Insulin resistance in normal rats infused with glucose for 72 h

Abstract

Insulin resistance is accentuated during periods of poor metabolic control in human non-insulin-dependent diabetes mellitus. The role of hyperglycemia in this suppression of insulin action is not clear. If glucose impairs insulin action, then the effect should be reproducible in vivo in tissues of normal intact rats. To test this possibility, normal rats were continuously administered 50% glucose in water (60-66 mg.kg-1.min-1) via an indwelling jugular catheter. After 72 h, these animals were hyperglycemic, hyperinsulinemic, and glucosuric compared with control rats infused for 72 h with normal saline (P less than 0.01). Basal glucose uptake in vivo was greater in muscle of glucose-infused rats. Insulin-stimulated glucose uptake in vivo and in vitro (by perfused hindquarters and isolated adipocytes) were suppressed in the glucose-infused group (P less than 0.01). Glycogen synthase activity was reduced 40% in extracts of muscle and adipose tissue of hyperglycemic rats. Basal and isoproterenol-stimulated lipolysis were increased, whereas insulin suppression of lipolysis was blunted in adipocytes from glucose-infused animals (P less than 0.01). Glucose infusion did not alter insulin binding by isolated adipocytes or solubilized skeletal muscle insulin receptors. These results suggest that a 72-h in vivo glucose infusion impaired insulin action in muscle and adipose tissue of normal rats by inducing postbinding defects similar to those observed in human diabetes mellitus during intervals of deteriorated metabolic control.

Prolonged glucose infusion into conscious rats inhibits early steps in insulin signalling and induces translocation of GLUT4 and protein kinase C in skeletal muscle

“…Together, these data indicate that neither expression of the components of the insulin signalling cascade nor their activity is significantly increased by continuous glucose infusion after 2 or 5 days. These data explain the earlier finding that glucose oversupply induces insulin resistance in skeletal muscle [39,40,49].…”

“…In this model, rats adapt to and minimize the degree of hyperglycaemia despite continuously ongoing systemic glucose oversupply [39,53]. This adaptation cannot be explained by compensatory renal glucose clearance [39,53]. As previously shown, not all glucose is taken up by muscle and fat tissue but also by the liver and other tissues indicating a role of these organs in glucose homeostasis [53].…”

“…Representative Western blots are shown from a set of three independent experiments take in vivo, we used the glucose-infused rat model originally developed by Leahy et al [38]. In this model, rats adapt to and minimize the degree of hyperglycaemia despite continuously ongoing systemic glucose oversupply [39,53]. This adaptation cannot be explained by compensatory renal glucose clearance [39,53].…”

“…Earlier studies with this model have shown that continuous glucose infusion induces both increased glucose metabolism and insulin resistance in rat skeletal muscle [39,40,49]. To see if increased glucose-uptake in glucose-infused rats is mediated by an enhanced insulin action, we studied the amount and activity of the known early steps insulin signalling proteins.…”

“…In this model, continuous systemic glucose oversupply induces insulin resistance in skeletal muscle and leads to significant hyperglycaemia [38±40]. Within days rats adapt to this state and reduce blood glucose to normal concentrations by processes which are not known [39,40]. The long-term glucose oversupply results in an increased glucose clearance with enhanced glucose uptake, lipogenesis and insulin action in adipose tissue while skeletal muscle showed a sustained insulin resistance with triglyceride accumulation [40].…”