After the iv injection of 2 micrograms isoproterenol, peripheral plasma insulin and C-peptide concentrations were measured in 16 nonobese normal subjects and 53 maturity-onset diabetic subjects. Basal insulin (P < 0.01) and C-peptide (P < 0.05) levels were increased in obese diabetic subjects compared to nonobese normal subjects. Isoproterenol-stimulated insulin (P < 0.01) and C-peptide (P < 0.05) increments were increased in obese diabetic subjects compared to nonobese diabetic subjects. Hepatic insulin extraction, measured by comparing the ratios of insulin increment to C-peptide increment after isoproterenol injection, was decreased in both nonobese and obese diabetics compared to normals (P < 0.05). No significant differences in the ratios were found between nonobese and obese diabetics or between patients on diet or sulfonylurea therapy. Age, sex, duration of disease, familial predisposition to diabetes, and diabetic retinopathy did not influence the ratios. Isoproterenol-stimulated C-peptide increments (P < 0.05) and fasting blood glucose levels (P < 0.05) were decreased in diabetics showing decreased hepatic insulin extraction compared to diabetics with normal hepatic insulin extraction. Isoproterenol-stimulated insulin increments in diabetics showing decreased hepatic insulin extraction were higher than in normals (P < 0.05). These studies indicate that hepatic insulin extraction decreases in nonobese and obese diabetic subjects. It might be postulated that the lesser amount of secreted insulin is able to show biological activities more efficiently in diabetics with decreased hepatic insulin extraction.