The effects of Ca2+ and calcitonin infusions on circulating glucagon, glucose, C-peptide, Ca2+, and calcitonin were investigated in hyper-glucagonaemic insulin-dependent diabetics. In 14 insulin-deprived diabetics and 12 healthy volunteers 2h infusions of saline (0.154 mol/1), Ca2+ (0.375 mmol/kg body weight), and calcitonin (4.5 IU/kg body weight) were performed. There were no significant changes during saline infusion. In the diabetics, Ca2+ infusions induced a rise of plasma Ca2+ up to 3.2 +/- 0.1 mmol/1 and a fall of circulating glucagon (-26.4 +/- 5.7%; p less than 0.001) and glucose (-23.3 +/- 3.6%; p less than 0.05). Plasma calcitonin rose to twice basal values (p less than 0.025). During calcitonin infusions plasma Ca2+ decreased slightly to 2.1 +/- 0.2 mmol/1; a fall was found in both glucose (-24.4 +/- 4.0%; p less than 0.05) and circulating glucagon (-22.5 +/- 4.3%; p less than 0.001). Two groups of 6 healthy volunteers were subjected to saline and Ca2+, or to Ca2+ and calcitonin infusions. Both Ca2+ and calcitonin infusions induced a fall of serum insulin (-30.1 +/- 6.6%; p less than 0.05). Calcitonin depressed circulating glucagon by -18.6 +/- 4.4% (p less than 0.025), whereas during Ca2+ infusions glucagon decreased only by -6.5 +/- 1.9% (p greater than 0.1). We conclude from our results that an increase of circulating calcitonin induced by Ca2+ infusions or by exogenous calcitonin administration appears to depress elevated circulating glucagon and glucose in insulin-dependent diabetics.