M. Alan Permutt, M.D.

DEPARTMENT OF Internal Medicine
Keywords: diabetes, gene expression, genome analysis, signal transduction, insulin gene transcription

Current projects include: Mechanisms for Premature Death of Islet Beta Cells in Wolfram Syndrome - We collected families with individuals having Wolfram Syndrome, a rare form of juvenile-onset diabetes, and positionally cloned the Wolfram gene (WFS1). We engineered mice with targeted disruption of WFS1 to develop an animal model for the disease. We are now assessing this gene’s role in protecting islet beta cells from ER stress induced apoptosis. Genetic Basis of Type 2 diabetes (T2D) - 300 families of Ashkenazi Jewish descent were collected. A whole genome scan identified regions of genetic susceptibility. Linkage disequilibrium mapping with SNPs identified multiple genes contributing to the risk for diabetes. We are now focusing on young onset familial T2D occurring disproportionately in minority populations. Functional Genomics of the Developing Endocrine Pancreas - We are collaborating with Harvard, the University of Pennsylvania, and the GSC at Washington University. To date over 40 pancreas and islet cDNA libraries have been constructed. Over 90,000 ESTs have been contributed to public databases (http://www.ncbi.gov). Novel mouse and human cDNAs have been arrayed for global gene expression profiling. Control of Insulin Biosynthesis - We demonstrated that glucose leads to transcriptional activation of early response genes in islet beta-cells. Nutrients promote beta cell survival through an Akt/PI3-kinase dependent survival pathway. Transgenic mice expressing a constitutively active Akt1 linked to an insulin gene promoter exhibited increased islet mass. Understanding signaling pathways involved in beta cell survival and growth can help in developing new targets for intervention.