Insulinotropic Properties of Synthetic Human Gastric Inhibitory Polypeptide in Man: Interactions with Glucose, Phenylalanine, and Cholecystokinin-8

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Abstract
The quantitative contribution of glucose-dependent insulinotropic polypeptide [gastric inhibitory polypeptide (GIP)] to the incretin effect after oral glucose (augmentation of insulin secretion over the degree that is explained by the glycemic rise) is not known. Therefore, hyperglycemic clamp experiments (8 mmol/L, corresponding to postprandial glucose concentrations) were performed in healthy volunteers, and synthetic human GIP was infused for 60 min at a rate (∼1.3 pmol/ kg-min) that results in plasma GIP concentrations similar to those occurring after oral glucose loads of 75 g. The MCR for exogenous GIP was ∼6 mL/kg-min; the decay after ceasing infusion was exponential with a t½ of about 18 min, and the resulting volume of distribution was about 140 mL/kg. At euglycemic (basal) plasma glucose concentrations (5.0 mmol/L) similar values were found. Insulin secretion was stimulated by hyperglycemia alone, but was greatly (2.3-fold based on Cpeptide) potentiated by GIP infusions (P ≤ 0.001 for integrated incremental values). When integrated incremental responses over 120 min of GIP, immunoreactive insulin, and immunoreactive C-peptide were compared after oral glucose and during GIP infusions, no significant differences were found. Peak glucose concentrations after oral glucose (7.6+−0.6 mmol/L) were similar to mean plasma glucose values during clamp experiments (8.2 +−0.1 mmol/L; P = 0.124). However, mean glucose concentrations after oral glucose were lower (6.0+−0.3 mmol/L; P = 0.0004). Additional infusion of sulfated cholecystokinin-8 (25 pmol/kg-h) or the amino acid phenylalanine (1.7 μmol/kg-min) did not further stimulate insulin secretion and had no influence on the pharmacokinetics of exogenous GIP. It is concluded that human synthetic GIP is insulinotropic in man and that this activity may well explain a substantial part of the incretin effect after oral glucose. There is no interaction with cholecystokinin or phenylalanine in concentrations found after mixed meals.