News & Research

University of Utah Salt Lake City, Utah

Transcriptional control of skeletal muscle insulin resistance

General Research Subject: Insulin Resistance Pre Diabetes

Focus: Insulin Action

Type of Grant: Basic Science

Project Start Date: January 1, 2010

Project End Date: December 31, 2012

Research Description

Glucose is obtained from the foods we eat and is required for life, yet alterations in how the body senses and utilizes glucose underlie the development of type 2 diabetes. Following a meal, glucose in the bloodstream is absorbed by skeletal muscle. In pre-diabetes, a condition called insulin resistance develops where glucose absorption into skeletal muscle is reduced. This leads to high blood sugar but insulin resistance can be a precursor to full blown diabetes. We are interested in how skeletal muscle senses and adapts to changes in glucose levels. We have identified a protein called MondoA that is highly expressed in skeletal muscle and is an important sensor of glucose concentration. When glucose levels are low, MondoA is inactive, but when glucose levels increase, MondoA binds to the control regions of genes and activates their expression. Our published data using cell line models indicates that hyperactive MondoA may be required for the development of insulin resistance. In this application, we plan to inactivate MondoA in skeletal muscle of mice to see if MondoA is required for skeletal muscle insulin resistance in animals. In addition, we will use state-of-the-art techniques to discover all of the genes regulated by MondoA, thereby allowing us to discover how skeletal muscle cells respond to glucose. These experiments will help us determine the mechanisms and pathways altered in insulin resistance. As such, we hope to discover new indicators for the earliest stages of insulin resistance and discover new targets for therapeutic intervention.

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? 

Our research covers the area of skeletal muscle insulin resistance. In other words, we are interested in why skeletal muscle in diabetic people does not take up as much glucose following a meal as muscle from unaffected individuals. Our work focuses on how skeletal muscle senses glucose and responds to glucose. We have discovered a gene regulatory protein called MondoA that we believe is one key to how skeletal muscle senses and responds to glucose. When MondoA is active, our data suggest that cells take in less glucose. Therefore high MondoA activity is correlated with insulin resistance. Our goal it to understand how MondoA senses glucose and determine the genes MondoA turns on in response to changes in glucose concentration. By meeting these goals, we hope to identify populations 'at risk' for developing type II diabetes earlier than currently possible and potentially develop new therapeutics that would block MondoA function to stimulate glucose uptake.

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

One key feature of diabetes is elevated blood glucose levels. Normally, glucose is taken into skeletal muscle following a meal and this tightly controls blood glucose levels. In diabetic patients, glucose is not taken into skeletal muscle efficiently and we are trying to understand why. Understanding the detailed mechanisms by which skeletal muscle senses and responds to glucose will potentially help identify at risk people before they develop diabetes and could lead to the development of novel drugs that would stimulate glucose uptake into skeletal muscle leading to an improvement in blood glucose levels.

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

Traditionally, my lab has been very interested in how glucose is used to fuel the growth of cancer cells. Our studies, and studies from other labs, have shown that many of same mechanisms used by cancer cells to sense glucose and other nutrients are also used by skeletal muscle. Given our long track record studying cancer cell metabolism and the growing epidemic of type II diabetes worldwide, we are poised to make important discoveries about how glucose use is dysregulated in diabetes. The funding from the American Diabetes Association will allow us to begin our studies in this important area. In the future, we will leverage the discoveries made possible by this funding from the American Diabetes Association to seek funding from the National Institutes of Health. 

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

I am a newcomer to the field of diabetes research, therefore this is a difficult question. However, in the field of cancer biology we have made important strides in understanding the molecular mechanisms that underlie different cancers and will, in the future, be able to target the specific molecular defects of an individual's cancer. Similarly, by understanding the molecular mechanisms underlie the development of type II diabetes, we should be able to place patients in to specific treatment groups thereby allowing for more effective treatment of this disease.