Table 1. FoxO Transcription Factors and Diabetes Mellitus.

FoxO Proteins	Biology
Expression and Structure	FoxO proteins possess a butterfly-like appearance on X-ray crystallography and nuclear magnetic resonance
	FoxO proteins are present throughout the body and have a conserved forkhead domain described as a “winged helix”
Post -Translational Modification	FoxO proteins are modified by phosphorylation, acetylation, and ubiquitylation through pathways involving Akt, SgK, SIRT1, and Wnt signaling with WISP1
	Akt and SgK phosphorylate FoxO proteins at different sites affording various pathways to control FoxO protein activity
Programmed Cell Death	Under some conditions, the activation of FoxO proteins may prevent apoptotic cellular injury during oxidative stress
	FoxO protein activation can lead to the induction of autophagy and increase cell survival, such as during the clearance of toxic mHtt protein in neurons and during starvation to maintain cardiac function
	However, activation of FoxO proteins usually leads to apoptotic membrane PS externalization and DNA degradation. In some circumstances, a reduction in autophagy is required to block oxidative stress injury
Cellular Signaling	Wnt signaling can promote cellular protection against apoptotic cell death through the inactivation of FoxO proteins
	WISP1 can limit FoxO3a activity, block caspase 1 and 3 activity, and promote SIRT1 nuclear trafficking
	FoxO proteins can control SIRT1 transcription and increase SIRT1 expression. In addition, SIRT1 promotes FoxO-driven SIRT1 autotranscription through the activation and deacetylation of FoxO proteins
	Agents that are protective during DM, such as EPO and nicotinamide, can phosphorylate and inactive FoxO proteins to lead to cellular protection
Outcomes with Diabetes Mellitus	Some clinical studies suggest a detrimental effect associated with FoxO proteins and DM
	Inactivation of FoxO proteins during DM may protect pancreatic β-cells, retinal cells, renal cells, and glucose homeostasis
	In some clinical populations, FoxO protein activation may be protective during metabolic disorders for the immune system, assist with insulin signaling, and maintain energy reserves

Akt: protein kinase B; DM: diabetes mellitus; DNA: deoxyribonucleic acid; EPO: erythropoietin; FoxO: mammalian forkhead transcription factors of the O class; mHtt: mutant Huntingtin; PS: phosphatidylserine; SgK: serum- and glucocorticoid-inducible protein kinase; SIRT1: silent mating type information regulation 2 homolog 1 (S. cerevisiae); WISP1: wnt1 inducible signaling pathway protein 1; Wnt: proteins derived from the Drosophila Wingless (Wg) and the mouse Int-1 genes