Rohit N. Kulkarni

Department of Cell Biology
Joslin Diabetes Center
One Joslin Place, Room 602
Boston, MA 02215
Tel: (617) 713-3460
Fax: (617) 713-3476
Email: rohit.kulkarni@joslin.harvard.edu
5 postdoctoral fellows, 2 research assistants

My laboratory is focused on the following areas:

THE ROLE OF PROGENITORS/STEM CELLS IN THE REGENERATION OF ß-CELLS Our recent studies indicate the presence of potential stem cells/progenitors within the islet itself that may play a role in the regeneration of beta cells in the adult organism. Several approaches including lineage trace analyses, transplantation, and parabiosis are being undertaken in genetically engineered mice to address this possibility. A related area of research focuses on understanding the pathways that modulate the life cycle of ß-cells.

THE ROLE(S) OF INSULIN/IGF-I SIGNALLING MECHANISMS IN REGULATION OF ISLET CELL GROWTH, APOPTOSIS AND ß-CELL REPLICATION.
Several studies, including our own, suggest that insulin/IGF-I signaling plays crucial roles in modulating islet function by regulating glucose sensing, protecting against beta cell death and in regulating the expression of transcription factors. Using the Cre-LoxP and FLP/Frt techniques, we have created genetic models to examine the roles of insulin and IGF-1 receptors in islet biology - e.g., we have created beta- and alpha-cell-specific insulin receptor and IGF-1 receptor knockouts. These in vivo models complement the in vitro models including primary islets from humans and rodents and beta cell lines derived from the knockouts. Using these powerful and unique reagents we are dissecting cross-talk between insulin, IGF-I and glucose signaling pathways in islet cells. A major effort is being directed towards evaluating specificity of insulin versus IGF-I signaling in beta-cell growth and apoptosis (ER stress) during embryonic and adult life. Together, these studies will provide critical information in two major ways - first, it will allow us to develop therapeutic strategies to prevent beta cell death and to examine alternative approaches to generate new beta cells for countering type 1 diabetes. Second, these studies will open new avenues to prevent beta cell failure in type 2 diabetes.

MECHANISMS THAT LINK TYPE-2 DIABETES AND OBESITY AT THE LEVEL OF THE ISLET.
Although the high incidence of type 2 diabetes in obese individuals is well documented, the mechanisms that promote islet dysfunction in these individuals are not understood. We propose a potential link between leptin signaling and insulin/IGF-I regulated pathways that can modulate glucose signaling, at the level of the islet, and participate in mechanisms that regulate islet function and growth. This hypothesis is being examined using beta-cell-specific insulin and/or IGF-1 receptor knockouts and leptin receptor (ObRb) knockout mice and studying pathways that link leptin/insulin signaling with individual pathways that utilize PPARgamma, PGC1alpha and TRB3 in islets

References:

• Kulkarni RN, Bruning JC, Winnay JN, et al. Tissue-specific knockout of the insulin receptor in the pancreatic beta-cell creates an insulin secretory defect similar to that in type 2 diabetes. Cell 96:329-339, 1999.
• Kulkarni RN, Holzenberger M, Shih D, et al. beta-cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass. Nature Genetics 31:111-115, 2002.
• Ueki K, Okada T, Hu J, Liew CW, Assmann A, ..... Kulkarni RN. Total insulin and IGF-1 resistance in pancreatic ß-cells causes overt diabetes. Nature Genetics, 2006
• Okada T, Liew CW, Hu J, Hinault C, ..... Kulkarni RN. Insulin receptors are critical for islet compensatory ß-cell growth response to insulin resistance. Proc Natl Acad Sci USA 104:8977-8982, 2007