Transcriptional regulation of human islet development and function

Background

Type 2 diabetes affects around 400 million people worldwide and is caused by the pancreas not producing enough insulin due to issues with β-cells (the insulin-producing cells). More than 250 genes have been linked to type 2 diabetes, many of which are active in the pancreas. This suggests that problems with how the insulin-producing β-cells and other cells in the pancreas (like α-cells) function, as well as how the cells are organized, play a key role in the development of the disease. 

Hypothesis

Through animal studies, we have discovered that the MafB transcription factor is crucial for the proper function and development of islet cells in the pancreas. Additionally, we've identified the transcription factors AUTS2 and ETV1 as targets of MafB and we propose that these factors regulate molecular processes that are critical to islet cell function. 

Methods

We plan to use human islets to study hormone secretion and employ embryonic stem (ES) cell differentiation models to explore how the transcription factors AUTS2 and ETV1 regulate islet development and function. 

Results

Our preliminary results show that ETV1 and AUTS2 regulate several proteins that are essential for islet function and we have found that variants in the AUTS2 and ETV1 genes are critical for the expression of these genes in islets. 

Conclusions

Our results will identify key proteins that are important for islet function and are affected in type 2 diabetic patients. 

Importance

By understanding the mechanisms behind β-cell differentiation and islet function, we can advance efforts to create functional β-cells from stem cells for transplantation. This knowledge will also help us better understand the causes of type 2 diabetes and improve strategies for treating the disease.