Many women with gestational diabetes later develop type 2 diabetes - but not for the same reasons

Women who have gestational diabetes have increased risk of type 2 diabetes in the years after delivery. Those who go on to develop the chronic disease fall into three “clusters,” each with a distinct molecular driver, according to a new study from University of Pittsburgh researchers published today in Diabetes/Metabolism Research and Reviews.

These clusters point to targets for potential precision-medicine approaches for type 2 diabetes.

“In type 2 diabetes research, many pathways will pop up again and again, and cause-and-effect interactions are difficult to understand,” said lead author Saifer Khan, Ph.D., research faculty member at the Vascular Medicine Institute at Pitt and the VA Medical Center, Pittsburgh. “By examining this very high-risk population, we were able to target the very early stages of disease and simplify the pathways.”

The team focused on 225 women who had a history of gestational diabetes and then developed type 2 diabetes within 12 years of delivery, selecting their cohort from The Study of Women, Infant Feeding and Type 2 Diabetes After Gestational Diabetes (The SWIFT Study). The researchers used blood samples that had been gathered periodically as the women progressed to the chronic disease, applying computational modeling and machine learning to metabolomic, proteomic and genomic data, as well as clinical measures such as triglycerides, insulin and glucose levels.

The researchers determined that in one cluster of study participants, their diabetes was driven by pancreatic beta-cell dysfunction; in a second cluster, it was driven by insulin resistance; and in a third cluster, the disease was driven by a mixture of the two. About 50% of study participants fell in this “mixed” cluster.

The work builds upon recent research the team published in Science Advances that was the first to identify molecular mechanisms of the progression from gestational diabetes to type 2 diabetes.

A goal of future research is developing approaches to easily whether women fall into one of the clusters, and then provide early interventions that prevent progression to type 2 diabetes.

Other authors on the study were Zhang Xiangyu, Ph.D., and Babak Razani, M.D., Ph.D., of Pitt and the VA Medical Center, Pittsburgh; Juile Van and Michael B. Wheeler, Ph.D., of University of Toronto; Stacey Alexeeff, Ph.D., of Kaiser Permanente Northern California; and Erica P. Gunderson, Ph.D., M.P.H., of Kaiser Permanente Northern California and Kaiser Permanente Bernard J. Tyson School of Medicine.

The National Institute of Child Health and Human Development (R01HD050625) and The National Institute of Digestive, Diabetes and Kidney Disease (R01DK118409) supported the SWIFT Study. Data analysis is supported by Canadian Institutes of Health Research (FRN 143219).