Reduced glucose clearance as the major determinant of postabsorptive hyperglycemia in diabetic rats.

The relationships between postabsorptive glucose concentration and hepatic glucose output (HGO) and glucose clearance were studied in rats one day after treatment with various doses of streptozotocin (STZ; 0, 15, 30, 40, 50, or 75 mg/kg; n = 6 per dose; study 1). Glucose fluxes were estimated using a prolonged (6-h) infusion of [3-3H]glucose to ensure complete tracer equilibration at hyperglycemia. Postabsorptive glucose was significantly increased at the high doses of STZ (50 and 75 mg/kg; P < 0.01) and was strongly correlated with glucose clearance across 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, postabsorptive glucose was increased twofold compared with the control (i.e., zero dose) group, with no change in HGO and a 45% decrease in glucose clearance, indicating that the hyperglycemia was due to a decrease in glucose clearance. To understand the cellular mechanisms of decreased glucose clearance in STZ diabetic rats, skeletal muscle glucose clearance and intracellular glucose and glucose 6-phosphate (G-6-P) concentrations 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 matched hyperglycemia (P < 0.05), suggestive of decreased glucose transport. In conclusion, postabsorptive hyperglycemia in STZ diabetic rats was largely due to decreased glucose clearance, although increased HGO may also have been a contributing factor at the highest STZ dose. The decrease in postabsorptive glucose clearance in STZ diabetic rats appeared to be associated with an impairment of glucose transport in soleus (type I) muscles.