The effects of glucose-dependent insulinotropic polypeptide on net splanchnic blood flow in lean humans.
Clinical Snapshot
PICO Framework
| P — Population | Healthy, lean adult male participants (n=8), without diabetes or metabolic disease |
| I — Intervention | Intravenous infusion of GIP at 1.5 pmol⁻¹ kg⁻¹ min⁻¹, administered alone or in combination with a hyperglycaemic-hyperinsulinaemic clamp |
| C — Comparator | Intravenous saline infusion, administered alone or in combination with a hyperglycaemic-hyperinsulinaemic clamp |
| O — Outcomes | Net splanchnic blood flow (SBF) measured by Fick's Principle using indocyanine green (ICG) as indicator via hepatic vein catheterisation |
Bottom Line
This small randomised crossover study (n=8) investigated whether intravenous GIP infusion alters net splanchnic blood flow in healthy lean males, both alone and during a hyperglycaemic-hyperinsulinaemic clamp. The primary finding was null: GIP did not significantly alter splanchnic blood flow under any tested condition (P=0.42). While the use of hepatic vein catheterisation with Fick's Principle is methodologically rigorous, the study is critically underpowered, reports no confidence intervals, and is restricted to a highly selected population that does not reflect patients receiving GIP-based therapies in clinical practice. The null result may reflect a true absence of acute GIP effect on net splanchnic haemodynamics in healthy individuals, or may simply reflect insufficient statistical power to detect a clinically meaningful difference. Importantly, these findings cannot be generalised to patients with obesity, type 2 diabetes, or cardiovascular disease — the populations in whom dual GIP/GLP-1 receptor agonists such as tirzepatide are prescribed. This study contributes useful mechanistic data to incretin physiology but should not be used to draw clinical conclusions about the haemodynamic safety or effects of GIP-based therapies in metabolically compromised patients. Larger, more representative studies are required.
Key Findings
P Value: P = 0.42 (overall comparison across all four conditions)
Effect Size: Not reported; the abstract states SBF was 'comparable across all experimental conditions' — no quantitative effect size or mean difference provided
Primary Outcome: Net splanchnic blood flow (SBF) measured by Fick's Principle with indocyanine green via hepatic vein catheterisation across 4 experimental conditions: GIP alone, saline alone, GIP with hyperglycaemic-hyperinsulinaemic clamp, saline with hyperglycaemic-hyperinsulinaemic clamp
Nnt Or Sensitivity: Not applicable for this mechanistic haemodynamic study; no NNT calculable from available data. The null result (P=0.42) suggests no statistically significant difference in SBF attributable to GIP infusion under any tested condition
Confidence Interval: Not reported
Clinical Application
The experimental methodology (hepatic vein catheterisation, ICG infusion, Fick's Principle measurement) is a specialised research technique not available in routine clinical practice. The findings are mechanistic and informative for physiological understanding rather than directly actionable in clinical settings. In Australia, tirzepatide (a dual GIP/GLP-1 receptor agonist) received TGA registration for type 2 diabetes management (Mounjaro) and obesity (Zepbound). Understanding the vascular and haemodynamic effects of GIP is increasingly relevant as these agents are prescribed more widely under PBS listings. This study's null finding regarding splanchnic blood flow in healthy lean males provides limited reassurance about haemodynamic safety in the broader clinical population, but cannot be extrapolated to patients with metabolic disease or cardiovascular comorbidities. RACGP guidelines for type 2 diabetes management increasingly incorporate GLP-1 and dual incretin therapies, and mechanistic data on their vascular effects in diverse populations are needed. Australian clinicians should note that this study does not address the haemodynamic effects of GIP in the populations most commonly treated in Australian primary care and endocrinology practice. The findings are directly applicable only to healthy, lean, young adult males. Extrapolation to patients with obesity, type 2 diabetes, insulin resistance, cardiovascular disease, or to women and older adults is not supported by this study. These excluded groups represent the primary clinical population receiving GIP-receptor agonist therapies.
Abstract
CONTEXT: Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone with potent vasoactive and metabolic effects in adipose tissue, but its effects on splanchnic blood flow (SBF) in humans remain unclear. Investigating potential regional differences is important for understanding the vascular actions of GIP in humans. OBJECTIVE: The aim of this study was to examine the effects of GIP on SBF, both independently and in combination with hyperglycemia and hyperinsulinemia. METHODS: In a randomized, controlled crossover study, 8 healthy, lean male participants underwent 4 separate experimental conditions. The interventions included intravenous infusions of either GIP at a rate of 1.5 pmol-1 kg-1 minute-1 or saline, administered alone or in combination with a hyperglycemic and hyperinsulinemic clamp, respectively. Splanchnic blood flow was measured by Fick's Principle after catheterization of a hepatic vein, using indocyanine green as indicator. RESULTS: Splanchnic blood flow remained comparable across all experimental conditions, including GIP and saline infusions, both with and without the hyperglycemic and hyperinsulinemic clamp (P = .42). CONCLUSION: Under the applied conditions, GIP does not appear to play a substantial role in the acute regulation of net SBF, either alone or in combination with induced hyperglycemia and hyperinsulinemia.
References
- 1.Asmar, M., Bülow, J., Holst, J. J., & Asmar, A. (2026). The effects of glucose-dependent insulinotropic polypeptide on net splanchnic blood flow in lean humans. The Journal of Clinical Endocrinology & Metabolism. https://doi.org/10.1210/clinem/dgag084
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