Objective
Individuals with a younger age of type 1 diabetes (T1D) onset lose insulin production faster and to a greater extent compared to those with adult-onset T1D. These differences may impact responses to immunomodulatory therapies, long-term glucose control, protection against hypoglycemia, and the development of diabetes-related complications. At present, very little is known about the molecular differences between juvenile and adult β cells that may underlie these metabolic variations. We hypothesize that differences in metabolic outcomes between individuals with pediatric versus adult onset T1D may be due to a reduced capacity of young β cells to handle stress and turn on adaptative and protective responses. The overarching objective of this project is to determine the cellular phenotypes in the pancreas that explain age-associated differences in metabolic outcomes of individuals with T1D. To address this gap in knowledge, we will determine the cellular orchestration of intact human pancreatic tissue to identify molecular mechanisms that may explain why young β cells lose function faster than adult β cells. Furthermore, we will identify the spatial localization of RNA molecules at a resolution of a single molecule to define the impact on cellular phenotypes in pancreatic tissue sections from nondiabetic and T1D donors.
Background Rationale
The rate and severity of the onset and progression of type 1 diabetes (T1D) varies significantly between individuals. Importantly, this variability of disease presentation can hamper efforts to monitor for disease onset and make it challenging to determine time points for intervention with new disease-modifying therapies. Emerging data from clinical studies suggest that age significantly influences disease-associated heterogeneity in T1D; however, the exact mechanisms explaining this difference are not known. Understanding the molecular etiologies underlying these age-associated differences in disease pathogenesis and progression is paramount in developing age-specific screening and treatment strategies for T1D.
Description of Project
Type 1 diabetes (T1D) is an autoimmune disease that causes progressive loss of the insulin-producing β cells of the pancreas, leading to insulin deficiency and dangerously high blood glucose levels. At present, the precise molecular mechanisms leading to the development of T1D are not well understood. However, clinical studies in humans indicate that age at diagnosis is a critical factor that may lead to metabolic differences in those with T1D. Data from these studies suggest that individuals diagnosed with T1D during childhood experience faster loss of insulin secretion and are less likely to produce insulin after disease onset compared to those with adult-onset T1D. Understanding how age at diagnosis impacts β cell function is critical, as the ability to produce even small amounts of insulin can improve glycemic control and offer protection against low blood glucose levels and other diabetes-related complications. In our study, we will make use of new, cutting-edge sequencing technologies to determine the spatially localized gene expression profiles of single cells in the pancreas from pediatric and adult organ donors with recent onset T1D. Application of these techniques will enable us to determine differences in gene expression within cells of the pancreas, allowing us to test whether juvenile β cells have a reduced capacity to mitigate stress and mount adaptive/recovery responses compared to adult β cells. A complete understanding of the molecular differences between young and adult β cells will allow for the development of age-specific screening and treatment strategies to better diagnose or prevent T1D. In addition, this work will generate a novel dataset that can be shared with other investigators in the field and used to answer additional questions about T1D development.
Anticipated Outcome
We anticipate that our comprehensive analysis of single-cell transcriptomics and spatial transcriptomics will enable us to understand differences in cellular phenotypes and cell-cell interactions between pediatric and adult pancreases. Identifying these differences will allow us to develop age-specific and more precise screening strategies and therapeutic interventions for treating type 1 diabetes (T1D). In addition, this work will generate a novel dataset that can be shared with other investigators in the field to answer additional questions about T1D development.
Relevance to T1D
Completion of the studies proposed in this project will define the molecular underpinnings of cellular and metabolic differences that exist between individuals with type 1 diabetes (T1D). These findings will pave the way for precision medicine approaches to better diagnose, treat, and manage T1D.