INTERSTITIAL MUSCLE INSULIN AND GLUCOSE-LEVELS IN NORMAL AND INSULIN-RESISTANT ZUCKER RATS

To study interstitial insulin and glucose concentrations, microdialysi s was performed in the medial femoral muscles in normal SD rats as wel l as in insulin-resistant obese Zucker rats during a euglycemic insuli n clamp. [C-14]inulin was given (0.1 mCi/rat) as a constant subcutaneo us infusion 24 h before the insulin clamp. Insulin infusion rates were 5-8 mU kg(-1) min(-1) (low rate) for 140 min and 10-20 mU kg(-1) min( -1) (high rate) for another 100 min. The relationship between insulin and [C-14]inulin dialysate recoveries was evaluated in vivo and in vit ro in plasma to calculate interstitial insulin concentration. Relative microdialysis recovery of interstitial insulin in vivo was 3.0 +/- 0. 3% (mean +/- SE, n = 68). In normal SD rats, plasma and interstitial i nsulin concentrations were identical when plasma insulin was less than or equal to 250 mU/ml, whereas interstitial insulin was lower when pl asma insulin was greater than or equal to 350 mU/ml. Half-maximal gluc ose infusion rate was achieved in the presence of plasma and interstit ial insulin concentrations of similar to 140 mU/ml, whereas maximal gl ucose disposal was seen at interstitial insulin concentrations of simi lar to 325 mU/ml, corresponding to similar to 500 mU/ml in plasma. In electrically stimulated and contracting (I Hz) normal muscle with mark edly increased blood flow, the dialysate insulin concentration was sig nificantly higher at high rates, but not at low rates, of insulin infu sion. In insulin-resistant obese Zucker rats, the interstitial insulin concentration was similar to that in plasma, even at pharmacological concentrations. The glucose infusion rate was significantly lower in t he obese Zucker rats at both insulin infusion rates than in the lean a nimals. The glucose content in dialysates from skeletal muscle was equ al in both obese and lean rats during the low insulin infusion rate. D uring the high insulin infusion rate, dialysate glucose concentrations decreased significantly in both groups but were significantly higher in the obese Zucker rats. The data suggest that transport of insulin a nd glucose diffusion across the capillary wall are rate limiting for i nsulin as well as for glucose metabolism in muscle in normal rats. Thi s does not appear to be the case in the insulin-resistant obese Zucker rats, where the reduced insulin responsiveness in muscle is due to mu scular cellular defects rather than an inhibited transcapillary delive ry of insulin.