My laboratory uses stem cells to investigate the cellular and molecular biology of diabetes, and to develop cell replacement therapies for diabetics. Diabetes is a disorder characterized by a loss of beta cell mass, and/or a loss of beta cell-autonomous function, leading to a deficiency of insulin and deranged regulation of blood glucose. Diabetes can be caused by mutations in single genes required for beta cell formation or function, such as KCNJ11 and SUR1, subunits of a potassium channel, GCK, a glucose phosphorylating enzyme, HNF1alpha, a transcription factor, WFS1 and PERK, both involved in the unfolded protein response. Using stem cell and iPS reprogramming technologies, we are now able to generate insulin-producing cells in vitro to generate cellular models of diabetes that reflect cell-autonomous defects in beta cell function. Such a disease model enables the direct analyses of the molecular physiology in these otherwise inaccessible cells, and allows testing strategies to improve beta cell function. Our aim is to apply these models to the study of type 1 diabetes and type 2 diabetes. The in vitro environment purposefully eliminates immune-mediated effects that are clearly important in T1D, and peripheral insulin resistance that is important in type 2 diabetes. The ability to compare beta cells of different subjects in the same environment should allow the identification of beta cell intrinsic factors that contribute to beta cell dysfunction in these more common forms of diabetes.
Yamada, M., Johannesson, B., Sagi, I., Burnett, L., Kort, D.H., Prosser, W., Paull, D., Nestor, M., Freeby, M., Greenberg, E., Goland, R.S., Leibel, R.L., Solomon, S.L., Benvenisty, N., Sauer, M., and Egli, D.
Human ooyctes reprogram adult somatic cells to diploid pluripotent stem cells Nature, in press, DOI 10.1038/nature13287. :. (2014)
Shang, L., Hua, H., Foo, K., Martinez, H., Watanabe, K., Zimmer, M., Kahler, D., Freeby, M., Chung, W., LeDuc, C., Goland, R., Leibel, R., and Egli, D.
Beta cell dysfunction due to increased ER stress in a stem cell model of Wolfram syndrome. Diabetes, , doi 10.2337/db13-0717. Nov. 13, :. (2013 )
Hua, H., Shang, L., Goland, R., Leibel,R., and Egli, D.
iPS derived beta cells model diabetes due to glucokinase deficiency. J Clin Invest.doi:10.1172/JCI67638, June 17.:. (2013 )
Paull, D., Emmanuele, V., Hirano, M., Sauer, M. and Egli, D
Nuclear genome transfer in human oocytes eliminates mitochondrial DNA variants. Nature, doi: 10.1038/nature11800. Dec. 19,:. (2012)
Noggle, S., Fung, H., Gore, A., Martinez, H., Crumm, C., Prosser, R., Oum, K., Paull, D., Druckenmiller, S., Freeby, M., Greenberg, E., Zhang, K., Goland, R., Sauer, M., Leibel, R., and Egli, D.
Human oocytes reprogram somatic cells to a pluripotent state. Nature. Oct5;478(7367):70-5. (2011)