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Serotonin plays key role in the development of post-bariatric hypoglycaemia

A study conducted at Harvard University has identified the central role of serotonin - a hormone involved in mood regulation - in the development of post-bariatric hypoglycaemia.

Credit: Journal of Clinical Investigation (2024). DOI: 10.1172/JCI180157
Credit: Journal of Clinical Investigation

"We identified that this type of hypoglycaemia is associated with the dysregulation of serotonin levels in the blood, a hormone that, in addition to controlling mood, is also capable of stimulating the secretion of the hormones insulin and GLP-1 in the body," explained Rafael Ferraz-Bannitz, who conducted the research during an internship abroad.


Postprandial hypoglycaemia is one of the main complications of bariatric surgery and can affect up to 30% of patients. Unlike ordinary hypoglycaemia, in which low blood sugar is usually associated with little food, postprandial hypoglycaemia occurs after meals and causes symptoms such as sweating, tremors, weakness and even mental confusion. Postprandial hypoglycaemia is estimated to affect up to 30% of those who undergo surgery.


"We observed that in individuals with post-bariatric hypoglycaemia, serotonin levels are low when they're fasting. However, after a meal, they increase significantly, unlike patients without symptoms or people who've not had bariatric surgery, whose serotonin levels decrease after a meal," explained Ferraz-Bannitz, who is currently a postdoctoral fellow at Joslin Diabetes Center and Harvard Medical School. "It's extremely debilitating. Patients even concentrate their food in just one meal a day because they know they're going to be very sick. Many are unable to work, drive or have even the slightest quality of life. And it's a problem that can affect up to 83,000 people every year in the US alone. In Brazil, the number is likely to be high as well, since it's the country that performs the second most bariatric surgeries in the world," the researcher emphasises.


The researchers analysed 189 metabolites (compounds produced by the enzymatic reactions of the metabolism) in the blood of three groups of individuals: 13 patients with post-bariatric hypoglycaemia; 10 who had undergone surgery but had no symptoms; and eight individuals who had neither undergone surgery nor had hypoglycaemia.


Blood was taken while the participants were fasting, 30 minutes after taking a shake (made up of proteins, carbohydrates, and lipids), and two hours after drinking the drink (the time when patients with postprandial hypoglycaemia usually show signs). The analysis showed changes mainly in the serotonin pattern.


"For many metabolites, we noticed significant differences between the group that developed hypoglycaemia and those who were asymptomatic,” added Ferraz-Bannitz. "However, the difference in the serotonin pattern was what most caught our attention. Individuals with post-bariatric hypoglycaemia had very low fasting serotonin levels. Curiously, in response to the meal, there was a fivefold increase in the levels of this hormone in these individuals.”


The researchers also found other important metabolic alterations.


"In the fasting state, these individuals showed a decrease in the levels of ten amino acids, including tryptophan [a precursor of serotonin], as well as biomarkers related to diabetes. On the other hand, we noticed an increase in the levels of ketones, bile acids, and some metabolites from the Krebs cycle )which is part of the energy production process in cells)," he reports.


According to Ferraz-Bannitz, previous in vitro studies had already shown that serotonin is able to stimulate the secretion of insulin in pancreatic beta cells and GLP-1 in intestinal neuroendocrine cells.


It is worth noting that insulin is responsible for transporting sugar from the blood to the body's cells, where it is used as a source of energy. GLP-1, on the other hand, is a hormone that is released in the presence of glucose and provides a sense of satiety by signalling to the brain that the individual is full.


"In this study, we've demonstrated in vivo that serotonin administration in mice was able to induce hypoglycaemia by increasing the endogenous secretion of insulin and GLP-1."


Thus, the results suggest that the post-meal increase in serotonin observed in individuals with post-bariatric hypoglycaemia may contribute to the increase in insulin secretion and, consequently, the development of hypoglycaemia and symptoms such as dizziness, tremors and mental confusion.

To better understand the role of serotonin in the development of post-bariatric hypoglycaemia, tests were conducted on mice.


"When serotonin was injected into the animals, they suffered a dizzying drop in blood glucose, inducing hypoglycaemia, a condition very similar to that of patients. When we evaluated the plasma of the mice, we observed that the injection of serotonin increased the secretion of insulin and GLP-1, the same hormones that are elevated in individuals who've developed postprandial hypoglycaemia.”


The researchers then decided to test the use of serotonin antagonists as a treatment strategy in mice.


"The use of ketanserin, a well-known serotonin receptor 2 blocking drug, proved to be very effective in the experiments. It was able to block serotonin-induced hypoglycaemia in the animals and promote a reduction in insulin and GLP-1 secretion. This is a promising result that suggests a potential therapeutic target for individuals with post-bariatric hypoglycaemia," he concludes.

 

With the results, the group, coordinated by Mary-Elizabeth Patti, professor at Harvard Medical School and senior investigator at the Joslin Diabetes Center, plans to conduct new clinical trials to prove the effectiveness of this potential treatment for people suffering from postprandial hypoglycaemia.


Although they have shown that serotonin may be responsible for triggering the entire hypoglycaemia process in people who have had bariatric surgery, the researchers still do not know what causes this difference in the pattern of the hormone.


"This is one of the acknowledged limitations of the study, as we didn't have access to biopsies of the intestines of these individuals to assess the amount and activity of serotonin-producing cells," concluded Ferraz-Bannitz. However, one of the hypotheses we raised is that hypoglycaemia may be associated with some alteration in the microbiota, bile acids, or other factors in the intestine—the organ that produces 90% of the body's serotonin. Future studies in Professor Patti's laboratory could answer this question.”


The findings were featured in the paper, ‘Postprandial metabolomics analysis reveals disordered serotonin metabolism in post-bariatric hypoglycemia’, published in the Journal of Clinical Investigation. To access this paper, please click here

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