REDUCED GLUCOSE CLEARANCE AS THE MAJOR DETERMINANT OF POSTABSORPTIVE HYPERGLYCEMIA IN DIABETIC RATS

The relationships between postabsorptive glucose concentration and hep atic glucose output (HGO) and glucose clearance were studied in rats o ne day after treatment with various doses of streptozotocin (STZ; 0, 1 5, 30, 40, 50, or 75 mg/kg; n = 6 per dose; study 1). Glucose fluxes w ere estimated using a prolonged (6-h) infusion of [3-H-3]glucose to en sure complete tracer equilibration at hyperglycemia. Postabsorptive gl ucose was significantly increased at the high doses of STZ (50 and 75 mg/kg; P < 0.01) and was strongly correlated with glucose clearance ac ross all doses (r = -0.85, P < 0.001) but less strongly with HGO (r = 0.46, P < 0.01). In the group treated with 50 mg/kg STZ, postabsorptiv e glucose was increased twofold compared with the control (i.e., zero dose) group, with no change in HGO and a 45% decrease in glucose clear ance, indicating that the hyperglycemia was due to a decrease in gluco se clearance. To understand the cellular mechanisms of decreased gluco se clearance in STZ diabetic rats, skeletal muscle glucose clearance a nd intracellular glucose and glucose 6-phosphate (G-6-P) concentration s were determined in normal and STZ (50 mg/kg) diabetic rats at their postabsorptive glucose levels as well as at matched hyperglycemia (12 mM; study 2). Glucose clearance was significantly decreased in soleus (P < 0.05) muscles of the diabetic rats, and this was associated with significantly decreased intracellular glucose and G-6-P levels at matc hed hyperglycemia (P < 0.05), suggestive of decreased glucose transpor t. In conclusion, postabsorptive hyperglycemia in STZ diabetic rats wa s largely due to decreased glucose clearance, although increased HGO m ay also have been a contributing factor at the highest STZ dose. The d ecrease in postabsorptive glucose clearance in STZ diabetic rats appea red to be associated with an impairment of glucose transport in soleus (type I) muscles.