Additive Glucagonotropic and Insulinotropic Effects of Glucose‐Dependent Insulinotropic Polypeptide and Alanine in Fasted Healthy Men
10 affiliations
- 1Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen Hellerup Denmark
- 2Steno Diabetes Center Copenhagen, University of Copenhagen Herlev Denmark
- 3Department of Biomedical Sciences Faculty of Health and Medical Sciences, University of Copenhagen Copenhagen Denmark
- 4Department of Clinical Medicine Faculty of Health and Medical Sciences, University of Copenhagen Copenhagen Denmark
- 5Department of Clinical Pharmacology Bispebjerg and Frederiksberg Hospital, University of Copenhagen Copenhagen Denmark
- 6Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen Copenhagen Denmark
- 7Division of Endocrinology, Department of Medicine Duke University Durham North Carolina USA
- 8Duke Molecular Physiology Institute, Duke University Durham North Carolina USA
- 9Department of Endocrinology and Nephrology Nordsjællands Hospital, University of Copenhagen Hillerød Denmark
- 10Novo Nordisk A/S Bagsværd Denmark
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/m2) 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 bsAUCglucagon 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.
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BibTeX
@article{warnoe2026additive,
title = {{Additive Glucagonotropic and Insulinotropic Effects of Glucose‐Dependent Insulinotropic Polypeptide and Alanine in Fasted Healthy Men}},
author = {Julie Warnøe and Aliya M. Thomas and David S. Mathiesen and Mathilde K. Preskou and Joachim Størling and Mikkel B. Christensen and Bolette Hartmann and Jens J. Holst and Samuel A. J. Trammell and Jonathan E. Campbell and Thomas F. Dejgaard and Asger B. Lund and Filip K. Knop and Lærke S. Gasbjerg},
journal = {Diabetes, Obesity \& Metabolism},
year = {2026},
month = sep,
doi = {10.1111/dom.71273},
url = {https://doi.org/10.1111/dom.71273},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Additive Glucagonotropic and Insulinotropic Effects of Glucose‐Dependent Insulinotropic Polypeptide and Alanine in Fasted Healthy Men
AU - Julie Warnøe
AU - Aliya M. Thomas
AU - David S. Mathiesen
AU - Mathilde K. Preskou
AU - Joachim Størling
AU - Mikkel B. Christensen
AU - Bolette Hartmann
AU - Jens J. Holst
AU - Samuel A. J. Trammell
AU - Jonathan E. Campbell
AU - Thomas F. Dejgaard
AU - Asger B. Lund
AU - Filip K. Knop
AU - Lærke S. Gasbjerg
PY - 2026
DA - 2026/09/08
JO - Diabetes, Obesity & Metabolism
DO - 10.1111/dom.71273
UR - https://doi.org/10.1111/dom.71273
AB - 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/m2) 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 bsAUCglucagon 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.
SN - 1462-8902
SN - 1463-1326
ER -