Insulin, beta-Arrestin 1, and GPCR Signaling

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Dr. Hupfeld is a clinically trained internist and endocrinologist, whose long-term career goals include conducting basic science research in the field of diabetes mellitus and teaching at a university medical school. The proposed funding period will enable him to fully develop research skills to be used as an independent scientist.. This training will occur in the outstanding environment of Jerry Olefsky's laboratory at the University of California(San Diego), with Dr. Olefsky serving as mentor. Through weekly lab meetings, close supervision by Dr. Olefsky, and the innumerable interactions with the many talented researchers in the Olefsky lab, Dr. Hupfeld will be provided with outstanding training in diabetes research. Beta-arrestin 1 is a critical protein involved in regulation of G protein-coupled receptor(GPCR) signaling. Binding of beta-arrestin 1 to many GPCRs leads to desensitization of Gs-mediated signal transduction. We have found that insulin treatment leads to dysfunction of beta-arrestin 1, and that this was associated with impaired desensitizaton of Gs-mediated signaling by the beta2 adrenergic receptor, a finding that has potential implications for dyslipidemia of type II diabetes mellitus. Beta-arrestin 1 is also important in promoting mitogenic signaling by many GPCRs. We have found that insulin-induced dysfunction of beta-arrestin 1 blocks mitogenic signaling by three GPCRs: the beta2 adrenergic receptor, the LPA receptor, and the IGF-1 receptor. Together, these findings indicate that insulin, through a mechanism involving dysfunction of beta-arrestin 1, can alter the signaling capabilities of several GPCRs. As dysregulation of GPCR signaling is a possible etiologic factor behind many of the components of the insulin resistance syndrome and type II diabetes mellitus, and insulin-induced dysfunction of beta-arrestin 1 can affect the signaling program of a wide variety of GPCRs, we feel this is an important new area of research. Thus the long-term goals of this proposal are 1)to expand our knowledge of the mechanisms behind the insulin resistance syndrome, and 2) to provide outstanding research training for Dr. Hupfeld, in the confines of a world-renowned diabetes research laboratory.