Sema4D Deficiency Enhances Glucose Tolerance Through Acceleration of GLUT2 Synthesis in Hepatocytes

Abstract

The glucose transporter 2 (GLUT2) is constitutively expressed in pancreatic beta cells and hepatocytes in mice. It is the most important receptor in glucose-stimulated insulin release and hepatic glucose transport. The Sema4D is a signaling receptor on cell membranes. The correlation between Sema4D and GLUT2 has not been reported previously. We investigated whether knockdown of Sema4D could exert a hypoglycemic effect based on the increased GLUT2 expression in Sema4D -/- mice hepatocytes. First, Sema4D -/- male mice exhibited significantly greater glucose tolerance than wild-type mice in a hyperglycemic environment. Secondly, Sema4D -/- mice had more retained GLUT2 in liver membranes after streptozotocin (STZ) injection according to an immunofluorescence assay. After STZ injection, Sema4D -/- male mice did not exhibit fasting hyperinsulinemia like wild-type mice. Finally, analysis of metabolomic and immunohistochemical data also revealed that Sema4D -/- mice produce hypoglycemic effects by enhancing the pentose phosphate pathway, but not glycogen synthesis. Thus, Sema4D may play an important role in the regulation of glucose homeostasis by affecting GLUT2 synthesis.