Alpha Cell Heterogeneity: Unveiling Novel Targets for T1D therapy

About This Grant

Project Summary (30 lines): Together with pancreatic beta cells, alpha cells maintain circulating glucose levels within the normal range so that glucose homeostasis can be achieved. In type 1 diabetes (T1D), beta cells are destroyed by chronic autoimmune responses, resulting in severe insulin deficiency. However, the function of alpha cells is also compromised, and it contributes to both hyperglycemia and hypoglycemia. While we recognize that alpha cells are influenced by signals from neighboring beta and delta cells, the orchestration of these interactions remains poorly understood. My preliminary data supports the hypothesis that alpha cells are also functionally heterogenous, and that distinct alpha cell subpopulations may play a role in different regulatory circuits and respond to different paracrine signals. This nuanced regulation is particularly vital for understanding the mechanisms governing alpha cell behavior under both normal and diabetic conditions. Addressing these questions is therefore essential for elucidating the complexities of alpha cell regulation, ultimately paving the way for advancements in diabetes research and potential therapeutic interventions. To address my hypothesis, I will implement a multi-faceted research strategy that leverages innovative methodologies, particularly utilizing human pancreatic tissue slices, a study approach that I contributed to establish. Most studies on human islets have relied on isolated islets or dispersed cell models, which often fail to replicate the native architecture, and intercellular interactions present in pancreatic tissue, limiting our understanding the complex network of alpha cells. Utilizing human pancreatic tissue slices, my project will preserve the islets natural environment, shedding light on their behavior and interactions in ways that isolated studies cannot. I will use viral vector to express reporters for calcium and cAMP signaling and employ live-cell imaging to monitor real-time intracellular responses to various stimulations, both activating and inhibiting alpha cells. In addition, I will perform molecular profiling through single nucleus RNA sequencing and potentially spatial transcriptomics to identify specific gene expression patterns linked to each alpha cell subpopulation. This dual approach will provide a comprehensive analysis of alpha cell heterogeneity and their interactions with neighboring beta and delta cells, addressing a significant knowledge gap in diabetes research. By uncovering the nuances of alpha cell regulation and their role in glucose homeostasis, this project is relevant to support the development of targeted therapies that can improve diabetes management by restoring alpha cell function. Starting with my PhD studies I have focused on investigating human islet cells in health and diabetes, and I have developed a focus on alpha cells during my post-doctoral fellowship. The proposal developed for this K01 application is an excellent vehicle to complete my training and prepare me to undertake an independent career focus on the study of pancreatic alpha cell biology.