Disproportionate hyperproinsulinemia is a feature of β-cell dysfunction in type 2 diabetes. It has been hypothesized that this abnormality represents an intrinsic abnormality of the β-cell and/or may result from an increase in β-cell secretory demand. To address this, six patients with type 2 diabetes and six age- and BMI-matched normal subjects received a combined 3-h insulin and somatostatin clamp to decrease β-cell secretory demand. An arginine stimulation test was performed before and at the end of the clamp to measure β-cell peptide release. In keeping with the reduction in secretory demand, C-peptide levels were suppressed by 60–80% during the clamp, as were proinsulin (PI) levels. The arginine-stimulated PI/C-peptide ratio decreased in the diabetic subjects from 4.4 ± 1.5% before to 1.8 ± 0.5% after the clamp (P < 0.01). This latter ratio was similar to that observed in the normal subjects before the somatostatin infusion (1.5 ± 0.3%). In the normal subjects, after the clamp the PI/C-peptide ratio had decreased to 0.8 ± 0.3% (P < 0.01). Thus, the postclamp PI/C-peptide ratio in the subjects with type 2 diabetes was elevated compared with that in the normal subjects (P < 0.05). Based on these observations, while relief of secretory demand on β-cells by somatostatin decreases the disproportionate elevation in PI levels in patients with type 2 diabetes, the failure to normalize this measure suggests that an intrinsic abnormality of β-cell function exists in subjects with type 2 diabetes that may be aggravated by increased secretory demand.