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 HbA1C (or ND, non-diabetic) and high levels of HbA1C (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 collected the clinical trials of FoxO1 inhibitor and agonist in diabetes, and discussed the therapeutic potential of FoxO1 activity in diabetes treatment.