Incretin Effects of Increasing Glucose Loads in Man Calculated from Venous Insulin and C-Peptide Responses*

TLDR

Peripheral insulin reflects both secretion and hepatic removal, and the observed discrepancy indicates that insulin elimination kinetics differ between oral and IV glucose, likely due to gastrointestinal factors that reduce hepatic extraction. The study measured integrated insulin secretion rates from peripheral venous C‑peptide using two‑compartment kinetic analysis in six healthy subjects after oral glucose loads of 25, 50, and 100 g and matched isoglycemic IV infusions, with similar hormone profiles achieved by infusing ~20 g IV glucose for each oral load. The results showed that oral glucose elicits a larger incretin‑mediated insulin response than IV glucose, with the incretin contribution increasing with higher glucose loads, and that peripheral insulin measurements overestimate secretion because oral ingestion reduces hepatic insulin extraction.

Abstract

Integrated insulin secretion rates calculated from peripheral venous C-peptide measurements by two-compartment kinetic analysis were measured in six young normal subjects after increasing oral glucose loads of 25, 50, and 100 g and respective isoglycemic glucose infusions. The differences in B-cell secretory responses between oral and iv glucose challenges were attributed to factors other than glycemia itself (incretin effect). Both insulin and C-peptide concentrations as well as calculated integrated insulin secretion rates increased with increasing oral glucose loads. Due to the similarity in the glucose profiles after all oral loads, almost identical amounts of iv glucose (∼20 g) were infused in all "isoglycemic" infusion experiments, with resulting similar hormone profiles and insulin secretion rates. The percent contribution of incretin factors to total immunoreactive insulin responses after 25, 50, and 100 g glucose (85.6%, 74.9%, and 93.0%; response to oral load, 100%) was significantly higher than their contribution to integrated C-peptide responses (27.6-62.9%) or calculated integrated insulin secretion rates (19.2-61.0%). These findings indicate that the degree of incretin stimulation of insulin secretion depends on the amount of glucose ingested. A discrepancy between the estimates of the incretin effect derived from peripheral venous insulin responses, on the one hand, and C-peptide responses or calculated insulin secretion rates, on the other hand, exists. Inasmuch as peripheral insulin values reflect both insulin secretion and hepatic insulin removal, this discrepancy suggests that elimination kinetics of insulin differ between oral and iv glucose administration. This difference can be related to a significantly reduced fractional hepatic insulin extraction after oral (46.9-54.6%) compared to iv (63.4- 76.5%) glucose administration when calculated by a three-compartment kinetic model. This reduction in fractional hepatic insulin extraction could be caused by gastrointestinal factors (hormones or nerves) stimulated in the course of glucose ingestion.