Elison, Weston; Bauchle, Casey; Bunker, Libby; Stephens, Samuel; Tessem, Jeffery (Brigham Young University)
Faculty Advisor: Tessem, Jeffery (Brigham Young University; Nutrition, Dietetics and Food Science)
Type 2 Diabetes (T2D) effects hundreds of millions of people worldwide, with that number increasing rapidly. It is characterized by increased insulin resistance and dysfunctional insulin secretion. The beta cell of the pancreas is the primary insulin secreting tissue, found in the endocrine tissue of the pancreas called islets of Langerhans. In T2D beta cells become glucose intolerant and disease progression is characterized by loss of functional beta cell mass. Previous studies have shown that the transcription factor Nkx6.1 is vital for beta cell differentiation, identity, and insulin secretion. Research has indicated that Nkx6.1 expression and protein levels decrease in pancreatic islets from human donors with T2D. Our data indicates that glucolipotoxicity, a common model for obesity and diabetes in cell culture, leads to decreased Nkx6.1 mRNA expression, protein levels and nuclear localization in Ins-1 832/13 cells. Nkx6.1 regulates genes in the nucleus , and its loss inhibits proper insulin secretion. We propose that reactive oxygen species created by metabolism of excess fuel decreases Nkx6.1 expression and Nkx6.1 target gene expression, as measured by quantitative polymerase chain reaction (qPCR). Also, increased glucose concentrations causes increased Nkx6.1 protein degradation and translocation out of the nucleus. Protein levels will be measured by western blot and localization by confocal microscopy. In order to understand how these changes effect beta cell function, we will measure glucose stimulated insulin secretion by sandwich Enzyme Linked Immunosorbent Assay (ELISA). We further propose that Nkx6.1 overexpression will restore beta cell function. These results will assist in unraveling the cause of beta cell dysfunction in T2D.