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Molecular Mechanisms for Insulin-Stimulated Glucose Transport: Regulation of Glut4 Translocation¹

Diabetes Unit, Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215

Abstract

Insulin stimulation of glucose uptake into muscle and adipose tissue is essential for glucose homeostasis and for normal growth and development. Insulin increases glucose transport by recruiting the facilitative glucose transporter, Glut4, from an in- tracellular vesicle pool to the plasma membrane. This occurs by an exocytotic process involving vesicle translocation, docking, fusion, and activation or exposure of Glut4 to the extracellular milieu. States of increased adiposity or diabetes in animals or humans are associated with resistance to insulin-stimulated glucose uptake. Investigations of the mechanisms reveal tissue-specific regulation of Glut4 with decreased gene expression in adipose cells but not in skeletal muscle. In obesity or diabetes, insulin resistance in skeletal muscle may result from alterations in the trafficking of the Glut4 vesicle or in the exposure or activation of Glut4. The molecular mechanisms regulating Glut4 trafficking include a complex network of intracellular signaling steps, as well as sequence motifs within Glut4 that target it to intracellular compartments. Furthermore, proteins that are involved in synaptic vesicle sorting and fusion have been identified in the Glut4 vesicle and may be involved in docking and fusion. Transgenic mice have been developed to help us understand how these mechanisms function in vivo and to assess the impact of altering Glut4 trafficking on body composition and whole body insulin action. Transgenic mice that overexpress Glut4 selectively in adipocytes have increased glucose tolerance and mild obesity due to adipocyte hyperplasia. Alternatively, mice that over-express wild-type p21-ras in adipoctyes are lean with increased insulin sensitivity; the mechanism at the cellular level involves increased translocation of Glut4 to the plasma membrane in adipocytes. Thus, altering the expression of Glut4 or of signaling molecules in insulin-sensitive tissues has important effects on nutrient partitioning and insulin action in whole animals.

Key Words: Glut4 • Insulin • Glucose Transport • Adipose Tissue • Muscle • Signal Transduction

¹ The authors thank P. R. Shepherd for allowing them to use Figure 1 and M. B. Muckian for assistance preparing the manuscript. K. Houseknecht was supported by a grant from the United States Department of Agriculture (940443). This work was supported by NIH grant DKR01-43051, USDA grant #9400703, and grants from the Juvenile Diabetes Foundation and American Diabetes Association (to B. B. Kahn).

² To whom correspondence should be addressed.