We have previously described, in insulin-dependent diabetic subjects (IDDM), a small, but significant, increase in the insulin clearance rate (ICR) during 0600-0800 h as compared with 0100-0300 h. To determine whether this increase was also seen at more physiologic levels of insulin replacement, we calculated ICR during euglycemic clamp studies in 13 patients with IDDM with a constant infusion of insulin at 20 mU/min/m2 and during insulin replacement from the Biostator GCIIS without exogenous glucose. During the euglycemic clamp study with constant insulin infusion at 20 mU/min/m2, the ICR was 16% higher at 0600-0800 h than at 0100-0300 h (264 ± 50 ml/min/m2 versus 228 ± 51 ml/min/m2; P<0.005). During insulin replacement by the Biostator, the mean insulin infusion rate increased by 92 ± 27% (7.5 ± 1.1 to 13.5 ± 1.2 mU/min/m2; P<0.001) and ICR increased by 123 ± 30% (130 ± 24 to 268 ± 51 ml/min/m2; P<0.01) during the prebreakfast period when compared with 0100-0300 h. There was a highly significant correlation (r = 0.97) between the increment in insulin infusion rate and the increment in ICR. Measurement of insulin concentration in saline solutions, delivered by the Biostator at a same rate and under similar conditions to those in this study, showed that insulin delivery was stable for the 8-h period of this study. We conclude that, at levels of insulin replacement that maintain blood glucose between 90 and 100 mg/dl, variation in the ICR is an important contributor to the 'dawn phenomenon' of increasing early morning blood glucose concentration and insulin requirements in diabetic subjects.