The metabolic abnormality of diabetes mellitus first appreciated and the most clinically notable sign of the disease is an elevation in blood glucose, due, in part, to a lack of insulin's stimulatory action on the clearance of sugars in peripheral tissues. Patients with Type II diabetes mellitus invariably display some degree of resistance to the affect of insulin on increasing glucose uptake. It is now recognized that there exists a family of genes which encode distinct, integral membrane glycoproteins which catalyze the stereospecific transport of hexoses. About 10 years ago, it was postulated that insulin augments glucose transport by causing the redistribution of carrier proteins from a still poorly-defined intracellular organelle to the cell surface. In the broadest terms, the major goal of these studies is to understand in molecular detail the mechanism by which insulin regulates the rate of facilitated glucose uptake into mammalian cells. This problem encompasses both the process by which an insulin-responsive peripheral target tissue, i.e. muscle or adipose tissue, in the course of cellular differentiation acquires the capacity to respond to the hormone with a substantial, rapid increase in glucose transport, as well the precise biochemical pathway by which binding of the hormone to its receptor leads to an increase in hexose flux. Initially, the process by which insulin induces the redistribution of transporters will be assessed quantitatively and the precise site of regulation by insulin, exocytosis or internalization, identified. In addition, the pathways by which the transporter is targeted to the insulin-regulated vesicle will be defined. For these experiments, it will be necessary to construct a mutant transporter recognizable from the extracellular surface of an intact cell. Next, the amino acid sequences contained within the. muscle/adipose tissue transporter isoform, GLUT4, that allow it to be exquisitely responsive to insulin will be identified; it is likely that this will represent a signal for the sorting of GLUT4 to the hormone-responsive organelle. Finally, an effort will be made to understand how the expression of the GLUT4 gene is regulated during two important conditions: when it is turned on in the course of cellular differentiation into an insulin-responsive tissue, and when it is turned off in diabetes mellitus, creating a state of insulin resistance.
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