Role of fatty acid oxidation in islet beta cell function
Obesity, insulin resistance, and pancreatic beta cell dysfunction are fundamental contributors to the development of type 2 diabetes mellitus (T2DM). During obesity, the number of pancreatic islet b-cells increases in response to peripheral demand for insulin (i.e., insulin resistance), with compensatory insulin hypersecretion. The mechanisms associated with these adaptive changes are not completely understood. We propose that altered lipid metabolism and lipid overload may be a key contributor to these phenotypes.
In this COBRE-funded project, we propose that as the lipid burden increases such as occurs during obesity, islet b-cells adapt to rely on increased oxidation of fatty acids. As obesity worsens, tissue lipid storage results when lipid supply exceeds oxidative capacity of the two organelles that metabolize lipid: mitochondria and peroxisomes. We hypothesize that this can lead to incomplete fatty oxidation products produced within the mitochondria, as well as lipotoxic lipid species in the cytosol, that impair insulin secretion.
The current project will employ two novel in vivo models of reduced fatty acid oxidation in pancreatic b-cells to directly test the hypothesis that reducing fatty acid oxidation in mitochondria and peroxisomes impairs b-cell function. Further, using state-of-the-art imaging capabilities, proteomics, metabolomics, and RNA sequencing analyses, and substrate oxidation, we are investigating the mechanism linking altered lipid metabolism and decreased beta cell function.
(pictured, L-R: Maggie Ducote, Research Associate; Susan Burke, PhD, Principle Investigator; Mary Grace Beck, Undergraduate Student Worker)