TOPLINE

A crossover trial found that oral sodium loading (OSL) led to greater urinary sodium excretion than intravenous sodium loading (ISL) in healthy individuals, but not in men with type 2 diabetes (T2D), suggesting impaired gut-kidney signalling. Acute intravenous infusion of the GLP-1 receptor agonist (RA) exenatide did not restore this response in men with T2D.

METHODOLOGY

• Researchers conducted a crossover trial to compare urinary sodium excretion following OSL vs ISL in men with T2D and to assess whether GLP-1 receptor agonism with exenatide could restore gut-kidney feed-forward signalling.
• They included 11 men (mean age, 60 years; mean BMI, 31.9) with T2D who had preserved kidney function and normoalbuminuria and were receiving metformin therapy with or without a sulphonylurea.
• Participants received three interventions in a random order, each separated by 1 week: ISL, OSL with placebo infusion (OSL-placebo), and OSL with exenatide infusion (10 µg over 5 hours; OSL-exenatide). Sodium loads were near equivalent (oral sodium-rich broth, 150 mmol; intravenous 3% NaCl, 154 mmol). All participants followed a standardised sodium intake < 90 mmol/d for 7 days before the first study visit and continued to adhere to this intake throughout the 3-week trial period.
• The primary outcome was cumulative urinary sodium excretion up to 24 hours post-intervention; secondary endpoints included 24-hour blood pressure, fractional sodium excretion, and measured glomerular filtration rate (mGFR).
• A comparison group of 10 healthy control individuals (mean age, 25 years) received equivalent OSL and ISL to evaluate natriuretic responses.

TAKEAWAY

• The three interventions showed similar median cumulative 24-hour urinary sodium excretion, with no statistically significant differences.
• Among healthy control individuals, urinary sodium excretion was significantly higher after OSL than after ISL at 2 hours (median, 12 vs 6 mmol; P = .042).
• No significant differences in 24-hour urinary volume or fractional sodium excretion were observed across the three interventions.
• Daytime and nighttime blood pressure, mGFR, and extracellular volume were comparable across the interventions.

IN PRACTICE

"Clarifying the mechanisms governing gut-kidney communication could redefine our understanding of sodium regulation in metabolic disease and support the development of targeted therapies designed to restore physiological sodium sensing, with potential benefits for salt-sensitive hypertension and cardiorenal protection," the authors wrote.

SOURCE

This study was led by Charlotte M. Mosterd, Amsterdam University Medical Center, Amsterdam, Netherlands. It was published online on September 12, 2026, in Clinical Kidney Journal.

LIMITATIONS

The investigation was designed as a mechanistic trial with a modest sample size. The trial used only short-term infusion of exenatide, so the results may have differed with longer-acting GLP-1 RAs or long-term therapy. In addition, faecal sodium excretion and sodium sequestration in tissues were not measured.

DISCLOSURES

This study received funding through a Rembrandt Grant (2018), with additional support for certain authors received through a Dutch Research Council Vici grant, a European Research Council Advanced Grant, and fellowships from the Dutch Kidney Foundation and the Dutch Diabetes Foundation. Some other authors reported receiving fees, grants, or research support; serving as consultants or advisory board members; and holding other ties with many pharmaceutical companies and organisations.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.