Diabetes and Obesity

Metabolic determinants of hepatic lipotoxicity

Serum free fatty acids (FFAs) are typically elevated in individuals who suffer from obesity and type-2 diabetes. Abnormal hepatic lipid accumulation caused by FFA overload leads to a condition known as nonalcoholic fatty liver disease (NAFLD), which is estimated to effect up to 30% of the U.S. population. As a result, NAFLD is now the leading cause of referrals to hepatology clinics in the U.S. Unfortunately, the factors that influence disease progression are poorly understood, and therapeutic strategies for preventing or reversing NAFLD are limited. Our research aims to identify the lipid intermediates and signaling molecules that induce lipotoxic cell death in FFA-treated hepatic cells and to determine the mechanism by which these species promote abnormal cell metabolism and oxidative stress.

Funding support: NSF CAREER
Graduate students: Rob Egnatchik, Alexandra Leamy
Key collaborators: Masa Shiota (MP&B), David Jacobson (MP&B), Robb Flynn (Surgery)

Regulation of glucose metabolism

Quantifying the contribution of different metabolic pathways to glucose production or disposal is critical to understanding the regulation of whole-body glucose homeostasis, and how it becomes dysfunctional in diabetic states. We are collaborating with several investigators in Vanderbilt’s Diabetes Research Center to develop novel techniques to quantify rates of glucose metabolism both in animal models and cultured cells. Currently, we are focusing on methods to simultaneously quantify in vivo rates of gluconeogenesis, glycogenolysis, TCA cycling, and anaplerosis in rodent models. We are also developing stable isotope approaches to quantify glucose cycling in cultured pancreatic islets.

Funding support: NIH R01 (O'Brien PI), NIH R37 (Wasserman PI)
Key collaborators: Richard O’Brien (MP&B), David Wasserman (MP&B), Owen McGuinness (MP&B)