Brian O'Neill, MD, PhD

Portrait
Assistant Professor of Internal Medicine - Endocrinology and Metabolism

Contact Information

Primary Office: 3314 PBDB
319-335-4736

Education

MD/PhD, Biochemistry, University of Utah

Resident, Internal Medicine, Beth Israel Deaconess Medical Center
Fellow, Endocrinology, Beth Israel Deaconess Medical Center

Center, Program and Institute Affiliations

Fraternal Order of Eagles Diabetes Research Center

Research Summary

I have been most fortunate to join the laboratory of Dr. C. Ronald Kahn during my endocrinology fellowship and beyond. My work thus far has investigated two interesting components of skeletal muscle physiology. In the projects which I developed under the tutelage of Dr. Kahn, I have investigated the impact of combined loss of insulin receptor (IR) and IGF-1 receptor (IGFR) signaling in skeletal muscle on glucose metabolism and protein turnover. Using mouse models, we show that loss of IR/IGFR in muscle does not lead to diabetes or changes in whole body glucose homeostasis, primarily due to increased basal glucose uptake when IR and IGFR are deleted. However, loss of IR/IGFR does markedly affect muscle mass by dysregulated protein turnover and autophagy, which is regulated chiefly by FoxO transcription factors. These findings are clinically relevant because skeletal muscle insulin resistance is a cardinal feature of type 2 diabetes and metabolic syndrome, and loss of muscle strength is accelerated in older individuals with uncontrolled type 2 diabetes, putting these patients at higher risk for injury and disability. In addition, I am testing the effects of genetic loss of IR/IGFR signaling, as well as diet-induced obesity and streptozotocin-induced diabetes, on muscle transcriptomics by RNA-seq techniques, and metabolite profiles using an unbiased large-scale metabolomics approach. Along with my expertise in mitochondrial studies, I plan to interrogate these data sets to discover metabolic pathways that are perturbed in states of insulin deficiency and insulin resistance. We hope these results will provide better insight into the metabolic complications and dysregulation of muscle physiology that occur in obesity and diabetes, and potentially identify novel therapeutic targets for treatment of these diseases. Ultimately, I plan to build a career studying the impact of diabetes and insulin resistance on protein turnover and mitochondrial metabolism.