The euglycemic clamp technique is a useful tool to evaluate insulin-mediated glucose uptake. The plasma phosphate concentration decreases during euglycemic clamp studies. Because insulin-dependent glucose uptake is closely related to phosphate uptake, we investigated whether modulation of plasma phosphate levels in the range observed during clamp studies influences insulin sensitivity. We studied 11 healthy (phosphate-replete) male volunteers (mean age, 27.5 +/- 1.8 yr;, mean body mass index, 23.9 +/- 1.6 kg/m2) in a double blind placebo-controlled cross-over study. The volunteers received in random order on two occasions either an infusion of sodium chloride (sham infusion) or an infusion of sodium phosphate. Insulin sensitivity was assessed under euglycemic conditions (clamp technique). The mean plasma phosphate concentration decreased with sham infusion from 1.09 +/- 0.17 to 0.64 +/- 0.13 mmol/L, whereas it increased with phosphate infusion from 1.06 +/- 0.19 to 1.32 +/- 0.13 mmol/L. In all volunteers except one the glucose disposal rate (M-value) was higher after phosphate infusion (mean M-value, 10.4 +/- 1.5 mg/kg.min) than that after sham infusion (mean M-value, 9.4 +/- 1.5 mg/kg.min; P < 0.01, by Wilcoxon's test for paired samples). There were no significant differences in mean plasma glucose, sodium, insulin, or arterialized standard bicarbonate levels with the two infusion protocols. Mean plasma calcium, albumin-corrected calcium, and potassium levels, however, were all significantly (P < 0.05) lower after phosphate infusion than after sham infusion. The mean PTH level decreased with sham infusion from 28 +/- 9 to 20 +/- 6 ng/L, whereas it increased with phosphate infusion from 26 +/- 9 to 36 +/- 8 ng/L, whereas it increased with phosphate infusion from 26 +/- 9 to 36 +/- 8 ng/L. The difference between the two infusion protocols was statistically significant (P < 0.01). The data presented illustrate that plasma phosphate (and calcium) levels may be confounders that should be at least monitored, and possibly controlled for, when performing euglycemic clamp studies.