Objectives: To examine whether glucagon-like peptide-1 (GLP-1), which has been suggested as a new therapeutic agent in type 2 diabetes, affects circulating islet amyloid polypeptide (IAPP), a B-cell peptide of potential importance for diabetes pathophysiology. Design: GLP-1 was administered in a buccal tablet (400 mg) to seven healthy subjects and nine subjects with type 2 diabetes. Serum IAPP and insulin levels were measured before and after GLP-1 administration.Results: In the fasting state, serum IAPP was 4.1 Ϯ 0.3 pmol/l in the controls vs 9.8 Ϯ 0.9 pmol/l in the subjects with type 2 diabetes (P < 0.001). IAPP correlated with insulin only in controls (r=0.74, P ¼ 0.002) but not in type 2 diabetes (r ¼ 0.26, NS). At 15 min after GLP-1, circulating IAPP increased to 6.0Ϯ0.5 pmol/l in controls (P ¼ 0.009) and to 13.8Ϯ1.2 pmol/l in type 2 diabetes (P ¼ 0.021). In both groups, serum insulin increased and blood glucose decreased compared with placebo. In controls serum IAPP increased in parallel with insulin (r ¼ 0.79, P ¼ 0.032), whereas in type 2 diabetes the increase in IAPP did not correlate with the increase in insulin. Conclusion: Type 2 diabetes is associated with elevated circulating IAPP; GLP-1 stimulates IAPP secretion both in healthy human subjects and in type 2 diabetes; IAPP secretion correlates with insulin secretion only in healthy subjects and not in type 2 diabetes.