To explore further the effects of the human amylin analog pramlintide on overall glycemic control and postprandial responses of circulating glucose, glucagon, and metabolic intermediates in type 1 diabetes mellitus, 14 male type 1 diabetic patients were examined in a double-blind, placebo-controlled, crossover study. Pramlintide (30 μg four times daily) or placebo were administered for 4 weeks, after which a daytime blood profile (8:30 am to 4:30 pm) was performed. Serum fructosamine was decreased after pramlintide (314 ± 14 μmol/L) compared with placebo (350 ± 14 μmol/L, P = .008). On the profile day, the mean plasma glucose (8.3 ± 0.7 v 10.2 ± 0.8 mmol/L, P = .04) and postprandial concentrations (incremental areas under the curve [AUCs] from 0 to 120 minutes) were significantly decreased during pramlintide administration (P < .01 for both) despite comparable circulating insulin levels (359 ± 41 v 340 ± 35 pmol/L). Mean blood glycerol values were reduced (0.029 ± 0.004 v 0.040 ± 0.004 mmol/L, P = .01) and blood alanine levels were elevated (0.274 ± 0.012 v 0.246 ± 0.008 mmol/L, P = .03) after pramlintide versus placebo. Blood lactate concentrations did not differ during the two regimens. During pramlintide administration, the AUC (0 to 120 minutes) for plasma glucagon after breakfast was diminished (P = .02), and a similar trend was observed following lunch. In addition, peak plasma glucagon concentrations 60 minutes after breakfast (45.8 ± 7.3 v 72.4 ± 8.0 ng/L, P = .005) and lunch (47.6 ± 9.0 v 60.9 ± 8.2 ng/L, P = .02) were both decreased following pramlintide. These data indicate that pramlintide (30 μg four times daily) is capable of improving metabolic control in type 1 diabetics. This may relate, in part, to suppression of glucagon concentrations. Longer-term studies are required to ascertain whether these findings are sustained over time.