Interstitial Muscle Insulin and Glucose Levels in Normal and Insulin-Resistant Zucker Rats

To study interstitial insulin and glucose concentrations, microdialysis was performed in the medial femoral muscles in normal SD rats as well as in insulin-resistant obese Zucker rats during a euglycemic insulin clamp. [¹⁴C]inulin was given (0.1 mCi/rat) as a constant subcutaneous 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 [¹⁴C]inulin dialysate recoveries was evaluated in vivo and in vitro 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 insulin concentrations were identical when plasma insulin was ≤250 mU/ml, whereas interstitial insulin was lower when plasma insulin was ≥350 mU/ml. Half-maximal glucose infusion rate was achieved in the presence of plasma and interstitial insulin concentrations of ∼140 mU/ml, whereas maximal glucose disposal was seen at interstitial insulin concentrations of ∼325 mU/ml, corresponding to ∼500 mU/ml in plasma. In electrically stimulated and contracting (1 Hz) normal muscle with markedly increased blood flow, the dialysate insulin concentration was significantly higher at high rates, but not at low rates, of insulin infusion. 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 the obese Zucker rats at both insulin infusion rates than in the lean animals. The glucose content in dialysates from skeletal muscle was equal in both obese and lean rats during the low insulin infusion rate. During 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 and glucose diffusion across the capillary wall are rate limiting for insulin as well as for glucose metabolism in muscle in normal rats. This does not appear to be the case in the insulin-resistant obese Zucker rats, where the reduced insulin responsiveness in muscle is due to muscular cellular defects rather than an inhibited transcapillary delivery of insulin.