Rohit N. Kulkarni, M.D., Ph.D.
Dr. Rohit N. Kulkarni, M.D., Ph.D., is a Principal Investigator in the Section on Islet Cell and Regenerative Biology at Joslin. He is also an Associate Professor of Medicine at Harvard Medical School. He received his medical degree from St. John’s Medical College and his doctoral degree from the Royal Postgraduate Medical School and University of London. After receiving his medical degree, he worked as a Clinical Registrar in the Diabetes Unit at Hammersmith Hospital in London, under the supervision of Stephen Bloom, M.D. At the same time, Dr. Kulkarni received the Weston Scholarship and the Overseas Research Student Award. After completing his doctoral degree, he was awarded the National Research Service Award (NIH) fellowship for postdoctoral training at Joslin Diabetes Center under the mentorship of C. Ronald Kahn, M.D. In 1999 he received the Mentored Clinical Scientist Development Award (K08) from NIH. Most recently Dr. Kulkarni was awarded the 2007 Endocrine Society Ernst Oppenheimer Award for Outstanding Work by a Young Investigator. He serves on the Editorial Boards of the Journal of Clinical Investigation and Diabetes.
Promoting growth and preventing death of insulin-producing beta cells is an important goal in the treatment of both type 1 and type 2 diabetes. Dr. Kulkarni focuses on understanding how beta cells grow in mice, and, by extension, in humans. His laboratory 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), Dr. Kulkarni’s 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. This approach may lead to strategies to generate new beta cells for transplantation and prevent beta cell death in islet grafts.
In new research on treating type 2 diabetes, Dr. Kulkarni is examining the interaction between leptin and insulin/IGF-1 molecular pathways. Leptin is a fat cell-derived protein that causes obesity when its activity is reduced in the body, as is often the case in patients with type 2 diabetes. His laboratory has been characterizing genetically engineered mice that lack leptin receptors in beta cells to examine a potential link between obesity and type 2 diabetes at the islet level. Knowledge gained from these studies may contribute to therapeutic targeting of protein defects relevant to type 2 diabetes in the context of obesity.
Ueki K, Okada T, Hu J, Liew CW, Assmann A,Dahlgren GM, Peters JL, Shackman JG, Zhang M, Artner I, Satin LS, Stein R, Holzenberger M, Kennedy RT, Kahn CR, Kulkarni RN. Total insulin and IGF-I resistance in pancreatic beta cells causes overt diabetes. Nat Genet 38:583-588, 2006.
Kulkarni RN, Jhala US, Winnay JN, Krajewski S, Montminy M, Kahn CR. PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance. J Clin Invest 114:828-836, 2004.
Du K, Herzig S, Kulkarni RN, Montminy M. TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver. Science 300:1574-1577, 2003.
Kulkarni RN, Holzenberger M, Shih DQ, Ozcan U, Stoffel M, Magnuson MA, Kahn CR. Beta-cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass. Nat Genet 31:111-115, 2002.
Kulkarni RN, Bruning JC, Winnay JN, Postic C, Magnuson MA, Kahn CR. Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell 96:329-339, 1999.