In previous studies with glucagon-like peptide-1 (GLP-1) we have observed that this peptide modulates fluid intake and increases renal sodium excretion in healthy volunteers and in patients with diabetes mellitus type 2. The effect of GLP-1 on thirst, water intake and on osmoregulation has, however, not been examined in detail in humans. Seventeen healthy male subjects were enrolled in two double-blind, placebo-controlled studies. In study part A, 8 volunteers participated in a protocol with an intravenous salt load of 26.7±0.9 g comparing the effect of an infusion of GLP-1 (1.5 pmol/kg× min) to isotonic saline (placebo). Sodium excretion and water intake were measured. In part B, 9 volunteers were challenged with an oral salt load of 27.7±0.5 g; sodium excretion and water intake were determined comparing an infusion of GLP-1 (1.5 pmol/kg× min) to isotonic saline (placebo). In part C, intestinal biopsies along the gastrointestinal tract were obtained from 14 healthy subjects. Expression of human GLP-1 receptor mRNA was measured by real-time polymerase chain reaction. In study part A, an increase in renal sodium excretion was demonstrated: FeNa rose from 1.6±0.3 (placebo) to 2.7±0.2%(GLP-1; p= 0.0005). There was no difference in water consumption between the two treatments: 1,291±69 (saline) vs. 1,228±74 ml (GLP-1; p= 0.49). In part B, an oral salt challenge of 27.7±0.5 g led to an increased renal excretion of sodium during GLP-1: FeNa increased from 1.6±0.2%(placebo) to 2.0±0.2%(GLP-1; p= 0.012). In contrast to part A, oral water intake was reduced by 36% under GLP-1 treatment: 1,848±331 ml (placebo) vs. 1,181±177 ml (GLP-1; p= 0.0414). Three subjects in part B did not finish treatment with GLP-1 because of diarrhea. Human GLP-1 receptor mRNA expression was highest in the proximal human small intestine compared to terminal ileum and colon (p< 0.02). GLP-1 acts on renal tissue reducing sodium absorption, probably via similar sodium transporters, which also may be localized in the gastrointestinal tract. This hypothesis needs to be confirmed by further studies.