Study reveals cause of one of the main complications of bariatric surgery

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

A study conducted at Harvard University in the United States has identified the central role of serotonin (a hormone involved in mood regulation) in the development of post-bariatric hypoglycemia. The results were published in the Journal of Clinical Investigation and, according to the authors, point the way to possible treatments.

“We identified that this type of hypoglycemia 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 [in the pancreas] and GLP-1 [an acronym for glucagon-like peptide-1, produced in the small intestine in response to food intake] in the body,” says Rafael Ferraz-Bannitz, who conducted the research during an internship abroad supported by FAPESP. The group also received funding from the U.S. National Institutes of Health (NIH).

“We observed that in individuals with post-bariatric hypoglycemia, 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,” adds Ferraz-Bannitz, who is currently a postdoctoral fellow at Joslin Diabetes Center and Harvard Medical School.

According to the researcher, although the problem is common – in the United States, the country with the highest number of bariatric surgeries in the world, it is estimated to affect up to 30% of those who undergo surgery – little was known about the mechanisms that trigger postprandial hypoglycemia. “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 United States 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 emphasizes.

How it was done

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

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 hypoglycemia usually show signs).

The analysis showed changes mainly in the serotonin pattern. “For many metabolites, we noticed significant differences between the group that developed hypoglycemia and those who were asymptomatic. However, the difference in the serotonin pattern was what most caught our attention. Individuals with post-bariatric hypoglycemia 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,” Ferraz-Bannitz told Agência FAPESP.

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.

There is a relationship between serotonin and the secretion of insulin and GLP-1. 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 signaling 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 hypoglycemia by increasing the endogenous secretion of insulin and GLP-1,” comments the researcher.

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

Serotonin blocker

To better understand the role of serotonin in the development of post-bariatric hypoglycemia, tests were conducted on mice. “When serotonin was injected into the animals, they suffered a dizzying drop in blood glucose, inducing hypoglycemia – 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 hypoglycemia,” he says.

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 hypoglycemia 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 hypoglycemia,” 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 hypoglycemia.

Although they have shown that serotonin may be responsible for triggering the entire hypoglycemia 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. However, one of the hypotheses we raised is that hypoglycemia 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,” says Ferraz-Bannitz.

About FAPESP

The São Paulo Research Foundation (FAPESP) is a public institution with the mission of supporting scientific research in all fields of knowledge by awarding scholarships, fellowships and grants to investigators linked with higher education and research institutions in the state of São Paulo, Brazil. FAPESP is aware that the very best research can only be done by working with the best researchers internationally. Therefore, it has established partnerships with funding agencies, higher education, private companies, and research organizations in other countries known for the quality of their research and has been encouraging scientists funded by its grants to further develop their international collaboration.

 

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