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 hepatoport al glucose sensor led to a paradoxical development of hypoglycemia that was associated with increased glucose utilization by a subset of tissues. In t his study, we tested whether GLUT2 plays a role in the portal glucose-sensi ng system that is similar to its involvement in pancreatic beta-cells, Awak e 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 co ncentrations were continuously monitored, Glucose turnover, glycolysis and glycogen synthesis rates were determined by the H-3-glucose infusion techni que. We showed that portal glucose infusion in RIPGLUT1 x GLUT2(-/-) mice d id not induce the hypoglycemia observed in control mice but, in contrast, l ed 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 transgene sis of this transporter in hepatocytes did not restore the development of h ypoglycemia after initiating portal vein glucose infusion. In the absence o f GLUTS, glucose turnover increased in Po-mice to the same extent as that i n RIPGLUT1 x GLUT2-/- or control Fe-mice, Finally, co-infusion of somatosta tin 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 func tion of the hepatoportal glucose sensor and that somatostatin could inhibit the glucose signal by interfering with GLUTS-expressing sensing units.