Endoplasmic reticulum stress in beta cells and autoimmune diabetes

Abstract

Type 1 diabetes results from the autoimmune destruction of pancreatic β cells, leading to insulin deficiency and hyperglycemia. Although multiple attempts have been made to slow the autoimmune process using immunosuppressive or immunomodulatory agents, there are still no effective treatments that can delay or reverse the progression of type 1 diabetes in humans. Recent studies support endoplasmic reticulum (ER) as a novel target for preventing the initiation of the autoimmune reaction, propagation of inflammation, and β cell death in type 1 diabetes. This review highlights recent findings on ER stress in β cells and development of type 1 diabetes and introduces potential new treatments targeting the ER to combat this disorder.

Figure 1. ER stress is intricately involved in the development of type 1 diabetes

In the pre-diabetes phase of type 1 diabetes, environmental events triggering the disease along with the autoimmune attack on the islet result in high levels of ER stress which causing both β cell death and dysfunction. Once a majority of β cells are destroyed clinical presentation of diabetes results. After initiation of insulin therapy, the lowering of glucose and insulin demand decreases ER stress levels on remaining β cells, resulting in increased insulin production in these cells. This phenomenon may explain the classic honeymoon period seen shortly after type 1 diabetes diagnosis and treatment. As the remaining β cells continue to be exposed to immune attack and ER stress-mediated propagation of inflammation, eventually the β cell mass is reduced to a point that results in inability of the β cells to secrete physiologically relevant amounts of insulin, resulting in the end of the honeymoon period.

Figure 2. Endoplasmic Reticulum Stress Induces Neoantigen Production and Propagation of Inflammation in β Cells

Physiologic ER stress inducing agents including viral infection, cytokines and hyperglycemia lead to ER calcium depletion which results in cytosolic calcium elevation, activating cell death pathways and inducing post-translational modification of β cell proteins. These modified β cell proteins then can interact with immune cells initiating autoimmunity. In addition, ER stress also increases levels of thioredoxin-interacting protein (TXNIP) and IL-1β which lead to β cell death and propagation of inflammation within the islet.