The development of a glucagon radioimmunoassay with a relatively high degree of specificity for pancreatic glucagon made possible studies of alpha cell function in healthy nondiabetic subjects and in patients with diabetes mellitus. In the former group mean fasting plasma glucagon averaged 108 μμg/ml (SEM ±10). In 12 juvenile-type diabetics fasting glucagon averaged 110 (±9) and in 33 adult-type diabetics the average was 114 (±8). The diabetic averages did not differ significantly from the nondiabetic subjects; however, when hyperglycemia was induced by glucose infusion in the nondiabetic subjects so as to simulate the fasting hyperglycemia of the diabetics, mean glucagon fell to 57 μμg (±8), which was significantly below the diabetic mean.

In 28 healthy subjects the infusion of arginine elicited a rise in glucagon of at least 100 μμg/ml with a peak level averaging 331 μμg/ml (±22) at 40 min. This response to arginine was diminished but not abolished during hyperglycemia induced by simultaneous glucose infusion. In everyone of 45 diabetic subjects tested the infusion of arginine elicited a rise in glucagon of at least 140 μμg/ml to levels significantly greater than in nondiabetics. The peak glucagon level in juvenile-type diabetics averaged 458 μμg/ml (SEM ±36) and in adult-type diabetics averaged 452 μμg/ml (SEM ±38). The glucagon response to arginine was unrelated to duration of diabetes, to body weight, type of diabetic treatment, or to other known factors. Marked hyperresponsiveness of glucagon to arginine infusion was observed in two patients with advanced Kimmelsteil-Wilson disease. Glucagon levels were markedly elevated in certain patients with severe diabetic ketoacidosis before treatment with insulin.

The findings suggest that alpha cell function is inappropriately increased in diabetes mellitus and could play a significant role in the diabetic syndrome.