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Callahan Dissertation_2014.pdf (3.45 MB)

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The independent effects of chronic high-fat feeding and long-term denervation in relation to development of diabetes

Callahan, Zachary J
http://rave.ohiolink.edu/etdc/view?acc_num=miami1417439183

Abstract Details

2014, Doctor of Philosophy, Miami University, Biology.
Type 2 diabetes is a characterized by a variety of metabolic perturbations including reduced insulin sensitivity, increased plasma glucose levels, and metabolic inflexibility. However, there is a lack of information investigating the temporal transition from a healthy to a disease state. This dissertation describes two studies that examined the independent effects of obesity and inactivity on the pathophysiology of diabetes. The first study focused on inactivity, using denervation of the sciatic nerve to identify and describe the effects that prolonged inactivity has on glucose transport, insulin signaling, and expression of genes involved in regulation of mitochondrial transcription. Although GLUT4 mRNA expression was significantly lower in muscle from denervated mice at all time points, GLUT4 protein was lower only during the first 3 weeks. GLUT 4 protein expression was higher in both the 28 and 56 days post-surgery animals. Protein expression of Akt, was also elevated in tissue from denervated muscle. Genes involved in transcriptional regulators of metabolism, glycolysis, and fatty-acid transport were all significantly lower in denervated tissue. These results suggest that short-term results noted in previous denervation studies may not be representative of long-term effects of inactivity and that there may be compensatory mechanisms that improve glucose uptake. The second study investigated the effects that prolonged high-fat feeding would have on body composition, mitochondrial function, intramuscular triglyceride (IMTG) content, and glucose metabolism. Using a transgenic mouse model that is susceptible to the development of a diabetic phenotype, we demonstrated that high-fat fed mice had significantly greater body mass and IMTG than normal-chow fed mice. Results from a glucose tolerance test revealed a larger glucose area-under-the-curve in transgenic mice fed a high-fat diet, indicating that these animals were beginning to develop a diabetic phenotype. There was no significant difference in cytochrome C oxidase enzyme activity at any time point among any groups and citrate synthase activity was greater only in the 24-week high-fat fed transgenic mice. Finally, there was no difference in genes encoding transcriptional regulators of metabolism or fatty acid metabolism. These results suggest that high-fat feeding leads to obesity and changes in body composition with increases in IMTG content and decrements in glucose metabolism before evidence of mitochondrial dysfunction.
Paul Schaeffer (Committee Chair)
93 p.
Biology
Denervation; inactivity; diabetes; obesity; mice; glucose uptake

Recommended Citations

Citations

  • Callahan, Z. J. (2014). The independent effects of chronic high-fat feeding and long-term denervation in relation to development of diabetes [Doctoral dissertation, Miami University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=miami1417439183

    APA Style (7th edition)

  • Callahan, Zachary. The independent effects of chronic high-fat feeding and long-term denervation in relation to development of diabetes. 2014. Miami University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=miami1417439183.

    MLA Style (8th edition)

  • Callahan, Zachary. "The independent effects of chronic high-fat feeding and long-term denervation in relation to development of diabetes." Doctoral dissertation, Miami University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=miami1417439183

    Chicago Manual of Style (17th edition)

miami1417439183
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This open access ETD is published by Miami University and OhioLINK.