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dc.contributor.advisorGregory Stephanopoulos.en_US
dc.contributor.authorAlemán, José O. (José Orlando)en_US
dc.contributor.otherHarvard University--MIT Division of Health Sciences and Technology.en_US
dc.date.accessioned2008-12-11T16:56:48Z
dc.date.available2008-12-11T16:56:48Z
dc.date.copyright2008en_US
dc.date.issued2008en_US
dc.identifier.urihttp://hdl.handle.net/1721.1/43743
dc.descriptionThesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2008.en_US
dc.descriptionThis electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.en_US
dc.descriptionVita.en_US
dc.descriptionIncludes bibliographical references (p. 289-300).en_US
dc.description.abstractMetabolic diseases are an increasing health concern in the developed world. Type 2 Diabetes, (T2D) affects over 100 million people worldwide and significantly contributes to chronic diseases such as atherosclerosis and kidney failure. This condition is characterized by deregulation of glucose homeostasis through the development of insulin resistance, manifested as increased glucose production in the liver. Hepatic gluconeogenesis provides de novo formation of glucose from three carbon precursors such as glycerol, lactate, pyruvate and alanine. The upregulation of this pathway underlies the persistent hyperglycemia observed in diabetic patients. We have developed stable isotope tracer methods to reconstruct hepatic glucose production fluxes by infusion of [13C, 2H]-glycerol and mass spectrometry analysis of plasma metabolites. Using this methodology we observe physiologic changes in liver cell lines and primary hepatocyte cultures in the presence of hormones insulin/glucagon and in response to gluconeogenic precursor availability. We put forth the hypothesis that in the presence of glycerol as a gluconeogenic substrate, glucose-6-phosphatase has an important role in modulating metabolic flux through upper gluconeogenesis. Infusion of simultaneous tracer combinations in vivo including a novel [U-13C,2H5]-glycerol allow detailed net flux and reversibility reconstruction of upper gluconeogenesis to an unprecedented degree in a single experiment. We deployed the developed methods to probe glucose overproduction in the liver insulin receptor knockout (LIRKO) transgenic model of Type 2 Diabetes, and found unexpected similarities in the metabolic flux profile not observed by genomic, protein or metabolite measurements.en_US
dc.description.abstract(cont.) Our results underscore the importance of flux measurement as a physiologic parameter akin to gene and protein expression in revealing the metabolic phenotype of cells, tissues and organisms. These methods have the potential to contribute as clinical assays to characterize excess glucose production as well as in drug development for new targets to control hepatic glucose production.en_US
dc.description.statementofresponsibilityby José O. Alemán.en_US
dc.format.extent333 p.en_US
dc.language.isoengen_US
dc.publisherMassachusetts Institute of Technologyen_US
dc.rightsM.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.en_US
dc.rights.urihttp://dspace.mit.edu/handle/1721.1/7582en_US
dc.subjectHarvard University--MIT Division of Health Sciences and Technology.en_US
dc.titleGluconeogenesis as a system : development of in vivo flux analysis of hepatic glucose production in Type 2 Diabetesen_US
dc.title.alternativeDevelopment of in vivo flux analysis of hepatic glucose production in Type 2 Diabetesen_US
dc.typeThesisen_US
dc.description.degreePh.D.en_US
dc.contributor.departmentHarvard University--MIT Division of Health Sciences and Technology.en_US
dc.identifier.oclc263175720en_US


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