Showing papers by "Michael F. Hirshman published in 1992"

Insulin resistance in obese Zucker rat (fa/fa) skeletal muscle is associated with a failure of glucose transporter translocation.

Abstract: The genetically obese Zucker rat (fa/fa) is characterized by a severe resistance to the action of insulin to stimulate skeletal muscle glucose transport. The goal of the present study was to identify whether the defect associated with this insulin resistance involves an alteration of transporter translocation and/or transporter activity. Various components of the muscle glucose transport system were investigated in plasma membranes isolated from basal or maximally insulin-treated skeletal muscle of lean and obese Zucker rats. Measurements of D- and L-glucose uptake by membrane vesicles under equilibrium exchange conditions indicated that insulin treatment resulted in a four-fold increase in the Vmax for carrier-mediated transport for lean animals [from 4.5 to 17.5 nmol/(mg.s)] but only a 2.5-fold increase for obese rats [from 3.6 to 9.1 nmol/(mg.s)]. In the lean animals, this increase in glucose transport function was associated with a 1.8-fold increase in the transporter number as indicated by cytochalasin B binding, a 1.4-fold increase in plasma membrane GLUT4 protein, and a doubling of the average carrier turnover number (intrinsic activity). In the obese animals, there was no change in plasma membrane transporter number measured by cytochalasin B binding, or in GLUT4 or GLUT1 protein. However, there was an increase in carrier turnover number similar to that seen in the lean litter mates. Measurements of GLUT4 mRNA in red gastrocnemius muscle showed no difference between lean and obese rats. We conclude that the insulin resistance of the obese rats involves the failure of translocation of transporters, while the action of insulin to increase the average carrier turnover number is normal.

Glucose transporter number, function, and subcellular distribution in rat skeletal muscle after exercise training.

Abstract: Endurance exercise training can result in increased rates f insulin-stimulated glucose uptake in skeletal muscle; however, this effect may be lost rapidly once training ceases. To examine a mechanism for these changes, the skeletal-muscle glucose transport system of female rats exercise-trained in wheelcages for 6 wk were studied against a group of untrained female rats. The trained rats were studied immediately following and 2 and 5 days after removal from wheelcages; both trained and untrained rats were studied 30 min after insulin (90 nmol/rat, intraperitoneal) or saline injection. The total number of skeletal-muscle plasma-membrane glucose transporters ( R o ), total muscle-homogenate and plasma-membrane GLUT4 protein, and rates of plasma-membrane vesicle D-facilitated glucose transport were higher in the exercise-trained rats immediately after exercise training and did not decrease significantly during the 5 days after cessation of training. On the other hand, exercise training did not alter microsomal-membrane total glucose-transporter number or GLUT4 protein, nor did training alter GLUT1 protein in total muscle homogenates nor either membrane fraction. The carrier-turnover number, an estimate of average functional activity of glucose transporters in the plasma membrane, was elevated slightly, but not significantly, in the trained muscle. In both the trained and untrained muscle, insulin administration resulted in translocation of glucose transporters from the microsomal-membrane fraction to the plasma membrane and an increase in the carrier-turnovernumber. These data suggest that increased rates of glucose uptake in endurance-trained skeletal muscle results primarily from an increase in the number—and not an increase in the average functional activity—of glucose transporters present in the plasma membrane. Furthermore, these increases persist for several days after cessation of exercise training. The specific increase in the GLUT4, but not the GLUT1 glucose-transporter isoform, in response to training demonstrates that a common, chronic physiological stimulus can regulate the expression of the two glucose-transporter isoforms present in skeletal-muscle tissue differentially.

Effect of exercise training and chronic glyburide treatment on glucose homeostasis in diabetic rats

Abstract: Exercise training and sulfonylurea treatment, either individually or in combination, were evaluated for their effects on plasma glucose concentrations, oral glucose tolerance, and glucose clearance in the perfused hindquarter of diabetic rats. Female rats that were injected with streptozocin (45 mg/kg iv) and had plasma glucose concentrations between 11 and 25 mM were considered diabetic and divided into sedentary, glyburide-treated, exercise-trained, and glyburide-treated plus exercise-trained groups. The sedentary streptozocin-treated rats were severely diabetic, as indicated by elevated glucose concentrations, impaired insulin response during oral glucose tolerance tests, and lower rates of glucose clearance in hindlimb skeletal muscle. Neither 8 wk of exercise training nor 4 wk of glyburide treatment alone improved these parameters. In contrast, the diabetic rats that were both trained and treated with glyburide showed some improvement in glucose homeostasis, as evidenced by lower plasma glucose concentrations, an enhanced insulin response to an oral glucose load, and a decrease in the severity of skeletal muscle insulin resistance compared with the diabetic controls. These data suggest that glyburide treatment or exercise training alone does not alter glucose homeostasis in severely insulin-deficient diabetic rats; however, the combination of exercise training and glyburide treatment may interact to improve glucose homeostasis in these animals.