Date of Award

12-2021

Degree Name

Doctor of Philosophy

Department

Chemistry

First Advisor

Dr. Susan R. Stapleton

Second Advisor

Dr. David Huffman

Third Advisor

Dr. Ekk Sinn

Fourth Advisor

Dr. Pamela Hoppe

Keywords

Metabolism, insulin, diabetes

Abstract

Diabetes is a chronic disease that effects 10 percent of the world’s population and causes more than 1.5 million deaths a year and billions of dollars in associated health care cost. It can lead to very serious complications such as renal failure, liver cirrhosis, heart attack, and vision loss. The most common type of diabetes is type 2 diabetes. Type 2 diabetes arises when blood glucose levels remain chronically high due to insulin resistance. The reason for this elevation is due to the failure of insulin to allow tissues to uptake glucose causing problems in subsequent metabolic pathways. Over the years, it has been shown that insulin regulates key enzymes in both carbohydrate and fat metabolism. The insulin regulation of these enzymes occurs primarily via the phosphoinositol-3- kinase / protein kinase B (PI3K/Akt) pathway. Once glucose is transported into the cells, it is converted into glucose-6-phosphate and can enter metabolic pathways such as the pentose phosphate pathway, and fatty acid synthesis which are regulated by the key enzymes glucose-6-phosphate dehydrogenase (G6PDH), and fatty acid synthase (FAS), respectively. Previously, we established an insulin resistance model using glucosamine in primary rat hepatocytes and reported that under glucosamine induced insulin resistance, the insulin induction of G6PDH expression was suppressed, while there was no effect on the insulin induction of FAS expression. The mechanism of this differential regulation, however, is unknown. We also previously reported that the insulin induction of sterol regulatory element binding protein 1c (SREBP1c), a key transcription factor in the insulin induction of both G6PDH and FAS was suppressed under insulin resistant conditions suggesting that it was not involved in the differential mechanism by insulin under insulin resistant conditions. In this study, we investigated the role of LXR, another important transcription factor in the regulation of metabolic genes by using its agonist TO901317. TO901317 had no impact on the insulin induction of G6PDH under normal or insulin resistant conditions. The effect of the LXR agonist on SREBP1c was muted in the presence of glucosamine however the LXR agonist’s effect on FAS expression was unaltered when glucosamine was present. LXR agonist did not have an effect on the insulin induced suppression of an inhibitor of SREPB1c processing, INSIG2 expression under normal or insulin resistant conditions. Taken together, these data strongly suggest that LXR acts as a differentiator in the regulation of FAS and G6PDH under glucosamine induced insulin resistant conditions.

Access Setting

Dissertation-Open Access

Additional Files
2021_Hachem_J_SWAA.pdf (972 kB)
Download

Share

COinS