Grant: Project Grant

Type 2 diabetes (T2D) is a major cause of heart disease, stroke and cancer. Caused by inadequate action of the hormone, insulin, T2D is often linked to obesity. With chronic overeating, the fat in our bodies (adipose) undergoes changes that make it "unhealthy", so that it is doesn't respond normally to the hormone insulin, and therefore promotes diabetes. How "healthy" adipose becomes "unhealthy" is not known. Such knowledge would be valuable, as drugs could be designed to prevent the changes from occurring. We recently found that a protein known as CD248 is made by cells (adipocytes) in the adipose. In humans and mice, the highest CD248 levels are strongly associated with the highest risk of diabetes. Mice and people with low levels of CD248, are resistant to diabetes, i.e., the adipose remains "healthy", even if they are obese. We also showed that by reducing CD248 in obese diabetic mice, we could reverse the diabetes and change the unhealthy adipose tissue to healthy adipose tissue. And thus, we've potentially uncovered an entirely new way to treat type 2 diabetes! Our goal is to understand how CD248 controls the switch between healthy and unhealthy adipose (and thus between non-diabetes and diabetes), and how it interacts with insulin and other proteins in the adipose tissue. Such information will help in the design of drugs. To achieve our goals, we will examine adipose tissue from mice that lack CD248 in different cells, using multiple biochemical, molecular and microscopic methods that are in our labs and those of our expert collaborators. In the end, we hope that we will identify strategies that reduce CD248 or interfere with its function, thereby leading to new and better treatments for type 2 diabetes.