News & Research

    University of California, San Diego, La Jolla, California

ADA mentor-based postdoctoral fellowship

General Research Subject: Type 2 Diabetes

Focus: Genetics\Type 2 Diabetes, Insulin Action\Insulin Resistance, Integrated Physiology\Insulin Resistance

Type of Grant: Mentor Based Postdoctoral Fellowship

Project Start Date: July 1, 2009

Project End Date: June 30, 2013

Research Description

This training program encompasses a combined in vitro and in vivo approach emphasizing basic research, animal research, and classical clinical investigation.  This program will offer trainees an opportunity to conduct basic research on genetically manipulated mice and rats, as well as cellular systems in which specific gene products are overexpressed or deleted.  In addition, molecular studies in various cellular systems to elucidate  detailed signaling pathways of insulin and growth factor action are ongoing.  In the clinical research setting, functional genomic studies to understand the genetic networks contributing to insulin resistance and the therapeutic effects of insulin sensitizers are an important emphasis. 

Other studies include clinical investigation of post-menopausal women with and without estrogen treatment to deduce the mechanisms whereby estrogen protects women from fat induced insulin resistance.  Taken together, this combination of basic and clinical investigation, supplemented by the ample resources and rich diabetes research environment at UCSD, provides a fertile program to allow trainees to develop their full scientific potential.

Reseacher Profile

Mentor: Jerrold Olefsky, MD   Postdoctoral Fellow: Yun Sok Lee, PhD

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

We have found that a transcription factor, called Foxo1, inhibits the effects of another transcription factor, called PPAR gamma, to mediate its activity to cause an increase in expression of target genes. The insulin sensitizing thiazoladinedione drugs, termed TZDs, bind to the PPAR gamma transcription factor, and stimulate the expression of genes which cause the clinical improvement in insulin sensitivity, which is well described in rodents and humans.  Our findings have shown that Foxo1 inhibits these effects of PPAR gamma, thereby, preventing the actions of TZDs to cause insulin sensitization.  We have also shown in knockout animals, that deletion of the Foxo1 gene removes this inhibitory effect, leading to enhanced activity of TZDs to reverse insulin resistance. 

This project will extend these findings, through a genome-wide assessment of all the promoter regions with which Foxo1 associates (the Foxo1 cystrome).  This project will also generate a series of tissue specific, doxycycline-inducible transgenic mouse models, in which wild type Foxo1 and mutant Foxo1 are expressed in adipose tissue, muscle, and liver.   The in vivo phenotypes of these transgenic mice will then be thoroughly assessed.

This project should elucidate the mechanisms and roles of Foxo1 as an important regulator of PPAR gamma.  In turn, PPAR gamma is the effector target of TZDs, and, therefore, these studies should improve our understanding of in vitro and in vivo TZD action to improve insulin resistance. As such, the findings from these studies could lead to improved methods of using TZDs or even new classes of TZDs with improved efficacy. 

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

This project will sharpen our understanding of the basic mechanisms of TZD action, and since these drugs are the most important insulin sensitizing medicines available, our studies will enhance our ability to use these drugs in the treatment of type 2 diabetic patients.  In addition, by refining our understanding of the molecular mechanisms of action of these drugs, we may also be able to design newer compounds with improved efficacy and safety.

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

I have been involved in diabetes research for many years, and this award will make an important contribution.  Through this award mechanism, I will be able to fund a post doctoral fellow in my laboratory, Dr. WuQiang Fan, who is an outstanding young scientist.  Through this training, Dr. Fan will be able to acquire all of the necessary experience and skills allowing him to emerge as a fully independent scientist, making important research contributions to the area of diabetes for many years to come. 

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

I see the future of diabetes research becoming more and more translational.  By this I mean that as we improve our molecular understanding of the basic etiology of this disease and the mechanisms of action of therapeutic agents like TZDs, this knowledge will be more rapidly translated into the clinical setting.  This will include a new appreciation of the heterogeneous nature of type 2 diabetes, with a more refined understanding of all of the different subtypes.  This will lead to a more personalized medicine approach in which specific therapeutic agents can be targeted to subgroups of type 2 diabetic patients, based on their specific patho physiologic manifestations.