In 23 diabetic patients, the disappearance from subcutaneous tissue of 125I-labelled short-acting insulin and of 133Xe (measuring subcutaneous blood flow (SBF] were registered simultaneously. Alterations in the SBF were produced either by orthostatic changes or by application of local heat or cold. The insulin absorption rate was related to the SBF in a curvilinear way with an almost linear relation at SBF below 2-3 ml . (min . 100 g)-1, whereas at SBFs above the value the insulin absorption rate increased less than proportional to SBF. Capillary diffusion capacity of the injected insulin was 0.0145-0.0874 ml . (min . 100 g)-1; indicating that insulin is absorbed in a polymeric form. This was supported by studies of insulin diffusion in agar gel at 37 degrees C, showing that insulin in the normal pharmacological concentration diffuses as a molecule of about 46,000 MW. In conclusion, the absorption of short-acting soluble insulin is curvilinearly related to the SBF. This can be explained by a diffusion-limited transport of insulin in the interstitial space, and increasing transcapillary transport of insulin at increasing blood flow rates caused by recruitment of capillaries, thus increasing exchange surface area and decreasing diffusion distance.