Through her work as a clinician-researcher focused on understanding the determinants of diabetes, Institute Associate Professor Marie-France Hivert  is looking to precision medicine as the key to unlocking more precise diagnostic, prevention, and treatment strategies for the disease than exist today. From postdoctoral fellowship to leading research and teaching activities, Dr. Hivert’s efforts have made significant contributions to advancing knowledge of precision medicine as a viable means of improving the lives of those suffering from, or at risk of, diabetes.

Diabetes impacts hundreds of millions of people globally, posing a substantial risk of life-threatening complications and premature death. The disease is categorized currently most commonly as type 1 and type 2 diabetes, and less frequently caused by single gene mutation (monogenic diabetes), or be a consequence from other health conditions/medications. Diabetes can also emerge during pregnancy, which is called gestational diabetes.

“Precision medicine presents the opportunity to refine our diagnosis for sub-types of diabetes and predict treatment responses and/or outcomes,” says Dr. Hivert. “This ability to home in on very specific factors to define more precisely sub-types of diabetes could help us better target our clinical management, treatment recommendations, and reduce diabetes-related complications.” 

Dr. Hivert’s research primarily focuses on the origins and primordial prevention of obesity and related co-morbidities, particularly type 2 diabetes and gestational diabetes (GDM), using genetics and other omics approaches, and their interaction with lifestyle and environmental factors. An endocrinologist by training, Dr. Hivert got her first exposure to precision medicine during a postdoctoral fellowship with investigators on the Framingham Heart Study, studying the pathology of prediabetes. At the time, genome-wide association studies (GWAS), a now common research approach to finding genetic contributions to common diseases, were beginning to gain traction. This work became the catalyst for Dr. Hivert‘s research focused on understanding the biological, environmental, and genetic determinants of glucose regulation during pregnancy, and how they might affect fetal development. While gestational diabetes is common and tends to resolve after delivery, it can have lasting effects on both mother and child in the short- and long-term. 

Precision medicine presents the opportunity to refine our diagnosis for sub-types of diabetes and predict treatment responses and/or outcomes.

Building a solid foundation for ongoing and future research

In 2010, Dr. Hivert began to construct a prospective, population-based research cohort called Genetics of Glucose regulation in Gestation and Growth (Gen3G). Based in Canada, the cohort is made up of over 1,000 women who enrolled in their first trimester of pregnancy and aims to increase our understanding of blood sugar regulation during pregnancy and its impact on offspring. 

Dr. Hivert and her team collected individual body measurements, answers to lifestyle questionnaires, and samples for biomarkers and DNA analyses in both the women and their newborns. This comprehensive set of data was recorded throughout pregnancy to delivery. To date, they have completed the follow-up of mothers and children at 3-5 years post-partum—and now have initiated the 10–12-year follow-up. 

Gen3G is a rich trove of data that Dr. Hivert and colleagues have curated as a resource for ongoing investigations, and as a springboard for future work. Two of Dr. Hivert’s key research projects, and several resulting publications, have used Gen3G data, focusing on the placenta as a source of more information about the development of GDM.
 

The role of the placenta in determining the cause of gestational diabetes

One study¹ is investigating genome-wide genetic expression in placenta tissue in the hopes of identifying proteins and microRNAs that can be used as early pregnancy biomarkers to identify women at high risk of gestational diabetes, or to develop therapeutic targets that can influence insulin secretion and insulin sensitivity inside and outside of pregnancy. The most recent findings from Dr. Hivert’s team were recently published in Nature Medicine, demonstrating that a deficit in placental IGFBP1 contribute to insulin resistance in pregnancy, and lead to higher risk of gestational diabetes.

A second study² seeks to understand how microRNA from the placenta regulates insulin sensitivity in pregnancy. A detailed understanding of the function and regulation of these placental microRNA may provide novel targets for the treatment of pathophysiological decreases in insulin sensitivity, which will in turn reduce adverse pregnancy outcomes. 

“The richness of Gen3G data and sample collection has also led to many additional collaborations, both nationally and internationally,” says Dr. Hivert.

While spearheading research with fellow experts in the field to turn up new evidence, Dr. Hivert also works extensively with colleagues across the globe to examine existing evidence to highlight areas where precision medicine can improve clinical practice and also provide a framework for the direction of future research.

Through the effort of the multiple working groups for each type of diabetes, we know that bringing together international diabetes experts from all around the world is already forging new collaborations. We hope that these relationships will flourish to accelerate the field of precision medicine in diabetes and make meaningful strides towards improving the lives of people living with diabetes.

An international effort to advance precision medicine for diabetes
Dr. Hivert has played a pivotal role in the Precision Medicine Diabetes Initiative (PDMI). A large international collaboration involving leaders in the field of diabetes, the PMDI was established in 2018 to improve diabetes care by realizing the promise of precision medicine for diabetes, in the hope of offering custom delivery of health care, with medical practices, testing decisions, and treatments tailored to the patient level. 

In October 2023, the group published “Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine” in Nature Medicine. The report summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2).

As a researcher well versed in the urgency of uncovering the factors beyond glycemia that might explain the heterogeneity of gestational diabetes, Dr. Hivert was the advocate for inclusion of GDM as part of the global PDMI effort. This resulted in her leadership of four working groups focused on precision medicine for GDM (prevention, treatment, diagnostic, and prognostic). 

“Through the effort of the multiple working groups for each type of diabetes, we know that bringing together international diabetes experts from all around the world is already forging new collaborations,” says Dr. Hivert. “We hope that these relationships will flourish to accelerate the field of precision medicine in diabetes and make meaningful strides towards improving the lives of people living with diabetes.”
 

Further clinical and educational leadership

As she and colleagues seek to fill knowledge gaps in the area of precision medicine (does it work? Will it improve outcomes? Is the cost worth the benefits?) with expanding research efforts, she continues teaching, mentoring, and practicing medicine.

Dr. Hivert provides outpatient clinical care for patients with diabetes and supervises clinical fellows at the MGH Diabetes Center and as part of the Diabetes in Pregnancy Program (DIPP) in collaboration with the MGH Obstetrics Department. 

At Harvard Medical School, her expertise spans multiple branches of the MD curriculum. She directs the HMS Curricular Theme Nutrition and Lifestyle Medicine, which aims to integrate nutrition and lifestyle education throughout the HMS curriculum. She developed and serves as co-director of the Advanced Integrated Science Course (AISC) Metabolism, Nutrition, and Lifestyle Medicine, a selective offered to 3rd and 4th year HMS students. 

Overall, Dr. Hivert’s extensive reach within the clinical, educational, and research community has helped make strides toward highlighting, and hopefully one day closing, gaps in the field of precision medicine. 

Click here for more on Dr. Hivert’s career and research