Lirglutide-based drugs are used for diabetes and obesity. They also affect water and salt balance. A study in the journal Science Advances showed that the drug directly lowers the level of the hormone that retains water and changes signals from the brain to the kidneys.
Liraglutide belongs to glucagon-like peptide-1 receptor agonists. Such agents mimic a digestive hormone, cause satiety and stimulate insulin release. Patients taking them often lose water and sodium in urine. Nausea and diarrhea can also lead to dehydration. Until now, the mechanism of the effect on water balance was unclear.
The key hormone regulating water is arginine vasopressin. It is produced by brain neurons, then stored in the pituitary gland (a gland at the base of the brain). When water is scarce, the pituitary releases the hormone into the blood. It reaches the kidneys and forces them to reabsorb water. Michael Greenwood of the University of Bristol and colleagues tested whether liraglutide disrupts this chain.
First, a small study was conducted with sixteen healthy adults. Their blood and urine were taken before and after a single dose of liraglutide. Participants also drank a slightly salty beverage. The analysis showed that the drug quickly lowered the level of arginine vasopressin in the blood. The level of copeptin, a marker released together with the hormone, also fell. Plasma potassium decreased, while urine sodium increased.
Because people take such drugs for a long time, the researchers moved to an animal model. Rats of both sexes were given liraglutide or placebo for fourteen days, and food and water intake were monitored. In the first hours, the drug reduced both. Over two weeks, the rats on the drug began drinking more water relative to food. Their normal drinking pattern was disrupted, indicating a failure of fluid regulation.
Then the tissues that produce and store the hormone were studied. In the hypothalamus (the brain area where it is produced), no changes in gene activity were found. In the pituitary gland, the amount of the hormone itself decreased. In females after fourteen days, the level of copeptin in the blood was also lower. It appears the drug blocked the release of the hormone from storage.
To understand the cause, the scientists analyzed proteins in pituitary tissue after four hours and after fourteen days. They mapped protein abundance and chemical labels on them. Such labels work as molecular switches, changing the behavior of proteins. The picture differed by treatment duration and by the sex of the animal. After fourteen days, females had a large-scale shift in proteins, while males had a smaller one.
Many of the altered proteins control the packaging and release of hormones. Proteins that direct microscopic storage vesicles with arginine vasopressin changed especially. Two such proteins in females after two weeks of treatment received special labels. In a laboratory cell culture, imitation of these labels directly suppressed the release of a marker similar to the hormone. This confirmed that the drug changes the control of hormone stores at the microscopic level.
Finally, the kidneys were studied. Normally, arginine vasopressin tells the kidneys to deploy water channels, aquaporins, for reabsorbing fluid. In treated rats, the genes for these channels were less active. Labels on the aquaporin proteins themselves indicated their destruction rather than use. The drug weakened the kidneys' ability to retain water.
The study has limitations. The human part was small: healthy volunteers, one dose. There were not enough participants to assess differences between men and women. Urine volume was not measured directly in the animals. Future work should show how hormonal shifts affect long-term use. Understanding the mechanisms will help doctors assess kidney and heart risks in patients with fluid retention.