B.S. /M.S Heinrich-Heine University, Duesseldorf, Germany Ph.D. Heinrich-Heine University, Duesseldorf, Germany Postdoc. Washington University, St. Louis, Missouri
Production and secretion of insulin from the beta cells of the pancreas is stimulated by increases in blood glucose levels, after each meal and this process is essential for maintaining normal glucose homeostasis. Defects in glucose-regulated production and secretion of insulin lead to diabetes mellitus, which affects over 8% of the American population. Our laboratory is interested in understanding the molecular mechanisms by which changes in glucose levels regulate insulin production and pancreatic beta-cell function. The major projects in the laboratory are:
1. Glucose-regulation of insulin gene transcription in pancreatic beta cells.
Glucose-induction of insulin gene expression is regulated by a cooperative interaction of three beta-cell specific transcription factors, Pdx-1, MafA and NeuroD1. The long-term goal of this project is to understand how glucose modulates the function of Pdx-1, MafA and NeuroD1 to stimulate insulin gene expression.
2. Role of O-linked GlcNAc protein modification in the development of diabetes.
Elevated levels of O-linked GlcNAc protein modification in response to hyperglycemia has been proposed to contribute to the secondary complications associated with diabetes, including cardiovascular disease, kidney failure, blindness etc. However, the exact mechanisms by which increases in O-GlcNAc levels interfere with glucose homeostasis remain to be established. This project addresses the role of O-linked GlcNAc modification of proteins in regulation of beta-cell function in the pancreas.
3. Studies on microRNA function in pancreatic beta cells.
MicroRNAs (miRNAs) are small non-coding ribonucleotides, that bind mRNAs and function as translational inhibitors. MiRNAs have been shown to be involved in many diseases including cancer, neurodegeneration and diabetes. We have identified several glucose-regulated miRNAs from pancreatic beta cells and are currently studying their function in insulin production and secretion.
In summary, the information obtained in pursuit of these projects should significantly advance our understanding of how glucose regulates insulin production and insulin secretion in pancreatic beta cells, and should enable the development of new strategies for the treatment and prevention of diabetes.
Mosley, A. L., and S. Özcan. 2003. Glucose regulates insulin gene transcription by hyperacetylation of histone H4. J. Biol. Chem. 278:19660-19666. PMID: 12665509. Mosley, A. L., Corbett, J. A., and S. Özcan. 2004. Glucose regulation of insulin gene expression requires the recruitment of p300 by the beta-cell specific transcription factor Pdx-1. Mol. Endocrinol.18:2279-2290. PMID: 15166251. Mosley, A. L., and S. Özcan. 2004. The pancreatic duodenal homeobox-1 protein (Pdx-1) interacts with histone deacetylases Hdac-1 and Hdac-2 on low levels of glucose. J. Biol. Chem. 279:54241-54247. PMID: 15496408. März, P., J. Stetefeld, K. Bendfeldt, C. Nitsch, J. Reinstein, R. L. Shoeman, B. Dimitriades-Schmutz, M. Schwager, D. Leiser, S. Özcan, U. Otten and S. Özbek. 2006. Ataxin-10 interacts with O-linked β-N-acetylglucosamine transferase in the brain. J. Biol. Chem. 281:20263-20270. PMID: 16714295. Vanderford, N. L., S. S. Andrali, and S. Özcan. 2007. Glucose induces MafA expression in pancreatic beta cell lines via the hexosamine biosynthetic pathway. J. Biol. Chem. 282: 1577-1584. PMID: 17142462. Andrali, S. S., Q. Qian and S. Özcan. 2007. Glucose mediates the translocation of NeuroD1 by O-linked glycosylation. J. Biol. Chem. 282:15589-15596. PMID: 17403669. Andrali, S., Sampley, M. L., Vanderford, N. L., and S. Özcan. 2008. Glucose Regulation of Insulin Gene Expression. Biochem. J. 415:1-10. PMID: 18778246. Tang, X., L. Muniappan, G. Tang and S. Özcan. 2009. Identification of glucose-regulated miRNAs from pancreatic beta cells reveals a role for miR-30d insulin transcription. RNA. 15:287-293. PMID: 19096044. Özcan, S., S. S. Andrali, J.E.L. Cantrell. 2010. Modulation of transcription factor function by O-GlcNAc modification. Biochem. Biophys. Acta. 1799:353-364. PMID: 20202486 Sampley, M.L, and S. Özcan. 2012. Regulation of insulin gene transcription by multiple histone acetyltransferases. DNA Cell Biol. 31:8-14. PMID: 21774670 Cantrell Stanford, J., A.J. Morris, M. Sunkara, G.J. Popa, K.L. Larson, and S. Özcan. 2012. Sphingosine 1-Phosphate (S1P) regulates glucose-stimulated insulin secretion in pancreatic beta cells. J. Biol. Chem. 287: 13457-13464. PMID: 22389505. Zhao, X., R. Mohan, S. Özcan, and X. Tang. 2012. MicroRNA-30d induces insulin transcription factor MafA and insulin production by targeting mitogen-activated protein 4 kinase4 (MAP4K4) in pancreatic beta cells. J. Biol. Chem. 287: 31155-31164. PMID: 22733810.