For Scientists Research Information Alumni Connection

Integrative Physiology and Metabolism

Understanding the roles played in diabetes and obesity by insulin resistance, exercise and nutrition

In type 2 diabetes, obesity and many other common disorders, the tissues of the body lose their ability to respond normally to insulin action. This is called insulin resistance.  Scientists in Joslin’s Section on Integrative Physiology and Metabolism tackle key questions such as “How do people with type 2 diabetes lose their ability to use insulin effectively? How does obesity help to drive this damage? And what innovative new treatments can help to stem these two epidemics?”

Joslin has long been a world leader in uncovering the multiple pathways of insulin signaling, learning how these pathways affect metabolism and growth, and how they are altered in type 2 diabetes and other insulin-resistant conditions. 

Using genetically engineered mice, researchers in this Section have defined the role of insulin resistance in each of the tissues of the body, including classical target tissues for insulin action such as liver, muscle and fat, as well as others such as insulin-producing beta cells and the brain.

This new knowledge has been extended to humans through another effort, the Joslin Cohort Study, done in collaboration with the Section on Clinical, Behavioral and Outcomes Research, which examines people on a spectrum of insulin resistance and risk for type 2 diabetes. This project seeks to find the early defects involved of insulin resistance, combining genetic and metabolic analyses of human samples with work in cells and animal models.

Joslin also has pioneered research in obesity and its role in insulin resistance and metabolism. Scientists study both white (energy-storing) and brown (energy-burning fat) and the different roles of subcutaneous versus intra-abdominal fat in creating a risk for diabetes and metabolic disease.

These studies have revealed that calorie-burning brown fat is present and active in adults, a discovery that may offer promising opportunities for therapies. Scientists now are studying a protein called BMP-7 that aids in forming and activating brown fat, using cellular studies, animal models and an early clinical trial. They also are developing new ways to measure brown fat mass and activity in humans.

Additionally, Joslin researchers are studying the relation between low birth weight and high rates of obesity and diabetes in adulthood. This work focuses on mothers who have insulin resistance or poor nutrition during pregnancy and how that affects their babies’ risks of these chronic conditions. The primary emphasis is on understanding the role of maternal nutrition, with an eye on potential protective strategies.

For centuries people have known that exercise helps to reduce not only obesity but blood glucose levels, and the long-term risk of type 2 diabetes. Another important component of research in this Section looks at the molecular mechanisms by which skeletal muscle is involved in diabetes, and how exercise can act as a treatment for diabetes—both in improving insulin sensitivity and in boosting blood glucose uptake outside of insulin-signaling pathways. Researchers also are studying the effects of longer-term adaptations to exercise and exercise training.