News & Research

Beth Israel Deaconess Medical Center Boston, Massachusetts

The role of endothelial PGC-1alpha in diabetes and diabetic complications

General Research Subject: Type 2 Diabetes

Focus: Integrated Physiology\Muscle

Type of Grant: Basic Science

Project Start Date: January 1, 2010

Project End Date: December 31, 2012

Research Description 

One of the worst complications of diabetes is the development of disease in small blood vessels, in particular those of the heart and limb. Poor perfusion to the limb can cause pain in the legs, difficulty walking, poor wound healing, intractable infections, and the need for amputation. How this occurs remains incompletely understood. In addition, the role of blood vessels in the development of insulin resistance itself also remains relatively little studied, despite the fact that blood vessels are everywhere in the body, and that problems with blood vessels are some of the earliest events seen in the development of diabetes. We are studying a molecular pathway, involving a powerful molecule called PGC-1, which lies at the heart of metabolism in muscle and a number of other tissues. Surprisingly, PGC-1 has been little studied in blood vessels. We recently showed that PGC-1 in muscle powerfully induces the formation of new blood vessels. We propose here to study in depth the role of PGC-1 in blood vessels and the consequences on the development of diabetes and diabetic complications. The outcome of these studies could significantly change our thinking of how blood vessels contribute to diabetes and diabetic complications, and may well lead to the development of novel therapeutic approaches.

Researcher Profile

What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes? 

The long-term aim of this project is to understand how metabolism in blood vessels contributes to type II diabetes. There are two key issues being addressed:  first, how does abnormal metabolism in blood vessels contribute to the many and aggressive complications of diabetes? And second, what role do blood vessels play in the development of insulin resistance and diabetes in the first place? Research in cellular metabolism in diabetes has focuses extensively on the roles of liver, muscle, and brain. Much less attention has been placed on the blood vessels. As an entry point into these questions, we will study a powerful molecule, named PGC-1, which regulates key metabolic pathway in many tissues. We will use genetic mouse models to study how this molecule, in blood vessels, affects diabetes. If successful, the project will significantly advance our basic understanding of diabetes and its complications, and may guide the development of novel therapeutic interventions. 

If a person with diabetes were to ask you how your project will help them in the future, how would you respond? 

In order to develop new therapies for diabetes, we must understand how diabetes comes about, and how its complications develop.  Many aspects of diabetes remain unresolved. In this project, we are studying blood vessels, and testing the idea that blood vessels play a key role in the development diabetes and diabetic complications. From a pragmatic point of view, blood vessels are attractive targets, because drugs can easily get to them. Identifying, and demonstrating, new therapeutic targets in blood vessels, as this project hopes to attain, may therefore lead to new medications for the treatment of diabetes.

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts? 

I am a cardiologist. Diabetes is by far the biggest contributor to cardiovascular disease in the industrialized world. I see everyday in my practice the ravages that this disease brings upon people. Understanding how diabetes occurs, and ultimately devising novel ways to impact favorably on the disease, would, for me, constitute a successful career. This award will serve as a launching platform to initiate this trajectory. 

In what direction do you see the future of diabetes research going? 

There are, I think, a number of major directions that diabetes research is going. These include:

1. Beta-cell replacement, in particular with stem cell technology
2. Understanding the metabolic syndrome at a cellular and molecular level
3. Understanding neural pathways that lead to obesity
4. Understanding diabetic complications, in particular vascular complications