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Hasty, R. Schrastöder, K. Wiede, H. Schröder, M. J. Koffenburg, E. Sjöld-Wimmer, M. J. Maier, H. A. Lindzen, M. S. Srivastava, T. Fransen. L. H. Karp, M. A. Svenskev, and H. Ritter J.
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Schröder]. PNAS 02(16):3613-3641. Taken together as presented, the new role of PBP1β may serve as a novel regulator of glucose control and glucose homeostasis in animals, birds, and fish. While PBP1β is known to regulate glucose homeostasis through the ER receptor signal transduction and insulin signaling, the mechanisms of action of these receptors in humans have been poorly known. The proposal is focused on the role of PBP1β in insulin resistance in birds and fish tissues, as well as its components in rodents, on the development of diabetes and on muscle development in mice. The information obtained to date follows the basic framework of two phases of investigation in the project: 1. Basic investigations Define the role of PBP1β in establishing blood glucose homeostasis and propose a series of physiologic and pathologic processes for diabetes development. 2. Therapeutic approach Under the direction of the Project 1, we propose a novel and successful therapeutic approach in diabetes for the treatment and management of diabetes in mice. The proposed proposal seeks to build upon existing data published in animal and in human trials. In order to prepare and evaluate the proposal, we have developed a model system to obtain mice models of different forms of diabetes, which can be used for the study of glucose control in humans. The model is driven by interactions between the receptors of the two receptor types and several transcription factors known to regulate glucose metabolism. 3. Mechanism of action of PBP1β An established target for inhibitor as a therapeutic drug has been shown to interfere with insulin signaling, lipogenesis, and glucose homeostasis, by reducing the levels of multiple genes involved in muscle insulin like growth factor adhesion molecules, glycogen synthase kinase 3 receptor, MAP kinase, insulin-like growth factor 1 (IGF-1), and insulin receptor substrate-binding protein (RBP). Another experimental approach is in glucose biosynthetic pathway [Chu Jiang, P. K. Dai, P. A. Zhang, M. Gipratis, S.
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V. Pancer, W.-W. Song, M. R. Heppner, A. P. Gossage, S. G. Li, R. H. Malkapin, J. Carradine, R. L. De Carlo, C. C. Dixit
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