Glucose sensing by the hepatoportal sensor is GLUT2-dependent - In vivo analysis in GLUT2-null mice

In the preceding article, we demonstrated that activation of the hepatoportal glucose sensor led to a paradoxical development of hypoglycemia that was associated with increased glucose utilization by a subset of tissues. In this study, we tested whether GLUT2 plays a role in the portal glucose-sensing system that is similar to its involvement in pancreatic beta-cells, Awake RIPGLUT1 x GLUT2(-/-) and control mice were infused with glucose through the portal (Po-) or the femoral (Fe-) vein for 3 h at a rate equivalent to the endogenous glucose production rate. Blood glucose and plasma insulin concentrations were continuously monitored, Glucose turnover, glycolysis and glycogen synthesis rates were determined by the H-3-glucose infusion technique. We showed that portal glucose infusion in RIPGLUT1 x GLUT2(-/-) mice did not induce the hypoglycemia observed in control mice but, in contrast, led to a transient hyperglycemic state followed by a return to normoglycemia; this glycemic pattern was similar to that observed in control Fe-mice and RIPGLUT1 x GLUT2(-/-) Fe-mice, Plasma insulin profiles during the infusion period were similar in control and RIPGLUT1 x GLUT2(-/-) Po- and Fe-mice. The lack of hypoglycemia development in RIPGLUT1 x GLUT2(-/-) mice was not due to the absence of GLUTS in the liver, Indeed, reexpression by transgenesis of this transporter in hepatocytes did not restore the development of hypoglycemia after initiating portal vein glucose infusion. In the absence of GLUTS, glucose turnover increased in Po-mice to the same extent as that in RIPGLUT1 x GLUT2-/- or control Fe-mice, Finally, co-infusion of somatostatin with glucose prevented development of hypoglycemia in control Po-mice, but it did not affect the glycemia or insulinemia of RIPGLUT1 x GLUT2(-/-) Po-mice, Together, our data demonstrate that GLUTS is required for the function of the hepatoportal glucose sensor and that somatostatin could inhibit the glucose signal by interfering with GLUTS-expressing sensing units.