Soluble T-cadherin secretion from endothelial cells is regulated via insulin/PI3K/Akt signalling

• DOI: 10.1016/j.bbrc.2024.150403
• Publication Date: 2024-07-14T10:44:26Z
• Authors: Tomonori Okita; Shunbun Kita; Shiro Fukuda; Yuta Kondo; Taka-aki Sakaue; Masahito Iioka; Keita Fukuoka; Keitaro Kawada; Hirofumi Nagao; Yoshinari Obata; Yuya Fujishima; Takeshi Ebihara; Hisatake Matsumoto; Satoshi Nakagawa; Tadashi Kimura; Hitoshi Nishizawa; Iichiro Shimomura
• Keywords: Mice, Knockout; Male; Endothelial cells; Insulin demand; Insulin signalling; 610; Endothelial Cells; Cadherins; Receptor, Insulin; Mice; Phosphatidylinositol 3-Kinases; soluble T-cadherin; Human Umbilical Vein Endothelial Cells; Animals; Humans; Insulin; Receptors, Leptin; Female; Peptides; Proto-Oncogene Proteins c-akt; Signal Transduction

Our recent report showed that soluble T-cadherin promotes pancreatic beta-cell proliferation. However, how and where the secretion of soluble T-cadherin is regulated remain unclear.Soluble T-cadherin levels significantly increased in leptin receptor-deficient db/db mice with hypoinsulinaemia or in wild-type mice treated with insulin receptor blockade by S961. Similar results were observed in human subjects; Diabetic ketoacidosis patients at the time of hospitalization had increased plasma soluble T-cadherin levels, which decreased after insulin infusion therapy. Patients with recurrent ovarian cancer who were administered a phosphatidylinositol-3 kinase (PI3K)-alpha inhibitor (a new anticancer drug) had increased plasma soluble T-cadherin and plasma C-peptide levels. Endothelial cell-specific T-cadherin knockout mice, but not skeletal muscle- or cardiac muscle-specific T-cadherin knockout mice, showed a 26 % reduction in plasma soluble T-cadherin levels and a significant increase in blood glucose levels in streptozocin-induced diabetes. The secretion of soluble T-cadherin from human endothelial cells was approximately 20 % decreased by insulin and this decrease was canceled by blockade of insulin receptor/Akt signalling, not Erk signalling.We conclude that insulin regulates soluble T-cadherin levels and soluble T-cadherin secretion from endothelial cells is positively regulated by insulin/insulin receptor/Akt signalling.