News & Research

    Salk Institute for Biological Studies, La Jolla, California

Regulation of glucose homeostasis by the cAMP responsive CREB coactivator TORC2

General Research Subject: Obesity

Focus: Integrated Physiology\Liver, Signal Transduction (Non-Insulin Action)\Transcriptional Regulation, Insulin Action\Signal Transduction

Type of Grant: Mentor Based Postdoctoral Fellowship

Project Start Date: July 1, 2009

Project End Date: June 30, 2013

Research Description

Humans operate on a mix of fuels depending on their level of physical activity: glucose is used for high-energy activities, while body fat is employed primarily during sleep. Two key hormones that are produced in the pancreas -- insulin and glucagon- function as the body's transmission system.  During feeding, the pancreas releases insulin, which promotes glucose burning, particularly in muscle.  At night, the pancreas releases glucagon into the bloodstream; this hormone signals the body to switch to fat burning and to conserve glucose supplies. In parallel, the liver replenishes the supply of glucose during this period, through a process called gluconeogenesis.

The proposed projects will examine how a set of genetic switches called TORCs (there are 3; TORC1, TORC2, and TORC3) regulate glucose and fat metabolism under fasting or feeding conditions.  Previous studies indicate, for example, that TORC2 turns on glucose production by the liver during fasting as well as in diabetes.  TORC2 appears to be a major target for Glucophage, the most widely used oral drug in the U.S. for treatment of insulin resistance. Glucophage turns off the TORC2 switch by causing a chemical change in the TORC2 protein known as phosphorylation. The central goal of the laboratory is to understand how these and other genetic switches are turned on or off during fasting and feeding in normal and diabetic animals. By developing a more comprehensive picture of the inner workings of the metabolic machinery, the laboratory will identify new targets that may be useful for diabetes treatment.

Reseacher Profile

Mentor: Marc Montminy, MD, PhD   Postdoctoral Fellow: Yiguo Wang, PhD

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

Our research is focused on how glucose and fat are metabolized in the body during fasting and in diabetes.  We are particularly interested in role that genetic switches, called transcription factors, play in this process.  By understanding the importance of these switches in metabolism, we can uncover what goes wrong with them in diabetes. 

A key challenge for the future is to identify particular organs in the body that function abnormally in the early course of this disease, before diabetes is apparent.  Using a imaging technology on live mice, we will evaluate how obesity affects glucose and fat metabolism in key tissues such as the liver, skeletal muscle, and adipose.  These studies will help to identify early changes in particular organs that hasten the progression to diabetes.

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

Our research may uncover a new area for drug development that would reinforce and strengthen current treatment regimens. 

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

Diabetes research provides clinical relevance to the basic science work our laboratory continues to do.  The work is also a natural outgrowth of the lab's interest in how hormones work in the body to regulate metabolism.   Perhaps the most rewarding aspect of these studies has been its potential to be integrated into a larger body of work from other laboratories and to provide clues for new therapies. 

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

I believe we will identify a number of diabetes susceptibility genes that, by themselves, have little effect on metabolism.  But in the right combination, these genes will profoundly affect an individuals risk to develop this disease.  Eventually, one can imagine a DNA test for 10 to 20 genes that will inform the patient as to his or her risk of developing insulin resistance.