The role of FOXO1 in β-cell failure and type 2 diabetes mellitus

Over the past two decades, insulin resistance has been considered essential to the aetiology of type 2 diabetes mellitus (T2DM). However, insulin resistance does not lead to T2DM unless it is accompanied by pancreatic beta-cell dysfunction, because healthy beta cells can compensate for insulin resistance by increasing in number and functional output. Furthermore, beta-cell mass is decreased in patients with diabetes mellitus, suggesting a primary role for beta-cell dysfunction in the pathogenesis of T2DM. The dysfunction of beta cells can develop through various mechanisms, including oxidative, endoplasmic reticulum or hypoxic stress, as well as via induction of cytokines; these processes lead to apoptosis, uncontrolled autophagy and failure to proliferate. Transdifferentiation between beta cells and a cells occurs under certain pathological conditions, and emerging evidence suggests that beta-cell dedifferentiation or transdifferentiation might account for the reduction in beta-cell mass observed in patients with severe T2DM. FOXO1, a key transcription factor in insulin signalling, is implicated in these mechanisms. This Review discusses advances in our understanding of the contribution of FOXO1 signalling to the development of beta-cell failure in T2DM.