News & Research

    Washington University in St. Louis, St. Louis, Missouri

Genetic control of islet beta cell growth and survival

General Research Subject: Type 2 Diabetes

Focus: Islet Biology\Apoptosis, Islet Biology\Beta Cell Growth and Differentiation, Islet Biology\Signal Transduction

Type of Grant: Mentor Based Postdoctoral Fellowship

Project Start Date: July 1, 2009

Project End Date: June 30, 2013

Research Description

Molecular mechanisms for loss of beta-cells are being discovered primarily in animal models. These studies have shown that insulin resistance in pancreatic beta-cells leads to cell death. Our lab created a transgenic mouse that over expressed a protein of the beta-cell insulin signaling pathway and demonstrated marked expansion of beta cells. This protein inhibits two proteins, FoxO1 and glycogen synthase kinase 3beta (Gsk3beta), each known to regulate carbohydrate and lipid metabolism in insulin target tissues, while also exhibiting anti-proliferative and pro-apoptotic (cell death) properties when expressed at high levels. Subsequent work in my lab has focused on these proteins in beta cells and their contribution to diabetes. To address this we have generated three beta-cell specific mouse models with: 1) over-expression of a constitutively active Gsk3beta (RIP-Gsk3betaCA), 2) conditional deletion of the Gsk3beta gene (ƒÒ-Gsk3betaKO), and 3) expression of a loss-of-function mutant of FoxO1 (RIP-FoxOdelta256). The main focus of my lab is directed at utilizing these models to test the hypothesis that diminished insulin signaling (i.e. resistance) leads to increased activity of FoxO1 and Gsk3beta, two anti-proliferative and pro-apoptotic proteins that work in concert to promote destruction of beta cells. The designed experiments with deficiencies of each protein in insulin resistant mice, will elucidate the contributions of these proteins to beta-cell failure in the context of insulin resistance. Failure of beta-cells to adapt to insulin demand and subsequent cell death might be considered the most pressing issue in diabetes research, and my lab proposes novel means to attack this problem.

Reseacher Profile

Mentor: Marshall Permutt, MD   Postdoctoral Fellow: Syed Danish Hasan, M.D.

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

My project mainly covers the molecular mechanisms of type 2 diabetes. We have become aware of the importance of insulin-signaling through the insulin receptor/insulin receptor substrate 2/PI-3kinase/AKT pathway for ß-cell proliferation and survival.

The loss of pancreatic ß-cell mass is a critical determinant for the development of this disease. The capacity for ß-cells to expand in response to insulin resistance is required to maintain glucose homeostasis and prevent type 2 diabetes. We have demonstrated the importance of two pro-apoptotic, anti-proliferative proteins that are negatively regulated by the insulin-signaling pathway. We have developed ß-cell specific mouse models with gain/loss of function of these proteins and are now uncovering molecular mechanisms. Our goals are to provide new means for enhancing ß-cell proliferation and survival.

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

We have already demonstrated the importance of two pro-apoptotic, anti-proliferative proteins that are negatively regulated by the insulin-signaling pathway. We are currently trying to uncover molecular mechanisms of diabetes and provide new means for increasing ß-cell proliferation and survival.  These studies would provide insights into the prevention and treatment of type 2 diabetes in the future.

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

Because there are 23.6 million children and adults in the United States or 7.8% of the population, who have diabetes, and the cause of diabetes continues to be a mystery, although both genetics and environmental factors such as obesity and lack of exercise appear to play roles, diabetes is a major threat to the health of many people.  Diabetes is also very common in my home country of China.  As a doctor and researcher, I want to help the patients and try my best to uncover the molecular mechanisms of diabetes.

This award allows me to continue my research. We have become aware of the importance of insulin-signaling for ß-cell proliferation and survival.  We will try to illustrate the potential importance of this pathway for expanding ß-cells in patients.

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

I think the future of diabetes research will focus on how to enhance ß-cell proliferation and reduce apoptosis.