Ercument Dirice, PhD

Beta Cell Regeneration in Type 1 Diabetes (Grant # 3-2010-474)   September 2010

Transplantation of isolated pancreatic islets. This work was performed by Dr. Sevim Kahraman Dirice, at Gene & Cell Therapy Center, Faculty of Medicine, Akdeniz University, TURKEY.

Immunoflourescent staining of mononuclear cells infiltrating (blue) into pancreatic islets where insulin producing beta-cells (red) are localized. Infiltration induces pancreatic beta-cell replication rates (BrdU staining in green). Images were taken at Kulkarni Lab, Joslin Diabetes Center, Harvard Medical School, USA

IProposed sheme for the pathogenesis of type 1 diabetes. Published in “Islet Cell Growth Factors” under the section “Pathways Underlying beta-cell Regeneration in Type 1, Type 2 and Gestational Diabetes, 2011

Brightfield and Flourescent microscopy of AdEGFP transduced pancreatic islets.

I am currently working as a Postdoctoral Fellow in the section of “Islet Cell & Regenerative Biology” at Joslin Diabetes Center which is the world’s largest diabetes research center, diabetes clinic and provider of diabetes education. Since its founding in 1898, the Joslin Diabetes Center has constantly evolved to meet the ever-changing challenges of diabetes. The Joslin is an institution on the front lines of the world epidemic of diabetes, leading the battle to conquer diabetes in all of its forms through cutting-edge research.

I received my MSc degree in 2003 as a research assistant in Medical Genetics at the Department of Medical Biology and Genetics and Human Gene and Cell Therapy Center of Akdeniz University Faculty of Medicine. During my MSc education my project was focused on the identification of novel markers to follow up the progression of prostate cancer. This research revealed a putative connection between the down-regulation of a novel tumor suppressor gene namely PTEN and the progression of prostate carcinoma.

After 2004, I studied as a PhD student in Medical Genetics. Our team was working on the role of Tumor Necrosis Factor-Releated Apoptosis Inducing Ligand (TRAIL) mechanism on cancer development.under the supervision of Prof. Dr. Salih Sanlioglu.  I have been studying the effect of TRAIL on rat/mouse pancreatic islet survival by using autoimmune diabetes mouse and rat models. My doctorate thesis was to develop novel gene therapy methods against type 1 diabetes. We have shown that the success of islet transplantation can be increased if complementary gene therapy modalities are employed prior to transplantation. My thesis named “Adenovirus mediated TRAIL gene (Ad5hTRAIL) delivery into pancreatic islets prolongs normoglycemia in STZ-induced diabetic rats” was  published by “Human Gene Thearpy”, official journal of European Society of Gene and Cell Therapy (ESGCT)(October 2009). In addition, the journal announced that October 2009 journal cover award has been given to our study. After completing my doctoral degree, I  was awarded the “Novartis Research Award for Diabetes” fellowship for postdoctoral training at Joslin Diabetes Center under the mentorship Rohit N. Kulkarni, M.D. PhD.(July, 2009).

Dr. Kulkarni focuses on understanding how beta cells grow in mice, and, by extension, in humans. Kulkarni Lab is examining unique genetically engineered mouse models that lack receptors or proteins in growth factor signaling pathways. Dr. Kulkarni is particularly interested in crosstalk among insulin/insulin-like growth factor 1 (IGF-1)-signaling and glucose-signaling pathways in regulating the development, replication and function of islet cells. One of his most important and unexpected findings is that insulin and IGF-1 play crucial roles in glucose sensing, which triggers insulin secretion, and compensate for each other to maintain the viability of beta cells.

These findings have implications for treating patients with type 2 diabetes because most of these patients develop insulin resistance. Dr. Kulkarni’s research suggests a vicious cycle: Not only is the beta cell producing insufficient insulin, but the cell itself is also resistant to insulin, which prevents glucose sensing and in turn lowers insulin secretion. To examine whether the problem begins in the insulin receptor itself, the Kulkarni laboratory is now examining the kinetics of turnover of insulin and C-peptide synthesis in mutant mice lacking insulin receptors in beta cells

This research also extends to the study of type 1 diabetes from a novel perspective. Rather than seeing beta cell death as the result of an autoimmune process (the usual theory about type 1 diabetes), our laboratory is working on the hypothesis that even before the autoimmune problem begins, there is dysfunction in insulin/IGF-1 signaling and increased vulnerability of beta cells to stress.In addition we are studying the pathways utilized by lymphocytes that allow regeneration in beta-cells in type 1 diabetes using NOD mice.

These studies will provide critical information on several fronts - first, it will allow us to gain greater insights into the fundamental physiological mechanisms that govern the normal growth and functioning of pancreatic islets; second, it will provide a physiological basis to identify targets in signaling pathways that would be useful to design potential therapeutic strategies to prevent beta cell death and to plan alternative approaches to generate new beta cells to prevent and/or cure type 1 and type 2 diabetes.