News & Research

    University of Pennsylvania, Philadelphia, Pennsylvania

HNF4alpha and HNF4gamma cooperate to regulate beta-cell growth and function

General Research Subject: Both Type 1 And Type 2 Diabetes

Focus: Islet Biology\Beta Cell Growth and Differentiation

Type of Grant: Mentor Based Postdoctoral Fellowship

Project Start Date: July 1, 2008

Project End Date: June 30, 2012

Research Description

Diabetes is a lifelong chronic disease with worldwide prevalence.  Lack of insulin production is a hallmark of both type 1 and type 2 diabetes. An important regulatory gene, called HNF4α, regulates growth and function of the cell (β-cell) secreting insulin. HNF4α is also the gene that is mutated in patients with MODY1, or Maturity Onset Diabetes of the Young. The  highly related gene, called HNF4γ, is also expressed in β-cells, but has not been tested for a role in insulin secretion or diabetes.

The goal of this project is to investigate whether HNF4α and HNF4γ cooperate to regulate β-cell growth and function in rodents and humans.  This overall goal will be pursued in three specific aims. 1) The contribution of HNF4γ in the β-cell growth and function will be evaluated by characterizing mice that have mutations in the gene. 2) Cooperative regulations of HNF4α and HNF4γ in the β-cell growth and function will be investigated in double mutant mice with ablation of both HNF4α and HNF4γ in insulin-producing cells. 3) Whether HNF4α and/or HNF4γ can be employed to stimulate β-cell proliferation will be determined in both rodent and human islets.

In conclusion, two unique lines of mutant mice will be studied to understand the regulation of β-cell growth and function by two important regulatory genes, HNF4α and HNF4γ. In addition, it will be explored whether these genes can be used to stimulate rodent and human islets to proliferate. The proposed studies will shed light on the novel strategies to stimulate expansion of functional islet cell mass and open an important avenue to future treatment options.

Reseacher Profile

Mentor: Kaestner, Klaus, PhD Fellow: John Le Lay, PhD

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

Diabetes is a lifelong chronic disease with worldwide prevalence.  Lack of insulin production is a hallmark of both type 1 and type 2 diabetes. An important regulatory gene, called HNF4α, regulates growth and function of the cell (β-cell) secreting insulin. HNF4α is also the gene that is mutated in patients with MODY1, or Maturity Onset Diabetes of the Young. The  highly related gene, called HNF4γ, is also expressed in β-cells, but has not been tested for a role in insulin secretion or diabetes.

The goal of this project is to investigate whether HNF4α and HNF4γ cooperate to regulate β-cell growth and function in rodents and humans.  This overall goal will be pursued in three specific aims. 1) The contribution of HNF4γ in the β-cell growth and function will be evaluated by characterizing mice that have mutations in the gene. 2) Cooperative regulations of HNF4α and HNF4γ in the β-cell growth and function will be investigated in double mutant mice with ablation of both HNF4α and HNF4γ in insulin-producing cells. 3) Whether HNF4α and/or HNF4γ can be employed to stimulate β-cell proliferation will be determined in both rodent and human islets.

In conclusion, two unique lines of mutant mice will be studied to understand the regulation of β-cell growth and function by two important regulatory genes, HNF4α and HNF4γ. In addition, it will be explored whether these genes can be used to stimulate rodent and human islets to proliferate. The proposed studies will shed light on the novel strategies to stimulate expansion of functional islet cell mass and open an important avenue to future treatment options. 

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

As you know, islet transplantation has become an option for patients with type 1 diabetes. However, the number of islets that can be obtained from organ donors is very limited, and will never be sufficient to meet demand. If we can develop ways to stimulate beta-cell proliferation of these islets in vitro to multiply them, then we will be able to treat a lot more patients. Also, we now know that in type 2 diabetics, beta-cell mass is insufficient to meet the body's demand. If we can find ways to safely stimulate beta-cell mass expansion in these patients, we would have a novel way to treat or even cure their diabetes. Therefore, it is important that we perform research to identify these new ways to make beta-cells proliferate.

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

Since my days as a graduate student at Johns Hopkins University, I have been interested in glucose metabolism and diabetes. In fact, my Ph.D. project was the cloning and characterization of the insulin-responsive glucose transporter, or GLUT4. Many of my friends have diabetes, or have children with diabetes, and it motivates me to know that some day discoveries made in my lab will be used to develop or refine new treatment options for these patients. With the cutbacks in federal research funding, it has become increasingly difficult to secure the resources necessary to carry out our work. The ADA postdoctoral award will allow me to retain a very promising and talented young researcher, and allow him to focus on diabetes research.

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

I see two major directions for the next ten years. The first is really a public health issue, focusing on weight control and exercise. This has to be stressed even more, as these types of intervention hold the greatest promise of dramatically decreasing the number of diabetics in the US. The second is to focus on expanding beta-cell mass. It is clear now that the reason why some obese people remain normoglycemic is because their beta-cell mass expands to adapt to the increasing needs of the peripheral tissues for insulin. We are exploiting rodent models to identify pathways to beta-cell proliferation, that could then be manipulated in patients to treat or cure diabetes.