Contact Info Steinnun Baekkeskov, Ph.D. UCSF Diabetes Center 513 Parnassus Ave. HSW 1027A, Box 0534 San Francisco, CA 94143-0534 Tel: (415) 476-6267 Fax: (415) 502-1447 Email: s_baekkeskov@biochem.ucsf.edu

Dr. Baekkeskov’s research focuses on the structure, function, cell biology and immunopathology of three autoantigens in type 1 diabetes, the GABA synthesizing enzyme glutamate decarboxylase 65 (GAD65), a tyrosine phosphatase of unknown function, IA-2, and a glycosilated islet cell membrane antigen, glima 38 of unknown function. These proteins are intracellular membrane proteins, which are expressed in pancreatic ß cells and neurons. They are targets of autoimmune processes associated with destruction of pancreatic ß cells and development of type 1 diabetes. GAD65 is also a target of autoimmunity involved in a rare neurological disorder, stiff-man syndrome. In pancreatic ß cells and neurons, GAD65 is synthesized as a hydrophilic molecule, which undergoes post-translational modifications to become membrane anchored. The Baekkeskov group has shown that a membrane anchoring signal and a Golgi targeting signal mediate the anchoring of the protein to the cytosolic face of Golgi membranes. In neurons, a palmitoylated trafficking signal regulates the exit of GAD65 from the trans-Golgi network to sorting endosomes where it enters a novel pathway that selectively targets the protein to presynaptic clusters in axon termini.  The Baekkeskov lab studies this novel pathway in ß cells and neurons and its role in targeting of the three autoantigens.
GAD65 synthesizes the inhibitory signaling molecule, GABA in neurons and in pancreatic ß cells. In the brain, the Baekkeskov lab has shown that GABA synthesized by GAD65 is required for fine tuning of inhibitory neurotransmission. The function of GABA in the pancreatic ß cell is, however, less clear. Results obtained in a transgenic mouse model expressing elevated levels of GAD65 and GABA in ß cells suggest that GABA secreted by ß cells is an autocrine inhibitor of first phase insulin secretion. The Baekkeskov lab is studying the mechanism by which GABA exerts this inhibition. 
Circulating autoantibodies to GAD65, IA-2, and/or glima 38 can be detected several years before clinical onset of type 1 diabetes, and can be used to detect individuals at risk of developing the disease. Furthermore, these proteins can potentially be used for immune therapeutic purposes to block or prevent autoimmune ß cell destruction. The Baekkeskov lab is developing a new animal model of type 1 diabetes to facilitate the development of antigen specific immune preventive methods to halt or block ß cell destruction and development of diabetes.

Selected Publications:

Schwartz, H., Chandonia, J-M., Kash, S. F., Tunnell, E., Domingo, A., Cohen, F., Banga, J. P., Madec, A.-M., Richter W., and Baekkeskov, S. High resolution epitope mapping and structural modeling of human glutamic acid decarboxylase 65. J. Mol. Biol. 287, 983-999 (1999).

Roll, U., Turck, C.W., Gitelman, S.E., Rosenthal, S.M., Nolte, M.S., Masharani, U., Ziegler, A.-G., and Baekkeskov, S.  Peptide mapping and characterization of glycosylation patterns of the glima 38 antigen recognized by autoantibodies in Type 1 diabetic patients. Diabetologia, 43, 598-608 (2000).

Shi, Y., Kanaani, J., Menard-Rose, V., Ma, Y-H., Chang, P-Y, Hanahan, D., Grodsky, G., and Baekkeskov, S. Increased expression of glutamic acid decarboxylase and GABA in pancreatic -cells impairs glucose-stimulated insulin secretion at a step proximal to membrane depolarization. Am. J. Physiol. Endocrinol. Metab. 279, 684-694, (2000).

Jaume, J. C., Parry, S. L., Madec, A.-M., Sønderstrup, G., and Baekkeskov, S. Suppressive effect of GAD65-specific autoimmune B lymphocytes on processing of T cell determinants located within the antibody epitope. J. Immunology 169, 665-672,  2002.

Kanaani, J., El-Husseini, A. E-D., Aguilera-Moreno, A., Diacovo, J. M., Bredt, D. S., and Baekkeskov, S. A combination of three distinct trafficking signals mediates axonal targeting and presynaptic clustering of GAD65. J. Cell Biol. 158, 1229-1238. 2002.