Dissecting the Heterogeneity of Human Islet Stress Responses in Type 2 Diabetes
Abstract
Type 2 diabetes (T2D) is a medical and public health crisis impacting the U.S. military Veteran, military beneficiary, and civilian populations. Strikingly, almost one in four (24%) Veterans receiving care at Department of Veterans Affairs (VA) clinics suffers from T2D, a rate approximately twice that of the general population (9.3%). Tragically, long-term complications of T2D include heart disease, stroke, diabetic retinopathy, and amputation (due to poor blood circulation), and T2D is associated with a 10-year shorter life expectancy. Moreover, increased diabetes incidence among U.S. children threatens to erode the pool of Service-eligible individuals. Ultimately, T2D results when the endocrine cells of the pancreas (pancreatic islets) fail to secrete sufficient insulin to compensate for the increased demands of insulin-resistant peripheral tissues. While T2D is commonly associated with obesity and sedentary lifestyle, it is clear that some individuals have higher risk of developing T2D due to their genetics. Importantly, the development and progression of T2D remains poorly understood. Excess inflammation and an increase in oxidative stress are two conditions commonly associated with the onset and progression of diabetes. Both conditions impose stress on islet cells in the pancreas, which impairs their normal function. We hypothesize that genetic variants linked to increased T2D risk change areas of the genome called regulatory elements that function like switches to turn genes on or off in islet cells in response to these stress conditions. Altered islet stress responses may provide the link between environmental and genetic factors that predispose some individuals to this devastating disease, but these gene-environment interactions have not been studied. To better understand the heterogeneity of diabetes and develop improved T2D diagnostics and treatments, a more precise understanding of gene-environment interactions that contribute to islet dysfunction and T2D is essential. The overall objective of this project is to determine how islet cells respond to diabetes-provoking stress conditions and to determine how T2D-associated genetic variants perturb these responses to contribute to islet dysfunction and T2D pathogenesis. To this end, we will use cutting-edge sequencing and genome-editing technologies to study how islet cells behave after exposure to oxidative and inflammatory stress. We will measure changes in the genome as a result of these two stress conditions in human islet samples from 100 non-diabetic organ donors. These experiments will uncover the genes and regulatory elements that influence how islet cells respond to diabetes-provoking stress. We will uncover how DNA sequence variation present in each of us alters these stress responses. Furthermore, we will monitor the response of each cell type within the islets to determine if and how they respond differently to these stressors. This will help define whether certain cell types can be therapeutically targeted in future studies. Finally, we will experimentally manipulate the islet stress-related genes to determine if they improve or impair islet health and resilience. The knowledge gained from this project will enable us to identify individuals at increased risk for abnormal islet stress responses and T2D and delineate the genes and pathways that can be targeted in future studies to correct impaired islet stress responses and prevent and/or treat T2D.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810401
Entities
People
- Michael L Stitzel
Organizations
- Jackson Laboratory
- United States Army