The multifaceted function of FoxO1 in pancreatic β-cell dysfunction and insulin resistance: Therapeutic potential for type 2 diabetes.

The forkhead box O1 (FOXO1), the first discovered member of the FoxO family, is a critical transcription factor predominantly found in insulin-secreting and insulin-sensitive tissues. In the pancreas of adults, FoxO1 expression is restricted to islet β cells. We determined that in human islet microarray datasets, FoxO1 expression is higher than other FoxO transcription factors. Our analyses of three human islet datasets revealed that FoxO1 expression tends to shows a negative correlation with type 2 diabetes and no correlation with body mass index (BMI) between individuals with low levels of HbA (or ND, non-diabetic) and high levels of HbA (or T2D, type 2 diabetes). However, FoxO1 function is multifaceted and mainly regulated by post-translational modifications including phosphorylation and deacetylation that involved in pancreatic β cell function and insulin sensitivity. This study summarized the molecular mechanisms underlying the role of FoxO1 activity in pancreatic β-cell dysfunction and insulin resistance in T2D. In addition, we discussed the therapeutic potential of FoxO1 inhibitors in diabetes treatment.