Hongju Wu, PhD
Tulane University School of Medicine
Associate Professor, Department of Medicine, Section of Endocrinology
Islet cell regeneration and intra-islet GLP-1 production in diabetes
Dr. Hongju Wu obtained her B. S. in Biochemistry from Wuhan University (China) in 1992, M. S. in Molecular and Cell Biology from Shanghai Institute of Cell Biology, Chinese Academy of Science in 1995, and Ph.D. in Neurobiology at the University of Alabama at Birmingham (UAB) in 2001. She continued her postdoc training at UAB in the field of gene therapy, and became a faculty member in 2003. She was recruited by the Endocrinology section in the Department of Medicine, Tulane University as an Associate Professor in December 2011. Her laboratory explores gene therapy and islet transplantation strategies for the treatment of diabetes. In addition, she is interested in islet cell biology involving the mechanisms of islet cell regeneration, and GLP-1 action in glucagon-producing alpha cells.
Ongoing research projects:
- Exploring novel strategies to promote the survival and regeneration of insulin-producing beta cells for the treatment of type 1 diabetes.
Type 1 Diabetes (T1D) results from insufficient insulin secretion that is caused by the lack of insulin-producing beta cells in pancreatic islets. A major focus of our laboratory has been to explore novel strategies to protect the beta cells and/or promote beta cell regeneration. One of the strategies is to introduce an anti-apoptotic and proliferation-inducing therapeutic gene, Akt1, into beta cells. We have achieved high Akt1 gene delivery efficiency into the beta cells, and examined its efficacy in vivo. Currently we are exploring this strategy in the context of islet transplantation. Another strategy our lab has been working on is to transdifferentiate glucagon-producing alpha cells into insulin-producing beta cells by manipulating their transcription factors. We have successfully turned off glucagon expression and turned on insulin expression in an alpha cell line using the transcription factor Pax4. We are now attempting to apply this strategy in diabetic mouse models to see whether it has any therapeutic effect.
- Proliferation of glucagon-producing alpha cells in diabetes development and incretin treatment.
Glucagon-producing alpha cells play a major counterpart role to the insulin-producing beta cells in the regulation of blood glucose homeostasis. Our previous studies have found alpha cells proliferate/ regenerate significantly when beta cells are destroyed. One of our ongoing projects is to elucidate the mechanisms of alpha cell regeneration. Interestingly, a recent study indicated that incretin-type drugs for diabetes treatment (i. e., the drugs based on GLP-1 action) may cause alpha cell hyperplasia. Although the results are highly controversial, it raised an important question regarding whether incretins impact alpha cell proliferation, which has not been studied systemically before. We have set forth to investigate this matter using linagliptin (developed by Boehringer Ingelheim), a DPP4 inhibitor that prolongs GLP-1 half-life thus enhancing endogenous GLP-1 activity. Additionally, we will evaluate whether linagliptin affects the GLP-1 va glucagon production in alpha cells (see below).
- GLP-1 production in pancreatic alpha cells and its regulation of glucagon secretion.
GLP-1 (glucagon-like peptide 1) shares the same precursor, proglucagon, with glucagon. It has been commonly believed that GLP-1 and glucagon are derived by tissue-specific posttranslational processing: in instestinal L-cells proglucagon is processed by prohormone convertase 1/3 (PC1/3) to give rise to GLP-1, while in pancreatic alpha cells, proglucagon is processed by prohormone convertase 2 (PC2) to form glucagon. However, several recent studies have indicated the possibility of GLP-1 production in pancreatic alpha cells. In agreement with these studies, we have also detected GLP-1 production in alpha cells. In addition, we found GLP-1 vs glucagon production in alpha cells can change with diabetes development. We are investigating this matter in more detail. We aim to tackle the mechanisms that regulate GLP-1 and glucagon production in alpha cells.
Genevieve E. Fava, PhD - Post-Doctoral Fellow
Yangqing Zhang, MD, PhD - Post-Doctoral Fellow
Thomas J. O’Malley, BS - Medical Student
Boehringer Ingelheim Pharmaceutical Inc.
Juvenile Diabetes Research Foundation (JDRF)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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