Additive Glucagonotropic and Insulinotropic Effects of Glucose‐Dependent Insulinotropic Polypeptide and Alanine in Fasted Healthy Men

ABSTRACT Aims/Hypothesis Glucose‐dependent insulinotropic polypeptide (GIP) is a bidirectional glucose‐stabilising hormone potentiating insulin secretion at high glucose levels and glucagon secretion during normal‐to‐low plasma glucose levels. Preclinically, GIP and the amino acid alanine show synergistic glucagonotropic effects at low glucose levels. We therefore evaluated the separate and combined effects of GIP and alanine infusions on plasma glucose, glucagon and C‐peptide in fasted, healthy men. Methods In this placebo‐controlled, randomised, double‐blind crossover study, 10 healthy men (mean age 22.9 ± 2.82 years, BMI 23.7 ± 2.07 kg/m 2 ) underwent four experimental days involving 90‐min i.v. infusions of saline + GIP (6 pmol/kg/min for 10 min, then 4 pmol/kg/min for 80 min), alanine + saline (28 μmol/kg/min), alanine + GIP, and saline + saline after a 10‐h fast. Results As expected, the infusions increased circulating levels of alanine and GIP according to the intervention. Alanine increased glucagon secretion, while GIP induced a more moderate glucagonotropic effect. The combination of alanine and GIP resulted in an additive increase in glucagon secretion with bsAUC glucagon being 38% ± 5% higher compared to alanine + saline ( p > 0.01) and 83% ± 7% higher than saline + GIP ( p < 0.01). C‐peptide was likewise higher with alanine + GIP than with either single infusion ( p < 0.01). Saline + GIP transiently raised C‐peptide and resulted in lowered plasma glucose compared with placebo ( p < 0.01) and alanine + saline and alanine + GIP ( p < 0.01). Conclusions/Interpretation In fasting healthy men, both GIP and alanine stimulate pancreatic hormone secretion, and combined administration additively enhances glucagon and C‐peptide responses. Alanine availability modulates the metabolic actions of GIP and may influence its glucose‐regulatory effects under fasting conditions. Trial Registration: ClinicalTrials.gov identifier: NCT06881472.