News & Research

    Vanderbilt University School of Medicine, Nashville, Tennessee

Mechanism of overnutrition-driven compensatory beta cell neogenesis

General Research Subject: Insulin Resistance Pre Diabetes

Focus: Islet Biology, Islet Biology\Beta Cell Growth and Differentiation, Islet Biology\Signal Transduction, Signal Transduction (Non-Insulin Action), Signal Transduction (Non-Insulin Action)\Transgenic Models

Type of Grant: Basic Science

Project Start Date: January 1, 2013

Project End Date: December 31, 2015

Research Description

Overnutrition leads to obesity, the major risk factor for type 2 diabetes. Only a fraction of obese individuals develop diabetes and there are fewer beta cells in these diabetic individuals than obese individuals without diabetes. This increased number of beta cells in non-diabetic obese individuals may help protect them from developing diabetes. The genetic mechanisms that link obesity to the induction of more beta cells are not well understood. The investigators have found that overnutrition, the leading cause of obesity, rapidly increases beta cell number in zebrafish, an animal model well suited for gene and drug discovery. The long term goal of this laboratory is to understand the cellular and genetic mechanisms by which overnutrition increases beta cell number.

This proposal seeks to determine how beta cells sense and signal overnutrition. Using a battery of pharmacological tests, the investigators have identify that endoplasmic reticulum (ER) stress in beta cells and FGF activity work downstream of, or in parallel to, hyperactivity of beta cells during the overnutrition-induced beta cell production. They will use genetic means to more vigorously test the model that overnutrition causes ER stress and FGF1 secretion in beta cells. FGF1 in turn induces the differentiation of progenitor cells into beta cells. Understanding how beta cells sense and signal overnutrition may help explain why some obese individuals are more prone to develop diabetes and potentially provide new treatment for diabetes.

Research Profile

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

Pancreatic beta cells produce insulin to maintain a nearly constant level of glucose in the blood. Muscle and other peripheral tissues of the body respond to insulin by removing glucose from the blood and storing it. Early in the development of diabetes these peripheral tissues may fail to respond to insulin, a phenomena referred to as insulin resistance. This leads to elevated blood glucose. Pancreatic beta cells compensate for insulin resistance by growing (increasing in number) and increasing their capacity to make insulin. If these cells fail to compensate for insulin resistance, diabetes develops.

The capacity to compensate for insulin resistance is a crucial determinant of susceptibility to type 2 diabetes. Our laboratory is interested in understanding the genetic basis of beta cell compensation. This particular project focuses specifically on the compensatory increase in beta cell number during insulin resistance. Specifically, we will determine how beta cells sense elevated insulin demand due to insulin resistance and what signal(s) are released to cause beta cells to increase in number. Identifying the key players involved in sensing and signaling during insulin resistance may improve diagnosis of diabetes susceptibility. These key players may also be novel drug targets to boost the compensatory capacity of beta cells and to prevent or treat of type 2 diabetes.

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

There are times and conditions when the beta cells that make insulin can grow, increase in number, when our body needs more insulin. During diabetes these cells fail to increase in number, which results in an inability to produce sufficient insulin to keep blood glucose levels in control. Using a genetic approach this project will identify key players (genes) that regulate beta cell growth. Identification of these key players may improve diabetes diagnostic and prognostic prediction for patients. These key players may also be targets for future drug therapies that will increase insulin production in diabetic and pre-diabetic patients.

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

The prevalence of Type 2 diabetes has almost doubled in the past 2 decades and the trend is projected to continue upward. Although the role of lifestyle and diet in the risk for developing diabetes is clear, it is also clear that our genetic makeup contributes strongly to risk. However, we have a very poor understanding of how genes affect diabetes risk. I am a geneticist and a strong believer that research should alleviate human sufferings. I became very interested in understanding the genetics of diabetes when I learned that several members of one of my best friend's family were diagnosed with diabetes.

Now that we have validated zebrafish as a diabetes model and provided evidence for an attractive hypothesis for compensatory beta cell growth, this award comes at a critical time to further validate our hypothesis and to extend our observations into mammalian systems.

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

We believe that the future of diabetes research lies in (1) identifying how genetics influences progression from insulin resistance to diabetes, (2) developing effective treatments for most of the identified alleles that contribute to diabetes susceptibility. These researches will be greatly facilitated by the use of whole organism physiology and genetic model organisms such as zebrafish. Advances in the two directions will provide personalized treatments for diabetes patients.