Abstract

Insulin resistance is a prominent feature of diabetic state and has heterogeneous nature. However, the pathogenetic sequence of events leading to the emergence of the defect in insulin action remains controversial. It is well-known that prolonged hyperglycemia and hyperinsulinemia are one of the causes of development of insulin resistance, but both hyperglycemia and hyperinsulinemia stimulate glucose uptake in peripheral tissue. Therefore, it is hypothesized that insulin resistance may be generated by a kind of protective mechanism preventing cellular hypertrophy. In this study, to evaluate whether the acutely increased glucose uptake inhibits further glucose transport stimulated by insulin, insulin sensitivity was measured after preloaded glucose infusion for 2 hours at various conditions in rats. And also, to evaluate the mechanism of decreased insulin sensitivity, insulin receptor binding affinity and glucose transporter 4 (GLUT4) protein of plasma membrane of gastrocnemius muscle were assayed after hyperinsulinemic euglycemic clamp studies. Experimental animals were divided into five groups according to conditions of preloaded glucose infusion: group I, basal insulin (14+/-1.9 micronU/ml) and basal glucose (75+/-0.7 mg/dl), by normal saline infusion; group II, normal insulin (33+/-3.8 micronU/ml) and hyperglycemia (207+/-6.3 mg/dl), by somatostatin and glucose infusion; group III, hyperinsulinemia (134+/-34.8 micronU/ml) and hyperglycemia (204+/-4.6 mg/dl), by glucose infusion; IV, supramaximal insulin (100+/-2.2 mg/dl), by insulin and glucose infusion; group V, supramaximal insulin(4813+/-687.9 micronU/ml) and hyperglycemia (233+/-3.1 mg/dl), by insulin and glucose infusion. Insulin sensitivity was assessed with hyperinsulinemic euglycemic clamp technique. The amounts of preloaded glucose infusion(gm/kg) were 1.88+/-0.151 in group II, 2.69+/-0.239 in group III, 3.54+/-0.198 in groupIV, and 4.32+/-0.621 in group V. Disappearance rates of glucose (Rd, mg/kg/min) at steady state of hyperinsulinemic euglycemic clamp studies were 16.9+/-3.88 in group I, 13.5+/-1.05 in group II, 11.2+/-1.17 in group III, 13.2+/-2.05 in group IV, and 10.4+/-1.01 in group V. A negative correlation was observed between amount of preloaded glucose and Rd )r=-0.701, p<0.001) when all studies were combined. Insulin receptor binding affinity and content of GLUT4 were not significantly different in all experimental groups. These results suggest that increased glucose uptake may inhibit further glucose transport and lead to decreased insulin sensitivity.

• Keywords: Glucose uptake;Insulin resistance;Hyperinsulinemia;Hyperglycemia;