Proximity Proteomic Identification of Trafficking and Secretory Markers of Islet (Dys)Function
Abstract
Topic Area: This proposal addresses the FY20 PRMRP Topic Area Diabetes. Overview: Type 2 diabetes (T2D) is a chronic health condition that results when endocrine cells in the pancreas (called islets) fail to secrete sufficient amounts of the hormone insulin, resulting in abnormal metabolism of carbohydrates and elevated levels of glucose in the blood. Over time, T2D can lead to a variety of diseases, including heart disease, kidney failure, dementia, peripheral neuropathy, and blindness. T2D is a common disorder that affects ~9% of the general population in the United States. Disease rates are even more alarming among military veterans—nearly one in four (24%) of the men and women who have served our country and who receive care through the Veterans Administration Clinics have T2D. T2D is putting an enormous strain on the healthcare system, with one in nine US healthcare dollars being spent to manage and treat T2D and T2D-associated chronic disease. These statistics underscore the public health crisis T2D has become. A critical problem is that, while T2D can be managed through dietary changes and/or regular administration of insulin, these strategies do not fully replace the precise glucose and insulin controlling properties of fully functioning islets. Therefore, there is an urgent need to develop new approaches to better manage T2D and prevent the chronic diseases that follow from it. Innovation: Significant time and money have been invested to identify the molecular and genetic features associated with T2D and the cellular processes leading to islet dysfunction. However, our proposal is innovative because it focuses on a critical process that has been largely unexplored: protein trafficking, processing, and secretion in islet beta cells. These processes work together and are required for producing and releasing insulin from islet cells that our bodies need to metabolize glucose. Our proposal is also innovative because we will study whether and how this process goes awry in islet beta cells that are distressed, as they would be in a patient with T2D. This is currently not known because most previous studies have investigated beta cells that are not under direct stress. Hypothesis and Aims: We hypothesize that diabetogenic stress response pathways and insulin resistance alter protein trafficking, processing, and/or secretion in islet beta cells. To test this hypothesis, we will specifically label and compare the proteins trafficked and secreted through the endoplasmic reticulum in healthy and distressed islet beta cells using innovative proximity proteomics (ER-TurboID) tools. In Aim 1, we will determine protein trafficking, processing, and secretion patterns in isolated human islets and EndoC-betaH3 beta cells under standard conditions or after exposure to stimulatory or stress-inducing agents. By comparing these patterns, we will identify common and specific changes linked to each islet stress response. In Aim 2, we will use ER-TurboID in a preclinical mouse model of diet-induced obesity and insulin resistance to identify secreted and circulating protein biomarkers of islet beta cell distress. Deliverables and Impact of Research: Completion of these aims will provide fundamental insights into protein trafficking, processing, and secretion defects in beta cells caused either by stress in cell culture or by whole-body insulin resistance. It will also identify specific protein targets and markers of distressed islet beta cells. This knowledge will contribute to the development of 1) potential new circulating biomarkers to identify and monitor at-risk individuals or assess treatment responses and 2) new therapeutic targets. New T2D biomarkers could provide immediate clinical relevance while new targets could fuel additional studies towards impacting the vast number of military and civilian individuals in the United States currently living with T2D.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110275
Entities
People
- Michael L Stitzel
Organizations
- Jackson Laboratory
- United States Army