Acute effects of GIP and GLP-1 receptor antagonism in totally pancreatectomized individuals: A randomized double-blind, placebo-controlled crossover study.

AIMS: The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) influence metabolism through strong effects on pancreatic hormone secretion but also in a pancreas-independent manner. Here, we investigated the isolated extrapancreatic effects of endogenous GIP and GLP-1 by applying hormone receptor antagonists in totally pancreatectomized individuals.

METHODS

Twelve totally pancreatectomized individuals each underwent four 270-min liquid mixed meal tests (480 kcal) in a randomized study design with infusions of the GIP receptor antagonist GIP(3-30)NH2 (800 pmol/kg/min), the GLP-1 receptor antagonist exendin(9-39)NH2 (450 pmol/kg/min), GIP(3-30)NH2 + exendin(9-39)NH2, and saline (placebo), respectively. Blood samples, appetite-related measures, heart rate, blood pressure, and ad libitum food intake data were collected. Participants continued their basal insulin but omitted bolus insulin in the morning of the experiment.

RESULTS

Infusions of GIP(3-30)NH2 and GIP(3-30)NH2 + exendin(9-39)NH2 attenuated meal-induced inhibition of bone resorption (carboxy-terminal collagen crosslinks) (nadir [mean ± SD] to 84 ± 9% and to 85 ± 8% of baseline, compared to placebo (64 ± 15%) (ps <0.05)). During exendin(9-39)NH2 and exendin(9-39)NH2 + GIP(3-30)NH2 co-infusion, GLP-1 plasma responses increased (ps <0.05). Infusion of GIP(3-30)NH2 or exendin(9-39)NH2 did not affect other measurements.

CONCLUSION

Endogenous GIP contributes to the regulation of postprandial bone resorption independently of pancreatic factors. In contrast, GIP receptor and/or GLP-1 receptor antagonism had no measurable effects on glucose metabolism, gastric emptying, appetite, food intake, triglycerides, or haemodynamics, supporting a pancreatic contribution to some of these effects of the endogenous hormones, although the surgical reconstruction may have influenced the sensitivity of the targets.