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Metabolic Pathways of Type 2 Diabetes: Intersection of Genetics, Transcriptomics, and Metabolite Profiling

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Date
2008-07-25
Author
Ferrara, Christine Therese
Advisor
Newgard, Christopher
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Abstract

Type 2 diabetes is characterized by insufficient insulin secretion to maintain euglycemia in the setting of peripheral insulin resistance. The majority of insulin-resistant diabetics are obese, yet not all insulin-resistant obese individuals develop diabetes. This obesity/diabetes dichotomy suggests that genetic factors play a pivotal role in disease pathogenesis.

Gene mapping has identified genetic quantitative trait loci (QTL) influencing disease-related phenotypes. To uncover molecular pathways leading from genotype to clinical trait, we classify phenotypes in greater depth and identify QTL that influence combinations of physiological traits, mRNA levels, and metabolite abundance. A major challenge then becomes deciphering the causal interrelationships among correlated phenotypes.

In this dissertation, we develop methods for building causal direction into an undirected network by including QTLs for each phenotype. We then apply and validate these methods in an F2 intercross between the diabetes-resistant C57BL/6 leptinob/ob (B6ob/ob) and the diabetes-susceptible BTBR leptinob/ob (BTBRob/ob) mouse strains. We show that genomic analysis can be integrated with liver transcriptional and metabolite profiling data to construct causal networks for specific metabolic processes in liver. This causal network construction led to the discovery of a pathway by which glutamine induces Phosphoenolpyruvate carboxykinase (Pck1) expression.

To investigate glutamine induction of Pck1 in the context of diabetes, we perform mRNA expression analysis and metabolic profiling in liver of the parental strains. We find glutamine is decreased with obesity in both strains; in the diabetes-resistant B6 strain, liver Pck1 expression parallels glutamine abundance, but in the diabetes-susceptible BTBR strain, Pck1 is elevated with obesity. Follow-up in vitro studies indicate that α-ketoglutarate, which is elevated nearly two fold in the livers of BTBR relative to B6 mice in vivo, may mediate the glutamine effect. We hypothesize that hepatic Pck1 is regulated by glutamine abundance in the liver of B6 animals, but in the presence of high α-ketoglutarate, Pck1 becomes uncoupled from glutamine regulation in the livers of diabetes-susceptible BTBR mice.

Our method of causal network construction led to the discovery of glutamine induction of a key hepatic gluconeogenic enzyme, a pathway potentially disrupted in the diabetes-susceptible BTBR mouse. Future studies will include identifying hepatic mediators of the glutamine effect, and applying QTL-directed networks to multiple organs to ultimately define causal relationships between tissues involved in diabetes progression.

Type
Dissertation
Department
Pharmacology
Subject
Agriculture, Agronomy
genetics
transcriptomics
metabolites
diabetes
obesity
Permalink
https://hdl.handle.net/10161/694
Citation
Ferrara, Christine Therese (2008). Metabolic Pathways of Type 2 Diabetes: Intersection of Genetics, Transcriptomics, and Metabolite Profiling. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/694.
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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 United States License.

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