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LIPID REGULATED KINASES IN INSULIN ACTION


Biography

Overview
Mechanisms that underlie clinical insulin resistance will only be clarified when we more fully understand how insulin controls metabolic processes, in particular, glucose transport. During the past decade, it has become increasingly clear that bioactive lipids and lipid- regulated signalling factors play important roles in the mechanisms whereby insulin controls glucose transport and other metabolic processes in muscle and adipose tissues. From very recent findings, it also appears that: (a) small G-proteins, Rho and ARF, are involved in the activation of certain insulin-sensitive lipid-signalling pathways; (b) protein kinase C-zeta (PKC-zeta) is rapidly activated by insulin; and (c) both Rho and PKC-zeta may play an important role in glucose transport. The hypothesis that will be tested presently is that glucose transport is regulated, at least in part, by insulin-induced alterations in: (a) phosphatidylinositol (PI) 3-kinase and a functionally inter- related small G-protein, Rho; (b) bioactive lipids, most notably, D3-PO4 derivatives of PI; and (c) downstream protein kinases, including PKC- zeta. We postulate that insulin, through PI 3-kinase, regulates Rho and PKC-zeta and both Rho and PKC-zeta, in turn, are required for, and may actively participate in GLUT4 translocation and glucose transport (see Fig. 1). We also postulate that GTPgammaS can enter this signalling pathway by activating Rho and PI3-kinase.

The specific aims are to: 1. Define the role of PI 3-kinase during insulin-induced activation of Rho. 2. Determine whether Rho is upstream of PKC-zeta in the action of insulin or GTPgammaS. 3. Define the role of PI 3-kinase in insulin-induced activation of PKC-zeta. 4. Examine the roles of PKC-zeta and Rho in insulin-stimulated glucose transport.
R01DK038079
FARESE, ROBERT V

Time
1987-08-01
2002-12-31
Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.