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The Metabolic Regulation and Vesicular Transport of GLUT4, the Major Insulin-Responsive Glucose Transporter^*

Boston University Medical Center, Department of Biochemistry Boston, Massachusetts 02118

Correspondence: Address reprint requests to: Paul F. Pilch, Ph.D., Boston University Medical Center, Department of Biochemistry, 80 East Concord Street, Boston, Massachusetts 02118.

Abstract

I. Introduction: GLUCOSE is the primary energy source for the brain under normal physiological circumstances and is acutely taken up by other mammalian cells for immediate use as metabolic energy or for storage as glycogen in liver and muscle. It also serves as a precursor to a variety of metabolites in many, if not all, tissues. Glucose is released into circulation from the liver in the fasting state as a result of glycogen breakdown and is used (oxidized) for the energetic needs of contraction in skeletal muscle. The entry of glucose into the blood is a function of the nutritional state of the mammalian organism, and the postprandial clearance of glucose from the circulation is tightly regulated by insulin. The mechanism of this regulation is the focus of this review. Since the cell membrane is impermeable to glucose, it is transported by specific carrier proteins or transporters that span the cell membrane and allow the binding and transfer of glucose across the hydrophobic lipid bilayer. Two general classes of glucose carriers have been described in mammalian cells: 1) the energy-dependent Na+/glucose cotransporter, which can concentrate glucose against a gradient, and 2) the facilitative glucose transporters, which work in the direction of the glucose gradient. The physiological function of the Na+/glucose cotransporter takes place in polarized epithelial cells where it transports glucose from the lumen of the intestine into the cell (1, 2). The subsequent facilitative transport of glucose out of the intestinal epithelium allows entry of glucose into the blood. The Na+/glucose cotransporter is also expressed in the kidney where it serves to retain glucose and prevent its spillage into urine. The entry of glucose into different tissues via facilitative glucose carriers must serve different physiological needs in these different tissues; these needs are met by a family of related transporter proteins, expressed in a tissue-specific manner, whose biochemical properties serve the appropriate physiological needs of the organism. These six proteins (and one pseudogene) are called GLUTs for glucose transporters. The focus of this review is GLUT4, the expression of which is limited to the major insulin target tissues of fat and cardiac and skeletal muscle where it serves as the major mediator of glucose uptake that responds to the hormone.

Footnotes

^* This work was supported in part by grants from the NIH (DK-30425 and DK-44269) and by a grant from the Juvenile Diabetes Foundation.

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