Highlight
Endogenous glucose-dependent insulinotropic polypeptide (GIP) significantly contributes to the postprandial increase in splanchnic blood flow among individuals with type 2 diabetes. Infusion of a GIP receptor antagonist leads to a measurable reduction in mesenteric arterial blood flow and attenuates insulin secretion without affecting plasma glucose levels. This randomized, placebo-controlled, crossover study provides important insights into vascular and endocrine regulation during glucose metabolism in this population.
Study Background
Type 2 diabetes mellitus (T2DM) is characterized by impaired glucose metabolism and vascular dysfunction, contributing substantially to its morbidity and mortality worldwide. Understanding the mechanisms that regulate blood flow to the digestive organs following food intake (postprandial state) is clinically important as it affects nutrient absorption, hormonal secretion, and glycemic control.
Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone that facilitates insulin secretion post-meal. In healthy individuals, GIP also plays a vascular role by increasing blood flow in the superior mesenteric artery, ensuring adequate nutrient delivery and metabolic regulation. However, in T2DM, vascular responses related to GIP receptor activation are often impaired or absent, potentially contributing to metabolic dysregulation.
This study addresses the gap in understanding the contribution of endogenous GIP to splanchnic blood flow regulation and insulin secretion in individuals with T2DM, with implications for therapeutic targeting of incretin pathways.
Study Design
This was a randomized, single-blinded, placebo-controlled, crossover study conducted at Rigshospitalet, Copenhagen. Ten participants aged 20 to 80 years with T2DM (BMI 20–35 kg/m2, HbA1c between 48 and 75 mmol/mol) were recruited. Four intervention sessions were performed in randomized order:
- Oral glucose (75 g) plus intravenous GIP receptor antagonist GIP(3-30)NH2
- Oral glucose plus intravenous saline (placebo control)
- Oral water plus intravenous GIP receptor antagonist
- Oral water plus intravenous saline
Splanchnic blood flow was measured using phase-contrast magnetic resonance imaging (MRI) focusing on the superior mesenteric artery, truncus coeliacus, and portal vein. Additional assessments included liver volume and oxygenation, gallbladder volume, and plasma measurements of insulin, C-peptide, glucose, glucagon, and GIP. Investigators were aware of the interventions, but participants were blinded.
Key Findings
Postprandial Splanchnic Blood Flow: Oral glucose intake alone induced a significant 57% increase in blood flow through the superior mesenteric artery (95% CI 26, 88). When the GIP receptor antagonist was infused during oral glucose administration, the increase in arterial blood flow was attenuated by 15% (95% CI -2, 32), achieving statistical significance (p=0.012). No significant changes in blood flow were observed during oral water ingestion regardless of antagonist or saline infusion.
Insulin and C-peptide Secretion: Infusion of the GIP receptor antagonist during oral glucose markedly decreased insulin secretion as indicated by lower plasma insulin and C-peptide levels, alongside a reduced C-peptide/glucose ratio, compared to saline control. This confirms the pivotal role of endogenous GIP in enhancing postprandial insulin release in T2DM patients. Importantly, plasma glucose concentrations and glucagon levels remained unchanged, suggesting specific modulation of insulinotropic pathways.
Additional Observations: Liver volume, liver oxygenation, and gallbladder volume did not show significant alterations across the different interventions, indicating that the primary vascular effects were localized to splanchnic arterial circulation.
Expert Commentary
The study provides compelling evidence supporting a dual endocrine and vascular role of endogenous GIP in patients with T2DM, revealing that despite known impairments in GIP receptor signaling, GIP contributes significantly to postprandial splanchnic perfusion and insulin secretion.
The use of phase-contrast MRI enables precise, non-invasive quantification of dynamic blood flow changes, strengthening the study’s mechanistic insights. However, the single-blinded design and small sample size limit broad generalizability; investigator unblinding could potentially introduce bias. Larger studies with double-blind protocols and diverse populations are warranted to validate these findings.
Further, the lack of effect on plasma glucose despite reduced insulin secretion suggests compensatory mechanisms or differing insulin sensitivity warranting investigation. The findings enrich understanding of GIP’s vascular effects, adding to the paradigm that incretin hormones modulate not only endocrine function but also blood flow regulation in metabolic disease.
Conclusion
This study elucidates that endogenous GIP plays a significant role in mediating the postprandial increase in splanchnic blood flow and insulin secretion in individuals with type 2 diabetes. Therapeutic modulation of the GIP receptor pathway might hold promise for improving postprandial hemodynamics and beta-cell function, offering potential advantages in diabetes management. Further research exploring long-term clinical outcomes and mechanistic pathways is essential to advance translational applications.
Funding and Trial Registration
This research was supported by the Novo Nordisk Foundation. The trial is registered at ClinicalTrials.gov under identifier NCT06426823.
References
1. Rasmussen RS, Nielsen SW, Alstrup L, et al. GIP contributes to postprandial regulation of splanchnic blood supply in humans with type 2 diabetes: a randomised, single-blinded, placebo-controlled, crossover study. Diabetologia. 2026 Jul 2. PMID: 42393405.
2. Holst JJ, Vilsbøll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol. 2009;297(1-2):127-136.
3. Nauck MA, Meier JJ. Incretin hormones: Their role in health and disease. Diabetes Obes Metab. 2018;20 Suppl 1:5-21.