News & Research

    Columbia University, New York, New York

Regulation of adult beta cell function

General Research Subject: Both Type 1 And Type 2 Diabetes

Focus: Islet Biology\Beta Cell Growth and Differentiation, Islet Biology\Beta Cell Transcription Regulation, Islet Biology\Metabolic Regulation

Type of Grant: Mentor Based Minority Postdoctoral Fellowship

Project Start Date: July 1, 2011

Project End Date: June 30, 2015

Research Description

NeuroD is an evolutionarily conserved regulatory factor that is critical for development of the pancreatic islet in mouse and humans. NeuroD-null mice die of severe diabetes shortly after birth due to the loss of their beta cells, and homozygous mutations of NEUROD in humans are responsible for neonatal diabetes.  Interestingly, heterozygous mutations in NEUROD predispose individuals to develop maturity onset diabetes of the young (MODY6), suggesting there is also a critical role for NeuroD in the function of adult beta cells. To determine the beta cell function of NeuroD, we have generated mice in which neuroD is deleted in the adult beta cells. These mice are severely glucose intolerant and display greatly reduced insulin secretion.  In this application, we propose to elucidate the precise role of NeuroD in regulating beta cell function and insulin gene expression.  Gaining a greater understanding of the role of NeuroD in regulating the pathophysiology of the beta cell will allow us to devise new protocols to maintain the functionality of beta cells in vivo and ex vivo.  In addition, we should be able to use this knowledge to develop new methods to promote and maintain the maturation state of a functional beta cell in vitro, currently a rate limiting obstacle in in vitro beta cell differentiation protocols.  Finally, these studies could also lead to the identification of methods to correct the defects associated with mutations in NeuroD that lead to a MODY phenotype.

Research Profile

Mentor: Sussel, Lori, PhD  Postdoctoral Fellow: Gross, Stefanie

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

The project is relevant to type 1 diabetes (regeneration) and type 2 diabetes (beta cell function and survival). NeuroD is an evolutionarily conserved regulatory factor that is critical for development of the pancreatic islet in mouse and humans. NeuroD-null mice die of severe diabetes shortly after birth due to the loss of their beta cells, and homozygous mutations of NEUROD in humans are responsible for neonatal diabetes. Interestingly, heterozygous mutations in NEUROD predispose individuals to develop maturity onset diabetes of the young (MODY6), suggesting there is also a critical role for NeuroD in the function of adult beta cells. To determine the beta cell function of NeuroD, we have generated mice in which neuroD is deleted in the adult beta cells. These mice are severely glucose intolerant and display greatly reduced insulin secretion. In this application, we propose to elucidate the precise role of NeuroD in regulating beta cell function and insulin gene expression.

Gaining a greater understanding of the role of NeuroD in regulating the pathophysiology of the beta cell will allow us to devise new protocols to maintain the functionality of beta cells in vivo and ex vivo. In addition, we should be able to use this knowledge to develop new methods to promote and maintain the maturation state of a functional beta cell in vitro, currently a rate limiting obstacle in in vitro beta cell differentiation protocols. Finally, these studies could also lead to the identification of methods to correct the defects associated with mutations in NeuroD that lead to a MODY phenotype.

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

One of the major components of Type 2 diabetes is beta cell dysfunction. The more we understand about how a beta cell functions to secrete insulin in response to glucose and other secretagogues, the better equipped we will be to repair dysfunctional beta cells using small molecules, drugs, or gene and protein therapies. We have shown that NeuroD is not only critical for the survival of beta cells, but also regulates the ability of beta cells to secrete insulin in response to glucose. Our research will begin to elucidate the mechanisms by which these processes are regulated and will identify novel pathways and molecules that can be targeted by drugs to optimize beta cell functions. Alternatively, they may reveal ways to reverse or correct the beta cell dysfunction that is associated with diabetes.

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 worked in the Diabetes field since the beginning of my career as an independent investigator. My grandmother was a type 2 diabetic and my cousin was a type 1 diabetic, and my interactions with them and their struggles impacted my choice to enter this career. Furthermore, during my entire career, my lab has been situated within a Diabetes center, first at the Barbara Davis Center in Colorado and now at the Naomi Berrie Center at Columbia University. My association with these outstanding clinical and research centers has continued to reinforce my belief that diabetes is a serious and growing disease, but with greater research efforts, we will gain greater understanding of how the beta cell develops and functions to aid in the development of treatment and cures.

What is most important about this award is that it enables me to support a highly talented postdoctoral scientist from Europe. With the current funding situation for research, it is difficult to secure funding for American postdocs and almost impossible to find funding for non-US postdocs. This award has allowed me to hire a very talented postdoc from Germany who can efficiently and independently move this project forward and develop her career as an independent scientist in the diabetes field.

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

With the exciting new technologies that are emerging with regards to genomics, high throughput sequencing, imaging, stem cells, cellular reprogramming and epigenetics, I believe we will see a surge in advancements in many aspects of diabetes research. All of these technologies facilitate our understanding of the genetics associated with diabetes and are allowing us to improve diagnosis and treatments. These advances will improve our ability to develop disease interventions and will improve the outcomes of diabetic patients.