The maintenance of intracellular and extracellular glucose concentrations are critical to the normal function and survival of complex multi-cellular organisms. The process is tightly regulated by the endocrine system, and in part, by the integrated function of insulin and glucose with the facilitative glucose transport proteins. Dysregulation of the mechanisms controlling the complex pathways mediating whole body glucose disposal could contribute to the etiology and pathophysiology of diabetes by impairing the function of the insulin producing P-cell or by causing peripheral insulin resistance. The plasma membrane is impermeable to glucose, the cellular uptake of this important nutrient is therefore accomplished by carrier proteins located in the plasma membrane that bind glucose and transfer it across the lipid bilayer. Two classes of glucose carriers have been described have been described in mammalian cells: the Na-glucose co-transporter and the facilitative glucose transporter. cDNA clones encoding the Na+ glucose co-transporter expressed in rabbit, and human small intestine have been isolated and characterized. A similar protein may be expressed in kidney. Facilitative glucose transporters, on the other hand, are widely distributed and are present on the surface of probably all mammalian cells. cDNAs encoding the different facilitative glucose-transporter isoforms have been isolated: GLUTI (human/rat/rabbit/pig/mouse); GLUT2 (human/rat/mouse); GLUT3 (human); GLUT4 translation termination signals, and does not encode for an expressed protein. An apparent glucose transport protein located in the endoplasmic reticulum termed GLUT7 has been identified as a component of the glucose-6-phosphatase complex in rat liver, but its existence has recently been questioned. Epidemiological studies have implicated hyperglycemia as an important causal factor for the initiation and progression of vascular dysfunction and disease. A key limiting step in the control of intracellular glucose and its metabolism is the rate of glucose uptake from the extracellular fluids. Whereas many of the studies on the characterization and regulation of glucose transport and transporters concentrated on tissues directly 'Involved in glucose homeostasis, these parameters have not been characterized in detail with vascular cells, where modulation of transport activity may be related to the development of diabetic vascular complications. From an observation in our laboratory of a novel glucose transport system in a capillary endothelial cell time differentially regulated by insulin and IGF-1, we have hypothesized that microvasculature plays a critical role in glucose homeostasis. Our long-term objective is molecular characterization of the glucose transporter in capillary endothelial cells and establish its relationship to Type I diabetes. The hypothesis we want to test through the Pilot Study proposed here is that (a) capillary endothelial cell glucose transporter is different from the family of the previously identified glucose transporter proteins; (b) its expression is cell cycle dependent and is developmentally regulated; and (c) adrenal medullary endothelial cells from diabetic rats as well as the microvascular endothelial cells from muscle biopsies from pediatric patients with Typ1 diabetes express quantitatively less or altered glucose transporter. The project upon completion will help in designing the strategies by which fundamental biochemical knowledge can be used to diagnose Type I diabetes. We will also train the residents/clinical fellows to work in a biochemistry/cell and molecular biology, laboratory, and will have opportunities to work together with the doctoral level graduate students/scientists.
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