Translation of Genetic Information to Clinical Practice

The clinical arm of the Diabetes Research Group aims to leverage genetic variation to elucidate disease heterogeneity, and understand its impact on human physiology and pharmacological response. While large-scale discovery efforts are providing important insight into the genetic architecture of T2D, the mechanism by which these variants contribute to disease states in humans often remains obscure.

One approach is to use catalogs of disease-associated genetic variation and its known effects on human physiology to guide the derivation of clusters, anchored in genetics but informed by physiology, that might subclassify type 2 diabetes into process-specific subtypes. This improved mechanistic understanding may facilitate the introduction of precision medicine in diabetes care.

To complement functional studies in cellular and animal models, the Diabetes Research Group has developed clinical studies to test how these variants influence human metabolism under static and dynamic conditions. These studies collect laboratory measures (e.g., oral glucose challenge, mixed meal tolerance tests) at baseline and after different pharmacological and nutritional perturbations, including:

  • glipizide, a sulfonylurea medication that stimulates insulin secretion and lowers glucose 
  • metformin, a commonly used medication that reduces production of glucose by the liver
  • a high-calorie, high-carbohydrate nutritional challenge reflective of the contemporary American diet
  • newer type 2 diabetes drugs, such as GLP-1 receptor agonists and SGLT2 inhibitors

The available datasets of clinical information, genetic measures, and laboratory assessments created from these studies provide a rich resource to examine the impact of genetic variation on human physiology. All interventions are performed on research volunteers who have provided samples and consent for genotyping. Research volunteers are actively recruited from the general population and from academic medical centers in the Boston area. Testing occurs in the Clinical and Translational Research Center and/or the Diabetes Research Center of the Massachusetts General Hospital. In addition, the group recruits individuals with known genotypes from the MassGeneral Brigham Biobank.

In addition, the Diabetes Research Group is responsible for genetic studies in major NIH-sponsored clinical trials, such as the Diabetes Prevention Program and the Glycemia Reduction Approaches in Diabetes (GRADE) comparative effectiveness study, as well as the sequencing and analysis of participants with atypical diabetes enrolled in the nationwide Rare and Atypical Diabetes Network (RADIANT).