Abstract

Pre-diabetes and Type 2 diabetes mellitus (T2DM) are metabolic diseases that affect more than one-third of the American population, and risk factors like chronic inflammation, which contribute to diabetic onset and progression, affect millions more. The underlying causes of these diseases and risk factors are complex; these include genetic and environmental interactions that affect multiple genes in ways that are not clearly understood in humans.In particular, genetic and environmental interactions may alter immune cells at the molecular level to become increasingly pro-inflammatory, which can worsen glycemic control, promote pre-diabetic and T2DM onset, and increase the likelihood of opportunistic diabetic infections. To study these types of changes, I am developing novel assays to construct dynamic maps of immune system changes during viral infections in insulin-sensitive (IS) and insulin-resistant (IR) human subjects. Because infections lead to reproducible inflammatory responses over time, the appearance of stronger or weaker inflammatory responses in IR subjects with hyperglycemia will help identify environmentally sensitive immune cell types that may be responsible for such inflammatory activity. High-throughput profiling will further identify molecular signatures that help push environmentally sensitive immune cells towards a more pro-inflammatory state. These will be integrated with genetic information from human subjects to form more precise links between genetic variation, physiological environment, and disease-associated inflammatory changes. This will help advance our capacity to functionally interpret genomic information for precision medicine, with potential for developing new immunomodulatory therapeutic strategies for glycemic control and new avenues for risk predication of pre-diabetes, T2DM, and diabetic complications.