News & Research

    University of Michigan, Ann Arbor, Michigan

Role of the transcriptional repressor Bcl-6 in GH-induced insulin resistance

General Research Subject: Insulin Resistance Pre Diabetes

Focus: Integrated Physiology\Insulin Resistance, Gene Chips and Microarrays, Signal Transduction (Non-Insulin Action)\Transcriptional Regulation

Type of Grant: Basic Science

Project Start Date: July 1, 2009

Project End Date: June 30, 2012

Research Description

Our lab identified a new gene that may be related to insulin resistance in response to growth hormone (GH), a hormone that can induce diabetes.  The gene for B-cell lymphoma 6 (Bcl6) was greatly suppressed by GH in fat cells after 48h.  This finding was surprising since Bcl6 is known for its immune functions and is often mutated in lymphomas.  Because of the presence of Bcl6 in fat cells, we propose that it may have metabolic functions. To learn whether Bcl6 has roles in sugar and fat metabolism, we propose measure Bcl6 in mice with altered metabolism, such as in fasting and after GH treatment.  We will test how metabolic regulation changes in mice with Bcl6 excess or deficiency.  Since the function of Bcl6 is to regulate other genes, we will find out what genes Bcl6 regulates in fat cells, using the 'high-throughput' technique of ChIP-sequencing, which can test every gene simultaneously.  The resulting genes that are known to be involved in metabolic pathways will be tested for responses to GH in functional studies.  We will also test whether creating Bcl6 excess or deficiency, in cells and in animals alters these genes in response to insulin and GH, and improves or worsens insulin resistance.  Our findings may identify Bcl6 as a new metabolic regulator and factor in insulin resistance, which has potential to serve as a new target for treatment of insulin resistance.

Reseacrher Profile

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

This project investigates mechanisms for insulin resistance that can lead to or be associated with diabetes.  We are analyzing a new regulatory gene that may be involved in insulin resistance.  We identified Bcl6, which codes for a gene repression factor, as a target of growth hormone (GH) in fat cells under conditions of insulin resistance.  Bcl6 had been known as a regulatory factor in the immune system.  We are testing whether Bcl6 plays a role in metabolism by examining the genes that it regulates.  We will test the function of Bcl6-regulated genes in cells and animal models.  Our findings may ultimately help identify genetic markers for insulin resistance, and will identify potential gene regulatory mechanisms and targets that may provide new modes of treatment for diabetes.

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

It is well accepted that changes in gene function contribute to the changes that lead to diabetes.  Our project will help us understand a new gene regulatory mechanism involving inhibition, that may contribute to metabolic abnormalities of diabetes, and will help us understand how this gene and its targets are involved in insulin resistance and diabetes.  Once we have such understanding, we can look for new ways to treat diabetes through genetic approaches.

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

Understanding diabetes captured my curiosity and my imagination when I worked in a diabetes research lab as a high school student.  Studying mechanisms that contribute to diabetes has thus been a driving force throughout my career.  My interest in growth hormone (GH) grew from appreciation that it can be diabetogenic.  The mechanisms for such an effect, and to what extent normal levels of GH contribute to diabetes or its complications, are still poorly understood.  This award allows me to apply some of the latest and most meaningful technologies, and new approaches utilizing bioinformatics, to these long-standing problems, with a goal of making predictions that can be tested with the established biological strategies that have been so informative in diabetes research.

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

New technologies and high-throughput strategies such as gene chips and 'next generation' DNA sequencing offer unprecedented opportunities for biomedical research, and are being effectively applied to diabetes.  They have increased discovery of novel biological effectors, have increased the scope of our understanding of biological events, and have increased the rate that we obtain new insights into diabetes.  I believe that we can anticipate ongoing expansion of our knowledge and ability to treat diabetes as these vast new bodies of information are utilized in the lab and clinic.