Targeting endothelial FOXO1 protects diabetic β-cells and improves wound healing

The forkhead box O1 (FOXO1) transcription factor plays critical roles in regulating not only metabolic activity but also angiogenesis in the vascular endothelium[1][1]–[4][2]. Our previous studies show that epsin endocytic adaptors can regulate both angiogenesis and lymphangiogenesis[5][3]–[7][4]. Endothelial cells (ECs) lining the inside of blood vessels are continuously exposed to circulating insulin and insulin-like growth factors (IGFs). Emerging evidences suggest that ECs can affect β-cell function[8][5]–[11][6]. Excessive IGF2, especially elevated local IGF2 levels in islets, may represent a risk factor for developing diabetes[12][7]–[15][8]; however, the underlying molecular mechanisms by which aberrant angiogenesis and endothelium-derived factors regulate pancreatic β-cell function in diabetes remain unclear. Here, we report that the pancreas of diabetic patients as well as the pancreas, skin, and plasma of streptozotocin/high fat diet (STZ/HFD)-induced diabetic mice and db/db mice contains excess IGF2, which can lead to β-cell dysfunction and apoptosis. Single-cell transcriptomics combined with mass spectrometry analysis reveal that endothelial-specific knockout of FOXO1 increases circulating soluble and cell-membrane or intracellular expression levels of IGF type 2 receptor (IGF2R) and CCCTC-binding factor (CTCF), while decreasing IGF2 levels in diabetes. Both IGFR2[15][8]–[17][9] and CTCF[18][10]–[21][11] can reduce IGF2 levels and may ameliorate β-cell decline associated with excess IGF2 in diabetes. Furthermore, depletion of FOXO1, epsins, or knockdown of ULK1 inhibits autophagy formation in ECs, preventing degradation of vascular endothelial growth factor receptor 2 (VEGFR2) to promote angiogenesis and improve wound healing in diabetes. Our findings reveal that endothelial FOXO1 regulates epsin-dependent angiogenesis and affects β-cell function and fate through CTCF and IGF2-IGF2R, providing a potential strategy for ameliorating diabetes and accelerating cutaneous wound healing. ### Competing Interest Statement The authors have declared no competing interest. [1]: #ref-1 [2]: #ref-4 [3]: #ref-5 [4]: #ref-7 [5]: #ref-8 [6]: #ref-11 [7]: #ref-12 [8]: #ref-15 [9]: #ref-17 [10]: #ref-18 [11]: #ref-21