D-GLUCOSE STIMULATES MESANGIAL CELL GLUT1 EXPRESSION AND BASAL AND IGF-I-SENSITIVE GLUCOSE-UPTAKE IN RAT MESANGIAL CELLS - IMPLICATIONS FORDIABETIC NEPHROPATHY

The complications of diabetes arise in part from abnormally high cellu lar glucose uptake and metabolism. To determine whether altered glucos e transporter expression may be involved in the pathogenesis of diabet ic nephropathy, we investigated the effects of elevated extracellular glucose concentrations on facilitative glucose transporter (GLUT) expr ession in rat mesangial cells. GLUT1 was the only transporter isoform detected. Cells exposed to 20 mmol/l glucose medium for 3 days demonst rated increases in GLUT1 mRNA (134%, P < 0.002), GLUT1 protein (68%, P < 0.02), and V-max (50%, P < 0.05) for uptake of the glucose analog [ 3(H)]2-deoxyglucose ((3)H2-DOG), when compared to cells chronically ad apted to physiologic glucose concentrations (8 mmol/l). The increase i n GLUT1 protein was sustained at 3 months, the latest time point teste d (77% above control, P < 0.01). In contrast, hypertonic mannitol had no effect on GLUT1 protein levels. Insulin-like growth factor I (IGF-I ; 30 ng/ml) increased the uptake of (3)H2-DOG by 28% in 8 mmol/l gluco se-treated cells (P < 0.05) and by 75% in cells switched to 20 mmol/l glucose for 3 days (P < 0.005). These increases in (3)H2-DOG uptake oc curred despite a lack of effect of IGF-I on GLUT1 protein levels (P > 0.5 vs. control). Therefore, hyperglycemia and IGF-I treatment both le ad to increases in mesangial cell glucose uptake, and hyperglycemia in duces increased GLUT1 expression, which can directly lead to the patho logical changes of diabetic nephropathy. The effects of high glucose a nd of IGF-I to stimulate (3)H2-DOG uptake also appear to be additive.