Sulphonylurea stimulates glucose uptake in rats through an ATP-sensitive K+ channel dependent mechanism

We studied the effect of gliclazide, a second-generation sulphonylurea, on rat skeletal muscle glucose uptake using perfused hindquarter muscle preparations. Gliclazide at concentrations of 10 to 1000 microgram/ml increased (p < 0.05) the basal glucose uptake. The effect of gliclazide on glucose uptake was immediate and dose-dependent, reaching a plateau at a concentration of 300 micrograms/ml; the half-maximal effect was obtained between 25 and 50 micrograms/ml. The glucose uptake stimulated by gliclazide (300-1000 micrograms/ml) did not differ from that achieved by 10(-9) mol/l insulin, and was lower (p < 0.05) than that obtained with 10(-7) mol/l insulin. The combination of gliclazide (300 micrograms/ml) and 10(-9) mol/l insulin produced an increase in glucose uptake (7.7 +/- 0.6 mumol.g-1.h-1, n = 8, mean +/- SEM) which was higher (p < 0.05) than that achieved with 10(-9) mol/l insulin (5.6 +/- 0.7 mumol.g-1.h-1, n = 11) and not different from that obtained with 10(-7) mol/l insulin (9.8 +/- 1.0 mumol.g-1.h-1, n = 11). Diazoxide (100 mumol/l), an ATP-sensitive K+ channel opener, reversed the stimulatory effect of gliclazide (100 microgram/ml) on muscle glucose uptake from 3.1 +/- 0.4 to 0.5 +/- 0.2 mumol.g-1.h-1, (n = 7, p < 0.001). The addition of diazoxide prior to gliclazide into the perfusion medium blocked the gliclazide-induced glucose uptake by the hindquarter muscle preparations. In conclusion, gliclazide alone has an immediate stimulatory effect on glucose uptake by skeletal muscle and together with insulin has an additive effect on muscle glucose uptake. The effect of gliclazide on muscle glucose uptake seems to be due to the inhibition of ATP-sensitive K+ channels.