Fasting plasma islet amyloid polypeptide concentrations and their responses to an oral glucose load were determined in non-diabetic control subjects and patients with abnormal glucose tolerance in relation to the responses of insulin or C-peptide. Plasma islet amyloid polypeptide was measured by radioimmunoassay. In the non-diabetic control subjects, fasting plasma islet amyloid polypeptide was 6.4 +/- 0.5 fmol/ml (mean +/- SEM) and was about 1/7 less in molar basis than in insulin. The fasting islet amyloid polypeptide level rose in obese patients and fell in patients with Type 1 (insulin-dependent) diabetes mellitus. In non-obese patients with impaired glucose tolerance and Type 2 (non-insulin-dependent) diabetic patients without insulin therapy, the level was equal to that of the control subjects, but a low concentration of islet amyloid polypeptide relative to insulin or C-peptide was observed in the non-obese Type 2 diabetic group. The patterns of plasma islet amyloid polypeptide responses after oral glucose were similar to those of insulin or C-peptide. However, compared to non-obese patients, a hyper-response of islet amyloid polypeptide relative to C-peptide was noted in obese patients who had a hyper-response of insulin relative to C-peptide. This study suggests that basal hypo-secretion of islet amyloid polypeptide relative to insulin exists in non-obese Type 2 diabetes and that circulating islet amyloid polypeptide may act physiologically with insulin to modulate the glucose metabolism.