UP-REGULATION OF BLOOD-BRAIN-BARRIER GLUT1 GLUCOSE-TRANSPORTER PROTEIN AND MESSENGER-RNA IN EXPERIMENTAL CHRONIC HYPOGLYCEMIA

An in vivo model of chronic hypoglycemia was used to investigate chang es in blood-brain barrier (BBB) glucose transport activity and changes in the expression of GLUT1 mRNA and protein in brain microvasculature occurring as an adaptive response to low circulating glucose levels. Chronic hypoglycemia was induced in rats by constant infusion of insul in via osmotic minipumps; control animals received infusions of saline . The criterion for chronic hypoglycemia was an average blood glucose concentration of <2.3 mmol/l (42 mg/dl) after 5 days. The average bloo d glucose concentration at the end of the experimental period in the r ats selected for study was 2.0 +/- 0.1 mmol/l (36 +/- mg/dl) vs. 4.9 /- 0.1 mmol/l (88 +/- mg/dl) in the controls. Internal carotid artery perfusion studies demonstrated an increase in the BBB permeability-sur face area (PS) product of 40% (P < 0.0005) in the chronically hypoglyc emic animals as compared with controls. Western blotting of solubilize d isolated brain capillaries demonstrated a 51% increase (P < 0.05) in immunoreactive BBB GLUT1 in the chronically hypoglycemic rats, and No rthern blotting of whole-brain poly(A+) mRNA revealed a 50% increase i n the GLUT1-to-actin ratio in the insulin-treated group (P < 0.05). No rthern blotting analysis of microvessel-depleted total brain poly(A+) showed that the increase in GLUT1 mRNA in the chronically hypoglycemic rats was restricted to the BBB. The present study demonstrates increa sed expression of GLUT1 mRNA and protein at the BBB in chronic hypogly cemia and suggests that this increase is responsible for the compensat ory increase in BBB glucose transport activity that occurs with chroni cally low circulating blood glucose levels.