Dysregulation of glucose transport and transporters in perfused hearts of genetically obese (fa/fa) rats

Abstract

Summary. The regulation of glucose transport in normal and insulin-resistant obese rat hearts have been studied by measuring glucose transport via the efflux of labelled 3-0-methyl-Dglucose. Glucose transporters in obese rat hearts were also investigated using the labelled cytochalasin B-binding assay. Basal, and insulin -or increasing workload-induced stimulation of glucose transport was decreased in obese rat hearts compared to those of normal ones. Total number of glucose transporters (plasma membrane plus microsomal ones) was about half that previously reported for normal rat hearts. Insulin or workload favoured the translocation of glucose transporters from an intercellular pool (microsomes) to the plasma membrane, as they do in normal rats. Due to the measured decrease in total number of transporters of obese rat hearts, those present in the plasma membrane (under basal conditions, or following stimulation by insulin or workload) were less than those previously found[ in normal rat hearts tested under identical conditions. In obese rat hearts, regulation of plasma membrane transporters was perturbed. The Hill coefficient (an index of positive cooperativity amongst glucose transporters) was paradoxically decreased by insulin while leaving affinity values unaltered. The Hill coefficient was unaltered by workload, although the affinity values were increased compared to respective controls. To sum up, obese rat hearts have decreased total transporter number, and although the two stimuli studied favour the translocation of available transporters, they fail to "activate" them adequately once present in the plasma membrane.

Exercise training increases glucose transporter protein GLUT‐4 in skeletal muscle of obese Zucker (fa/fa) rats

“…The genetically obese Zucker (fa/fa) rat has proven to be a useful model for the study of mechanisms of insulin resistance because of the well characterized defect in insulin-stimulated glucose uptake by skeletal muscle [1,2,15]. Although insulin receptor binding is decreased in soleus muscle from obese Zucker rats compared with lean rats [ 1,331, the major mechanism underlying the insulin resistance in obese Zucker rats resides in the glucose transport system [2,34]. In the current study we found that the previously observed defect in glucose transport is not accompanied by a depletion of the GLUT-4 glucose transporter protein.…”

Impaired glucose metabolism in the heart of obese Zucker rats after treatment with phorbol ester

“…1,2 In these animals, insulin-stimulated glucose uptake into cardiac and skeletal muscles is markedly decreased, 3,4 and insulin fails to recruit the predominant glucose transporter isoform GLUT-4. 5,6 Obese Zucker rats also exhibit diminished glucose uptake, glucose oxidation 7 and incorporation of glucose into glycogen 8 as well as differences in protein turnover and amino acid metabolism.…”

Rosiglitazone Treatment in Zucker Diabetic Fatty Rats Is Associated With Ameliorated Cardiac Insulin Resistance and Protection From Ischemia/Reperfusion-Induced Myocardial Injury

“…Insulin resistance in the heart has been demonstrated in obese rats, associated with decreased GLUT4 protein content and impaired GLUT4 translocation to the sarcolemma (9,10). Cardiac insulin resistance was also demonstrated in diabetic patients with cardiac diseases (11)(12)(13).…”

“…NMR analysis was performed at 9.4 Tesla (WB-400 Avance NMR spectrometer; Bruker Medical, Billerica, MA). Protonobserved, carbon-enhanced spectroscopy was performed on tissue extract samples for measuring [3][4][5][6][7][8][9][10][11][12][13] Western blot analysis for determination of Akt, Akt-pS473, glycogen synthase kinase-3␤-pS9, and FKHR-pS256. Myocardial Akt, phospho-Akt (Akt-pS473), phospho-FKHR (forkhead transcription factor; FKHR-pS256), and phospho-glycogen synthase kinase (GSK)-3␤ (GSK-3␤-pS9) in the ischemic myocardium after 4-h reperfusion were determined by Western blot analysis as reported previously (26).…”