Despite some evidence of self-regulation of insulin secretion, it is unclear whether endogenous insulin influences insulin secretion independently of blood glucose. The aim of the present study was to examine this question in humans. Seven healthy fasting man were given two-hour porcine insulin infusions (40 mU/min) with and without maintenance of euglycemia (glucose clamp). Intravenous glucose required to maintain basal blood glucose levels (4.2 +/- 0.1 mmole/liter) during insulin infusion was 34.3 +/- 3.0 gm with a mean rate of 273 +/- 29 mg/min in the second hour of insulin infusion. During the glucose clamp, mean C-peptide levels were not significantly altered from fasting levels of 1.91 +/- 0.24 ng/ml, but when blood glucose levels fell by approximately 1 mmole/liter, C-peptide fell to 0.37 +/- 0.07 ng/ml. Plateau insulin levels were significantly higher during euglycemia than during mild hypoglycemia (53.2 +/- 5.6 mU/liter versus 38.5 +/- 3.6 mU/liter, P less than 0.01). Plasma nonesterified fatty acids were suppressed equally in the two studies. However, a rise in plasma glucagon seen during mild hypoglycemia was absent when euglycemia was maintained. We conclude that insulin self-regulation (either direct of neurally mediated) is not physiologically important in the basal state in normal humans and that the blood glucose-insulin feedback loop dominates in the short-term control of basal insulin secretion.