 diabetes later. Studies estimate that out of 10 people with gestational diabetes, between three and five will go on to develop type 2 diabetes within 10 years postpartum.

“Clinically, there’s really no way to accurately tell whether or not you will get type 2 diabetes after a gestational diabetes pregnancy,” says Michael Wheeler, a professor of physiology at U of T’s Temerty Faculty of Medicine.

To answer this question, Wheeler and his team partnered with Erica Gunderson at Kaiser Permanente in California to look at clinical and metabolic data from over 1,000 women enrolled in the Study of Women, Infant Feeding and Type 2 Diabetes After Gestational Diabetes (the SWIFT study).

They found that women who developed type 2 diabetes post-pregnancy had a unique profile of metabolites in their blood including, most notably, lower levels of a compound called sphingolipids. This signature was detectable during the early postpartum period when the women had recovered from gestational diabetes and were years away from developing type 2 diabetes.

In their new study published in Science Advances, the researchers narrowed in on a specific subset of SWIFT Study participants — Hispanic women who were at higher risk of both gestational and type 2 diabetes — to understand how reduced sphingolipids contribute to type 2 diabetes onset.

By combining metabolic and genetic data, the researchers traced the lower sphingolipid levels to a specific variation in the CERS2 gene, which they then recreated in mouse models. Mice with this human version of CERS2 produced less insulin and were less able to regulate their blood sugar levels.

Wheeler, who is also a member of the Banting and Best Diabetes Centre, adds that while these findings point to a potential mechanism driving the evolution of gestational diabetes to type 2 diabetes, there are likely other important genetic and environmental factors at play.

In a second study from Wheeler and the SWIFT study team, the researchers describe three unique metabolic profiles among early postpartum women who progressed to type 2 diabetes after experiencing diabetes during pregnancy. Each profile represents a distinct pathway of progression to type 2 diabetes.

One profile was caused by dysfunction in the pancreatic beta-cells that produce insulin, whereas another was driven by insulin resistance, when the body doesn’t respond well to insulin to take up glucose from the blood. The third profile stemmed from a combination of the two.

“These are three different groups of people with a history of gestational diabetes that probably need three different interventions to prevent future type 2 diabetes” says Wheeler, noting the need for more personalized approaches to prevent and manage the disease.

The findings were published recently in Diabetes/Metabolism Research and Reviews.

Both studies were led by Saifur Khan, a former postdoctoral fellow in Wheeler’s lab who is now a research faculty member at the University of Pittsburgh.

Wheeler envisions these findings being used to develop a blood test that a person could take at their first postpartum visit to help determine their risk for developing type 2 diabetes later. His team is also applying the same approach to a different cohort to discover metabolic markers that can accurately predict gestational diabetes risk very early in pregnancy.

In addition to increasing the pregnant person’s risk of type 2 diabetes and cardiovascular disease, gestational diabetes can also have generational effects on the baby. It raises the risk of complications during birth and of the child experiencing overweight or obesity, diabetes or cardiovascular disease later in life.

“Gestational diabetes is a disease that affects relatively young, otherwise healthy women. If you could prevent gestational diabetes, you could prevent disease to both the parent and child, which would be highly impactful.”

This research was supported by the Canadian Institutes of Health Research, Diabetes Canada, McKamish Family Foundation, National Institutes of Health and Samuel and Emma Winters Foundation.