EFFECTS OF GLUCOSE AND INSULIN ON DEVELOPMENT OF IMPAIRED INSULIN ACTION IN MUSCLE

Rat hindquarters were perfused for 2 h with either 0, 5, or 25 mM glucose in combination with either 0, 50, or 20,000-mu-U insulin/ml, whereupon responsiveness of glucose uptake to 20,000-mu-U insulin/ml and 25 mM glucose was measured. Perfusion with 25 mM glucose and 20,000-mu-U insulin/ml resulted in an initial glucose uptake of 43.6 +/- 3.9-mu-mol.g-1.h-1, which decreased to 18.7 +/- 1.6-mu-mol.g-1.h-1 after 2 h (P < 0.001). Omission of glucose from the perfusate prevented the decrease in responsiveness, whereas 5 mM glucose caused a lesser decrease (to 28.3 +/- 2.2-mu-mol.g-1.h-1). At 0 and 50-mu-U insulin/ml the effects of glucose were present but were less pronounced. The decrease in insulin responsiveness of glucose uptake (55%) was accompanied by a lesser decrease (29%) in muscle glucose transport, whereas glucose transport in muscle membrane vesicles, muscle insulin binding, and insulin receptor tyrosine kinase activity were unchanged. Muscle glycogen synthase activity decreased (P < 0.005) during perfusion with 25 mM glucose and 20,000-mu-U insulin/ml but did not decrease during perfusion with no glucose and 20,000-mu-U insulin/ml. It is concluded that insulin responsiveness of glucose uptake in muscle is decreased by exposure to glucose in a dose-dependent manner and the inhibitory effect of glucose is enhanced by simultaneous insulin exposure. The mechanism behind this insulin resistance could partly be explained by a decrease in muscle membrane glucose transport, possibly caused by changes in intracellular milieu.