The relationships between first-phase insulin secretion to i.v. glucagon and i.v. arginine were studied in 19 healthy adult volunteers (Group I) and in 21 subjects at risk for Type 1 (insulin-dependent) diabetes mellitus with either a "normal" (n = 11; Group IIa) or a "low" insulin response to i.v. glucose (n = 10; Group IIb). Groups I and IIa displayed similar insulin responses to the three secretagogues. In contrast, Group IIb demonstrated lower insulin responses to both glucagon and arginine than control subjects (p less than 0.007 and p less than 0.04 respectively) or than "normo-responders" to glucose (p less than 0.007 and p less than 0.04 respectively). In Group IIb however, arginine-stimulated insulin release was increased compared to the response to glucose (p less than 0.006), while glucagon and glucose led to non-statistically different responses. Five "low-responders" developed Type 1 diabetes. As a group, they displayed lower responses to glucagon and to arginine than subjects who up to now have not developed the disease (p less than 0.05 and p less than 0.0003 respectively). In the subjects who progressed to diabetes, the responses to glucose and glucagon were similarly blunted. In the "low-responders" who have not developed the disease, no statistical difference could be detected between mean responses to glucagon and glucose, but four out of these five subjects had a glucagon-stimulated response within the control range and higher than their corresponding response to glucose. Arginine led to a higher stimulation than glucose, in subgroups that either progressed to diabetes (p less than 0.006) or did not (p less than 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)