Insulin insensitivity and delayed transcapillary delivery of insulin in oophorectomized rats treated with testosterone

The importance of transcapillary insulin delivery as a regulated step was e xplored in an insulin resistant rat model. Oophorectomized female rats were exposed to testosterone (OVX + T) for 8 weeks and examined with insulin cl amps, muscle microdialysis, and analyses of insulin distribution kinetics. The results were compared with those obtained in sham-operated control rats . After OVX + T, onset of glucose uptake in skeletal muscle was significant ly (P < 0.001-0.05) delayed compared with controls as measured by the gluco se infusion rate (GIR) during a euglycaemic, hyperinsulinaemic clamp (5 mU kg(-1) min(-1)). The increase in interstitial insulin concentrations was al so significantly (P < 0.05) delayed (15-20% lower) in OVX + T treated rats compared with control rats, but to such a small magnitude that this alone c ould not explain the late onset of the insulin effect. Skeletal muscle capi llary density, examined histochemically, was diminished (P < 0.01-0.001) by 20-25% after treatment with OVX + T compared with control animals, as was the peripheral blood flow (P < 0.05) by 40-45%, measured with the microsphe re technique. Insulin binding was reduced in proportion to the reduced (P < 0.01) vascular surface area by OVX + T treatment. Transcapillary transport rate of insulin, measured by comparisons of the kinetics of inulin and ins ulin spaces in muscle with time, tended (ns) to be lower after OVX + T comp ared with control rats (30-40%) as a reflection of the lower capillary surf ace area. The data suggest that the delayed onset of insulin action after O VX + T results from combined defects in the muscle cell at a postreceptor l evel and, to a lesser extent, from retarded transcapillary delivery of insu lin.