Examining how the brain controls obesity

Project title: Understanding Pathways of Fetal Metabolic Programming to Stop the Transgenerational Risk of Diabetes
Institution: Harvard Pilgrim Health Care Institute, Harvard Medical School
Pathway project publications: 6
Promoted to associate professor in 2017

Major accomplishments:

My Pathway project aims to understand how genes influence glucose regulation in pregnancy and how maternal glucose in turn may influence higher risk of obesity and diabetes for offspring later in life. To pursue these aims, I have built a prospective pre-birth cohort from which we now leverage the rich phenotypes and samples collected during pregnancy and at birth. Currently, we are conducting analyses using the most recent technological advances.

We found that known type 2 diabetes genetic variants were associated with risk of developing gestational diabetes (GDM) in pregnant women. We demonstrated that GDM is a heterogeneous condition and we defined sub-types of GDM based on dynamic indices of insulin secretion and insulin sensitivity. Women with GDM characterized by a insulin sensitivity defect are more likely to have complications at delivery; in contrast, women with GDM characterized by insulin secretion defect don't have higher rate of complications, but carry higher genetic risk of type 2 diabetes.

This past year, we began testing associations between maternal glucose and DNA methylation across the genome (>850,000 epigenetic markers) in 448 fetal placenta samples collected at delivery from Gen3G participants. These studies will uncover links between maternal glucose during pregnancy and risk for diabetes and obesity in the offspring later in life.

Impact statement:

My Pathway award has allowed me to conduct important research regarding how genes influence blood glucose regulation in pregnancy and determining how genetics characterized subtypes of gestational diabetes. Not all women with diabetes in pregnancy have the same type of diabetes; refining how we define diabetes in pregnancy may change how we treat diabetes during pregnancy. Most importantly, better understanding and more clearly defined subtypes of diabetes in pregnancy will allow for more intensive treatment in women at higher risk of complications during pregnancy. Based on our findings, we may be able to identify more precisely women and children who are at higher risk for complications during or after pregnancy. Our investigations about how maternal glucose might influence epigenetic factors in placenta and in offspring will increase our knowledge of the pathophysiology of gestational diabetes and may lead to discovery of novel therapeutics, or of biomarkers of long term consequences in children. I hope the results of my projects will help to prevent consequences of diabetes in pregnancy for mothers and their children over the long-term.

The Pathway award has been highly influential in my career development. Since I was awarded, I was promoted to Associate Professor. The funding has allowed me to employ the most recent technological advances and to contribute to multiple international consortia in the field of genetics and epigenetics, in addition to leading our own analyses within Gen3G.