The glucagon-suppressing activity of insulin and somatostatin were compared at high and low glucose concentrations. In normal dogs made hyperglucagonemic by phloridzin pretreatment, insulin and somatostatin suppressed glucagon at rates of 47 +/- 8 and 35 +/- 8%/h (NS), respectively, despite profound hypoglycemia. In severely hyperglycemic alloxan-diabetic dogs, insulin and somatostatin suppressed glucagon at rates of 48 +/- 13 and 54 +/- 6%/h, respectively, not different from the nondiabetic dogs. After phloridzin pretreatment to eliminate hyperglycemia in the diabetic dogs, insulin and somatostatin suppressed 51 +/- 8 and 31 +/- 10%/h (NS), respectively. Glucose infused in the phloridzin-pretreated insulin-deprived group suppressed glucagon only partially; insulin was required to reduce it further. We conclude that insulin and somatostatin suppress glucagon at similar rates irrespective of ambient glucose levels, and that diabetic hyperglucagonemia represents the summation of stimulation by insulin lack minus suppression by the associated hyperglycemia.