Glucose Transporter-1 in the Hypothalamic Glial Cells Mediates Glucose Sensing to Regulate Glucose Production In Vivo

OBJECTIVE: Circulating glucose inhibits glucose production in normal rodents and humans, but this glucose effectiveness is disrupted in diabetes due partly to sustained hyperglycemia. We hypothesize that hyperglycemia in diabetes impairs hypothalamic glucose sensing to lower glucose production, and changes of glucose transporter-1 (GLUT1) in the hypothalamic glial cells are responsible for the deleterious effects of hyperglycemia in vivo. RESEARCH DESIGN AND METHODS: We tested hypothalamic glucose effectiveness to increase hypothalamic glucose concentration and lower glucose production in rats induced with streptozotocin (STZ) uncontrolled diabetes, STZ and phlorizin, and whole-body and hypothalamic sustained hyperglycemia. We next assessed the content of glial GLUT1 in the hypothalamus, generated an adenovirus expressing GLUT1 driven by a glial fibrillary acidic protein (GFAP) promoter (Ad-GFAP-GLUT1), and injected Ad-GFAP-GLUT1 into the hypothalamus of rats induced with hyperglycemia. Pancreatic euglycemic clamp and tracer-dilution methodologies were used to assess changes in glucose kinetics in vivo. RESULTS: Sustained hyperglycemia, as seen in the early onset of STZ-induced diabetes, disrupted hypothalamic glucose sensing to increase hypothalamic glucose concentration and lower glucose production in association with reduced GLUT1 levels in the hypothalamic glial cells of rats in vivo. Overexpression of hypothalamic glial GLUT1 in STZ-induced rats with reduced GLUT1 acutely normalized plasma glucose levels and in rats with selectively induced hypothalamic hyperglycemia restored hypothalamic glucose effectiveness. CONCLUSIONS: Sustained hyperglycemia impairs hypothalamic glucose sensing to lower glucose production through changes in hypothalamic glial GLUT1, and these data highlight the critical role of hypothalamic glial GLUT1 in mediating glucose sensing to regulate glucose production.