Leibel, Rudolph L
Molecular physiology of beta cells created from humans with monogenic forms of diabetes mellitus.
General Research Subject: Type 2 Diabetes
Focus: Genetics\Type 2 Diabetes, Islet Biology\Beta Cell Growth and Differentiation
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2011
Project End Date: June 30, 2015
It is now possible to make 'stem' cells from human skin or blood cells. These so-called 'iPS' cells have the capacity to develop into any cell type in the body. This end is achieved experimentally by coaxing iPS cells in the desired direction by exposing them to molecules designed to recapitulate the developmental process in the embryo. However, these developmental steps are not yet fully understood, especially for the insulin producing beta cell. The cells created so far partially replicate the functions of true beta cells. We want to improve the quality of such beta cells as a step towards being able to use such cells to study the most fundamental bases for the development of diabetes and, ultimately, to generate cells that could be transplanted into humans as substitutes for cells lost to the disease. How will we know when we have made a 'genuine' beta cell? A critical test will be: does the beta cell made from skin of a patient with a form of diabetes due to a single gene mutation recapitulate precisely the abnormalities detected in the metabolism of that patient? If so, we will know that we have made a beta cell that is 'true' to its underlying genetic constitution. Achievement of this goal will enable the of study the molecular basis for these rare forms of diabetes, but, more importantly, assure us that cells derived from patients with diabetes of more complex etiology -- e.g. type 1 and type 2 --can be used in a similar way.
Mentor: Leibel, Rudolph, MD Postdoctoral Fellow: Hua, Haiqing
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
This project is aimed at creating insulin-producing cells from skin cells obtained by biopsy. Using a recently described technique called 'induced pluripotent stem cell' (iPS), we are causing skin cells grown in culture to revert to stem cell status. This status recapitulates that present in early embryonic cells that have the potential to develop into any cell type/organ in the body. Then, using a series of chemical steps, we 'coax' these stem cells to develop into insulin-producing (beta-like) cells. Both processes are still part science, part 'art'; in particular we and others are working on the development of better protocols for the creation of insulin-producing cells.
One series of experiments involves making such cells from the skin of patients with diabetes caused by mutations in genes that affect the development and/or function of the beta cell. Referred to as MODY (maturity onset diabetes of the young), these instances of diabetes resemble type 2 diabetes, but are due to single genes. In collaboration with clinicians in the Naomi Berrie Diabetes Center at Columbia, and with support of the Helmsley and NY Stem Cell Foundations, we have obtained skin cells from such subjects and converted them to insulin-producing cells and are studying these cells to assess the extent to which their biology reflects that seen in the patients. This is a critical step in confirming the validity of inferences reached by experimental use of such cells. We are also obtaining skin cells from patients with gestational diabetes and type 1 diabetes, and using these cells for similar purposes.
Our goals are: 1. To be able to recapitulate aspects of the pathogenesis of diabetes using cells created from subjects who actually have various forms of the disease. These cells can be used to determine the molecular bases for diabetes, and to test approaches to preventing or treating the disease. 2. Ultimately, cells created in this way could be used for transplantation into patients with diabetes.
These studies are aimed simultaneously at the creation of a resource (stem cells from patients with diabetes) that can and will be used to understand the molecular and functional bases for both type 2 and type 1 diabetes (as well as rarer instances of MODY). Such understanding, and the cells themselves, will enable development of new pharmacologic and cellular interventions for diabetes, and, ultimately, provide knowledge needed to prevent or cure these disorders.
Why is it important for you, personally, to become involved in diabetes research?
I am co-Director of the Naomi Berrie Diabetes Center at Columbia. I have a long standing interest in the regulation of body weight, and the contributions of obesity to the development of diabetes. As a physician, I have seen the physical, psychological and dollar costs of diabetes, and am committed to doing all that I can to eliminate the disease. As a pediatrician, I have been alarmed at the increase in incidence of type 2 diabetes in children, a recent development that bodes ill for the well being of communities around the world.
What role will this award play in your research efforts?
I have been fortunate to have ADA support via the Mentored Fellowship Program since 1995. I have used this award to fund fellows in research projects related to the related to body weight regulation and type 2 diabetes. Most of these individuals have been non-U.S. cititzens who were not eligible for NIH fellowships; the ability to support them using these ADA funds has been critical to my being able to help in the training of research scientists from around the world. Their productivity has been outstanding, and several have returned to their countries of origin to continue their research.
In what direction do you see the future of diabetes research going?
I believe that two areas of research will be particularly important:
1. The field will be increasingly focused on the biology of the beta cell, from both the perspective of its early development, and the impact of intrauterine environment on those processes, and the adverse consequences of peripheral insulin resistance, elevated blood glucose and fatty acids for beta cell performance.
2. The ability to control body weight, even to the extent of maintaining a modest 10% weight reduction, could prevent or reverse many instances of type 2 diabetes. The types of interventions needed to sustain a reduced body weight are quite different than those needed to induce weight loss. In many ways, the former is much more tractable than the latter. The biology of weight-reduced state is a research area that our group is certainly pursuing.
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