Incretin Effect Due to Increased Secretion and Decreased Clearance of Insulin in Normal Humans

To assess the contribution of changes in insulin secretion and clearance to the incretin effect (greater insulinemia after oral than after intravenous glucose), 10 healthy subjects were studied after oral glucose (1 g/kg body wt) and again when glucose was infused intravenously at rates to match arterialized plasma glucose concentrations after oral glucose. Although basal and integrated plasma glucose did not differ between oral and intravenous glucose, integrated responses of insulin (3.3 ± 0.5 vs. 1.8 ± 0.4 mU ml⁻¹ · 240 min⁻¹, P < .001), C-peptide (456.5 ± 58.5 vs. 327.9 ± 46.3 μg · ml⁻¹ · 240 min⁻¹, P = .002), gastric inhibitory polypeptide, (16.8 ± 3.5 vs. −2.8 ± 1.0 μg · ml⁻¹ · 240 min⁻¹, P < .001), and insulin secretion (6.6 ± 1.1 vs. 4.7 ± 0.7 U.240 min⁻¹, P = .003) were greater with oral than intravenous glucose. However, insulin clearance, whether calculated as the molar ratio of integrated C-peptide to integrated insulin responses (6.9 ± 0.7 vs. 14.2 ± 3.8, P = .005) or from the formula insulin clearance equals insulin secretion divided by integrated insulin responses (1.1 ± 0.2 vs. 2.5 ± 0.7 L.min⁻¹ · m⁻², respectively, P = .002), was less for oral than for intravenous glucose. Therefore, the incretin effect is mediated both by increased secretion and decreased clearance of insulin.