Extrarenal potassium disposal is an important defense against hyperkalemia in patients with end-stage renal disease. Both insulin and epinephrine are important modulators of this process. Hemodialysis patients are prone to developing hyperkalemia during fasting. We tested the hypothesis that the infusion of physiologic doses of insulin prevents fasting hyperkalemia in hemodialysis patients, both by a direct stimulation of extrarenal potassium disposal, as well as by augmenting the potassium-lowering effect of epinephrine. Ten stable, nondiabetic maintenance hemodialysis patients were studied prospectively in a Clinical Research Center. They were fasted for 18 hours, followed by an acute infusion of epinephrine at 0.01 μg/kg/min, in the absence or presence of prior beta-blockade with propranolol. Serial measurements of plasma potassium, insulin and glucose were obtained. The patients were restudied under the same experimental protocols, while receiving a continuous infusion of insulin with dextrose. The plasma potassium increased by 0.58 ± 0.13 mmol/liter (P = 0.002) after 18 hours of fasting. Administration of insulin with dextrose at a dose that doubled the plasma insulin levels within the physiologic range (9.3 ± 1.1 vs. 20.2 ± 2.3 mU/liter, P < 0.002), completely prevented the rise in plasma potassium (+0.06 ± 0.13 mmol/liter, P = 0.64). Epinephrine did not significantly change the plasma potassium during fasting alone (+0.05 ± 0.09 mmol/liter, P = 0.59), whereas it lowered the potassium significantly (-0.16 ± 0.04 mmol/liter, P = 0.003) when the subjects were receiving insulin with glucose. Epinephrine in the presence of beta-blockade produced similar increases in plasma potassium in the absence or presence of concomitant administration of insulin with glucose (0.25 ± 0.10 vs. 0.20 ± 0.03 mmol/liter). These observations demonstrate that insulin-with-glucose at physiologic doses prevents fasting hyperkalemia in hemodialysis patients, both by directly stimulating uptake of potassium into the cells, as well as by potentiating the potassium-lowering effect of beta-adrenergic stimulation. We propose that when hemodialysis patients prone to hyperkalemia are fasted in preparation for surgery or a diagnostic procedure, a continuous infusion of insulin with dextrose may prevent hyperkalemia.