Study discovers biomarker-related genetic predisposition

Among those who have had gestational diabetes, about 35% will develop type 2 diabetes within a decade. A new study led by Dr. Saifur Khan, Ph.D., cardiology research faculty member at the University of Pittsburgh Vascular Medicine Institute, is the first to identify molecular mechanisms of the progression from gestational diabetes to type 2 diabetes.

The discovery, reported in Science Advances, could lead to new therapies and interventions to reduce the risk of this progression.

“Many of these women who have had gestational diabetes go on to develop type 2 diabetes at a relatively young age, before 40,” said Khan. “There is an urgent need to identify root causes in order to develop early detection, prevention and targeted interventions using precision medicine.”

The team examined a cohort from The Study of Women, Infant Feeding and Type 2 Diabetes After Gestational Diabetes (The SWIFT Study), focusing on 143 Hispanic women aged 20 to 45 who had a history of gestational diabetes. Among them, 65 progressed to type 2 diabetes within eight years of delivery. The remaining 78 women served as controls.

By examining human metabolomic, lipidomic and genomic data, the team found that those who went on to develop type 2 diabetes had reduced levels of a kind of lipid known as sphingolipids in their blood at their disease-free stage, then traced decreased production of sphingolipids to a mutation in a gene known as CERS2. The team validated this finding in mouse models as well as in experiments using insulin-secreting cells donated from humans.

The findings suggest that lower levels of circulating very long chain sphingolipids could serve as an early indicator for the progression from gestational diabetes to type 2 diabetes.

“These insights could pave the way for novel therapeutic strategies aimed at targeting the sphingolipid pathway,” said Khan, also of the VA Medical Center, Pittsburgh.

“Therapeutic interventions designed to restore proper sphingolipid metabolism by enhancing CERS2 activity or minimizing its downstream deleterious effects on pancreatic insulin secretion capacity may help improve pancreatic beta cell function, insulin secretion, and glucose regulation in individuals at high risk of developing type 2 diabetes, especially those with a history of gestational diabetes.”

In future studies, the team will explore how CERS2’s loss of function contributes to pancreatic beta cell dysfunction and assess CERS2 activity and sphingolipid metabolism as targets.

Other authors on the study were Xiangyu Zhang, Ph.D., and Babak Razani, M.D., Ph.D., of Pitt and VA Medical Center, Pittsburgh; Wenyue W. Ye, M.D., Julie A. D. Van, Ishnoor Singh, Yasmin Rabiee, Kaitlyn L. Rodricks and Michael B. Wheeler, Ph.D., all of University of Toronto; Rebekah J. Nicholson and Scott A. Summers, Ph.D., of University of Utah; Anthony H. Futerman, Ph.D., of Weizmann Institute of Science; Erica P. Gunderson, M.D., Ph.D., of Kaiser Permanente Northern California and Kaiser Permanente Bernard J. Tyson School of Medicine.

Among those who have had gestational diabetes, about 35% will develop type 2 diabetes within a decade. A new study led by Dr. Saifur Khan, Ph.D., cardiology research faculty member at the University of Pittsburgh Vascular Medicine Institute, is the first to identify molecular mechanisms of the progression from gestational diabetes to type 2 diabetes.

The discovery, reported in Science Advances, could lead to new therapies and interventions to reduce the risk of this progression.

“Many of these women who have had gestational diabetes go on to develop type 2 diabetes at a relatively young age, before 40,” said Khan. “There is an urgent need to identify root causes in order to develop early detection, prevention and targeted interventions using precision medicine.”

The team examined a cohort from The Study of Women, Infant Feeding and Type 2 Diabetes After Gestational Diabetes (The SWIFT Study), focusing on 143 Hispanic women aged 20 to 45 who had a history of gestational diabetes. Among them, 65 progressed to type 2 diabetes within eight years of delivery. The remaining 78 women served as controls.

By examining human metabolomic, lipidomic and genomic data, the team found that those who went on to develop type 2 diabetes had reduced levels of a kind of lipid known as sphingolipids in their blood at their disease-free stage, then traced decreased production of sphingolipids to a mutation in a gene known as CERS2. The team validated this finding in mouse models as well as in experiments using insulin-secreting cells donated from humans.

The findings suggest that lower levels of circulating very long chain sphingolipids could serve as an early indicator for the progression from gestational diabetes to type 2 diabetes.

“These insights could pave the way for novel therapeutic strategies aimed at targeting the sphingolipid pathway,” said Khan, also of the VA Medical Center, Pittsburgh.

“Therapeutic interventions designed to restore proper sphingolipid metabolism by enhancing CERS2 activity or minimizing its downstream deleterious effects on pancreatic insulin secretion capacity may help improve pancreatic beta cell function, insulin secretion, and glucose regulation in individuals at high risk of developing type 2 diabetes, especially those with a history of gestational diabetes.”

In future studies, the team will explore how CERS2’s loss of function contributes to pancreatic beta cell dysfunction and assess CERS2 activity and sphingolipid metabolism as targets.

Other authors on the study were Xiangyu Zhang, Ph.D., and Babak Razani, M.D., Ph.D., of Pitt and VA Medical Center, Pittsburgh; Wenyue W. Ye, M.D., Julie A. D. Van, Ishnoor Singh, Yasmin Rabiee, Kaitlyn L. Rodricks and Michael B. Wheeler, Ph.D., all of University of Toronto; Rebekah J. Nicholson and Scott A. Summers, Ph.D., of University of Utah; Anthony H. Futerman, Ph.D., of Weizmann Institute of Science; Erica P. Gunderson, M.D., Ph.D., of Kaiser Permanente Northern California and Kaiser Permanente Bernard J. Tyson School of Medicine.