Insulin Misfolding Dynamics and Insulin Signaling Dysfunction

Mc Laughlin Research Institute, Great Falls MT

Investigators

Linked publications, trials & patents

Abstract

Type 2 diabetes mellitus (T2DM) is a chronic condition of dysregulation of glucose metabolism that affects millions of Americans. In normal glucose homeostasis, insulin release acts as the key to enable entry of glucose into a cell where it can be utilized in aerobic respiration to create ATP, the energy molecule of the cell. In those with diabetes, the process of release and entry is disrupted, and higher insulin levels are needed to enable glucose entry in the cells. This disruption in the cycle of insulin release and glucose entry into the cell creates a positive feedback system characterized by the requirement of more and more insulin over time, which in turn ultimately requires even more insulin leading to insulin resistance and the need for administration of exogenous insulin through subcutaneous delivery. The root cause of impairment of insulin-glucose homeostasis in some individuals and not others is not clear. However, risk factors include age, obesity, lack of activity and living in a rural community. The overall goal of this project is to directly examine the state of the insulin protein, specifically the structure of the insulin protein, and the role the structure plays in the function of the glucose metabolism pathway. Our three specific aims will use our assay to detect misfolded insulin to examine insulin fibrillization in response to protein destabilizing conditions linked to T2DM in preclinical studies. Concurrently, we will extend our studies to animal models in order to examine the role that misfolded insulin plays in insulin resistance and metabolic dysfunction in vivo. This work is innovative as we seek to understand the incidence and consequences of insulin fibrilization and formation of amyloid structure and outcomes in insulin signaling for glycemic control. Moreover, we use innovative methods in the proposed research including our Real Time-Quaking Induced Conversion (RTQuIC) which provides a novel tool for us to examine observed factors that prompt insulin misfolding and then investigate the presence of misfolded insulin in different body tissues. This work is significant to the Center for Integrated Biomedical and Rural Health Research (CIB-RHR), and rural states like Montana, as aging populations in rural areas have a higher incidence of T2DM than urban areas and face greater challenges in T2DM care.