Conclusions drawn from the pancreatic (or islet) clamp technique - suppression of endogenous insulin, glucagon and growth hormone secretion with somatostatin and replacement of basal hormone levels by intravenous infusion - are critically dependent on the biological appropriateness of the selected doses of the replaced hormones. To assess the appropriateness of representative doses, we infused saline alone, insulin (initially 0.20 mU·kg^-1·min.^-1) alone, glucagon (1.0 ng·kg^-1·min.^-1) alone and growth hormone (3.0 ng·kg^-1·min.^-1) alone intravenously for four hours in 13 healthy individuals. That dose of insulin raised plasma insulin concentrations ~3 fold, suppressed glucose production and drove plasma glucose concentrations down to subphysiological levels (65±3 mg/dL, P<0.0001 vs. saline) resulting in nearly complete suppression of insulin secretion (P<0.0001) and stimulation of glucagon (P=0.0059) and epinephrine (P=0.0009) secretion. An insulin dose of 0.15 mU·kg^-1·min.^-1 caused similar effects but a dose of 0.10 mU·kg^-1·min.^-1 did not. The glucagon and growth hormone infusions did not alter plasma glucose levels or those of glucoregulatory factors. Thus, insulin "replacement" doses of 0.20 and even 0.15 mU·kg^-1·min.^-1 are excessive and conclusions drawn from the pancreatic clamp technique using such doses may need to be re-assessed.