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 explored in an insulin resistant rat model. Oophorectomized female rats were exposed to testosterone (OVX + T) for 8 weeks and examined with insulin clamps, 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 significantly (P < 0.001-0.05) delayed compared with controls as measured by the glucose infusion rate (GIR) during a euglycaemic, hyperinsulinaemic clamp (5 mU kg-1 min-1). The increase in interstitial insulin concentrations was also 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 could not explain the late onset of the insulin effect. Skeletal muscle capillary 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 microsphere 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 insulin spaces in muscle with time, tended (ns) to be lower after OVX + T compared with control rats (30-40%) as a reflection of the lower capillary surface area. The data suggest that the delayed onset of insulin action after OVX + T results from combined defects in the muscle cell at a postreceptor level and, to a lesser extent, from retarded transcapillary delivery of insulin.
Holmäng
A
A
Department of Heart and Lung Diseases and the Wallenberg Laboratory, Göteborg, Sweden.
Niklasson
M
M
Rippe
B
B
Lönnroth
P
P
D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects / Q000502:physiology; D001786:Blood Glucose; D002196:Capillaries / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015309:Glucose Clamp Technique; D007328:Insulin / Q000493:pharmacokinetics / Q000502:physiology*; D007333:Insulin Resistance / Q000502:physiology*; D007444:Inulin / Q000493:pharmacokinetics; D017551:Microdialysis; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000494:pharmacology*
D001786:Blood Glucose; D007328:Insulin; D013739:Testosterone; D007444:Inulin