| dc.description.abstract | Multiple studies have shown that elevated fasting blood glucose (FBG) levels are associated with increased risk of heart disease, type 2 diabetes, and many other conditions. Given the biological importance of FBG, genetic studies were performed to identify genes that regulate FBG levels. These analyses identified common, naturally occurring variants in ~30 genes with the strongest association being identified in G6PC2. G6PC2 is an enzyme that catalyzes the conversion of glucose-6-phosphate to glucose and free phosphate and is predominantly expressed in pancreatic islet beta cells—the cells responsible for insulin secretion. Insulin is the most important factor controlling blood glucose levels. These genetic data implicate G6PC2 as a target for therapies designed to lower FBG levels. Mouse studies have shown that G6pc2 deletion results in decreased FBG due to an increase in the sensitivity of glucose-stimulated insulin secretion (GSIS) to glucose. The first part of this dissertation will probe the impact of several mutations in G6PC2 on the expression and activity of the protein and determine the effect of mutations that alter function on human glucose levels using the Vanderbilt biobank, BioVU.
G6PC2 is found in the endoplasmic reticulum (ER) membrane with the active site oriented to the ER lumen, but until recently only low-resolution biochemical data were available for G6PC2. Recent publication of the AlphaFold2 algorithm has resulted in the generation of a predicted structure for G6PC2, allowing for the generation of new hypotheses investigating the structure-function relationship of the protein. Part two of this dissertation investigates several important structural motifs in the G6PC2 protein, as predicted by the AlphaFold2 algorithm and sequence analysis. Part three of this dissertation determines the therapeutic potential of a previously identified small molecule inhibitor of G6PC2. The performed studies elucidated key residues required for G6PC2 activity, support G6PC2 as a novel target for lowering FBG, and will aid in the future development of optimized G6PC2 inhibitors. | |
