269-LB: Modeling Alpha-Cell Dysfunction Using Stem Cell–Derived Alpha Cells

Abstract

Type 1 Diabetes (T1D) therapies have focused on restoring beta cell function via exogenous insulin or islet transplant. While promising, these approaches fail to account for the role of alpha cells and intra-islet communication in disease etiology. Alpha cells secrete glucagon and maintain effective paracrine signaling with beta cells to maintain glucose homeostasis and metabolic control. Mounting evidences suggest that impaired alpha cell function is a significant contributor to disease progression. Understanding triggers of alpha cell dysfunction and the resulting effects will be crucial for restoring both beta and alpha cell function in T1D. Lack of human alpha cell models have limited progress towards this goal. We recently reported a protocol to generate human alpha cells from stem cell sources (SC-alpha). Using these SC-alpha cells, we have established a T1D disease model to identify the triggers that induce alpha cell dysfunction. Importantly, we have identified defects in proglucagon processing that mimic those observed in diabetes and have identified conditions that modulate proglucagon processing and secretion. Here we demonstrate that exposure of SC-alpha cells to diabetogenic stressors such as hyperglycemia, hyperlipidemia, and ER stress impacts the processing of proglucagon and ultimately results in alpha cell dysfunction. We show that upon exposure to these stressors, SC-alpha cells secrete elevated glucagon compared to the control conditions and show a loss of glucose responsiveness. We also observed changes in the secretion of alternate proglucagon processing products, GLP-1, GLP-2, and glicentin. Interestingly, glicentin levels were affected by ER stress induction, but were unaffected by other stressors, suggesting that ER stress plays a direct role in the disruption of proglucagon processing, leading to alpha cell dysfunction. Identifying triggers of alpha cell dysfunction and assessing impacts in proglucagon processing will be a step towards restoring islet paracrine signaling. Disclosure S. Shrestha: None. Q. P. Peterson: None.