Archive for month: December, 2024

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.

Reference:

Rafael Ferraz-Bannitz, Cameron Cummings, Vissarion Efthymiou, Pilar Casanova Querol, Postprandial metabolomics analysis reveals disordered serotonin metabolism in post-bariatric hypoglycemia, Journal of Clinical Investigation, DOI:10.1172/JCI180157 

A new study published in the Journal of American Medical Association showed that the majority of individuals tolerated the brexpiprazole + sertraline therapy, which reduced posttraumatic stress disorder (PTSD) symptoms.

4 clusters of symptoms are indicative of posttraumatic stress disorder (PTSD) which are, intrusive reliving of the event, avoidance of internal and external connections with the trauma, unfavorable changes in mood and thought patterns, and increased arousal and reactivity. In the US and across the world, PTSD is quite common (estimates vary between research).

The only medications for PTSD that have been authorized by the US Food and Drug Administration are sertraline and paroxetine, both of which are selective serotonin reuptake inhibitors (SSRIs). Yet, 42% of PTSD patients in a large meta-analysis did not improve with SSRI therapy. Atypical antipsychotics like brexpiprazole have a wide range of pharmacological effects on the dopaminergic, serotonergic, and noradrenergic neurotransmitter systems, which are linked to mental disorders like PTSD. This trial looked at the effectiveness, safety, and tolerability of treating PTSD with a combination of brexpiprazole and sertraline (brexpiprazole + sertraline) against sertraline + placebo.

From October 2019 to August 2023, a double-blind, randomized clinical study using a parallel design was carried out. The investigation was conducted at 86 clinical trial locations in the United States and included a 1-week placebo run-in period followed by an 11-week randomized, parallel-arm period (with a 21-day follow-up). Adult PTSD outpatients (volunteer sample) were recruited. From randomization (week 1) to week 10, the main outcome was the difference in the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total score, which gauges the intensity of 20 PTSD symptoms, between brexpiprazole + sertraline and sertraline + placebo. Adverse incidents were included in safety evaluations.

A total of 1327 people had their eligibility evaluated. 416 individuals were randomly assigned following 878 screen failures. Brexpiprazole + sertraline had a completion rate of 137 out of 214 individuals (64.0%), whereas sertraline + placebo had a completion rate of 113 out of 202 participants (55.9%). In comparison to sertraline + placebo, brexpiprazole + sertraline showed a statistically significant improvement in the CAPS-5 total score at week 10 (LS mean difference: −5.59).

Also, all important secondary and additional effectiveness endpoints were satisfied. For brexpiprazole + sertraline, treatment-emergent adverse effects included nausea, exhaustion, weight gain, and somnolence, with an incidence of 5% or higher. Adverse event-related discontinuation rates were 20 of 196 individuals (10.2%) for sertraline + placebo and 8 of 205 participants (3.9%) for brexpiprazole + sertraline. Overall, this study found the effectiveness of brexpiprazole + sertraline as a novel, effective therapy for PTSD.

Source:

Davis, L. L., Behl, S., Lee, D., Zeng, H., Skubiak, T., Weaver, S., Hefting, N., Larsen, K. G., & Hobart, M. (2024). Brexpiprazole and Sertraline Combination Treatment in Posttraumatic Stress Disorder. In JAMA Psychiatry. American Medical Association (AMA). https://doi.org/10.1001/jamapsychiatry.2024.3996

New global study reports a 60% drop in global mortality from diarrheal diseases, but children and the elderly still have the highest death rates, particularly in sub-Saharan Africa and South Asia. That’s according to the latest and most comprehensive study from the Global Burden of Disease (GBD) conducted by the Institute for Health Metrics and Evaluation (IHME) and published today in The Lancet Infectious Diseases journal.

In 2021, diarrheal diseases caused 1.2 million deaths worldwide, which is a substantial drop from 2.9 million deaths recorded in 1990. The largest decrease was among children under 5 years with a 79% decline, but that age group still had the highest mortality rate among all ages, followed by those 70 years and older, making it a leading cause of death across all ages.

Regional disparities in diarrheal disease deaths remain stark. Regions with high-income countries see less than one death per 100,000 population in children under 5. In sub-Saharan Africa, more than 150 deaths per 100,000 population were in children under 5, which is the highest mortality rate for children in that age group when compared to all other global regions. South Asia had the highest mortality rates among those aged 70 years and older with 476 deaths per 100,000. Diarrheal mortality rates declined substantially across age groups in most super-regions.

Researchers analyzed the overall burden of diarrheal diseases by measuring disability-adjusted life years, or DALYs. That’s the sum of the number of years of life lost and the number of years lived with disability. DALYs declined from 186 million in 1990 to 59 million in 2021, but 31 million of those 2021 DALYs were in children younger than 5 years. Major risk factors for diarrheal DALYs include poor neonatal conditions such as low birthweight and preterm birth, child growth failure, unsafe water, and poor sanitation.

The decline in diarrheal mortality and morbidity suggests health interventions are working. They include oral rehydration therapy, enhanced water, sanitation, and hygiene infrastructure, and global immunization efforts against rotavirus. Preventive measures against key risk factors and pathogens could further reduce the global burden; according to researchers’ estimates, if leading risk factors were eliminated around the world, DALYs could be reduced to less than 5 million in 2021.

“The new granular-level analysis by our study can further help decision-makers better target and prioritize the evidence-based strategies to fight diarrheal diseases,” said Dr. Hmwe Hmwe Kyu, study author and associate professor at IHME. “In spite of the encouraging progress made combating diarrheal mortality, a multipronged approach is required to simultaneously tackle live-saving solutions while also prioritizing preventive interventions to alleviate burdens on health systems.”

WHO-recommended rotavirus vaccines, now administered in over 100 countries, have led to substantial reductions in hospitalizations and deaths from diarrhea. With more vaccines being added to WHO’s Expanded Programme on Immunization, combining them could reduce manufacturing costs and make scheduling easier.

“In addition to increasing immunizations globally, we need to expand vaccine development to target specific pathogens that cause diarrheal diseases and consider combining vaccines to create a broader protection. This approach would be efficient and cost-effective for regions that are hit hardest by this global health crisis,” said Dr. Heidi Soeters, epidemiologist with WHO’s Department of Immunization, Vaccines and Biologicals.

For the first time, this research incorporates pathogen-specific data from WHO’s Global Pediatric Diarrhea Surveillance network from many high-burden countries.

The GBD is the most comprehensive assessment of health, which includes granular estimates of burden across all age groups, sexes, and locations, as well as risk factors for 204 countries and territories from 1990 to 2021. More data on the burden of diarrheal diseases are available via IHME’s visualization tools.

Reference:

Kyu, Hmwe Hmwe et al., Global, regional, and national age-sex-specific burden of diarrhoeal diseases, their risk factors, and aetiologies, 1990–2021, for 204 countries and territories: a systematic analysis for the Global Burden of Disease Study 2021, The Lancet Infectious Diseases,DOI:10.1016/S1473-3099(24)00691-1 

China: A recent single-center, prospective cohort study has revealed potential risks associated with the use of low-dose prednisone during pregnancy, particularly concerning glucose metabolism. The study, published in the Journal of Reproductive Immunology, found that prolonged use of low-dose prednisone during pregnancy may disrupt postprandial blood glucose levels and elevate the risk of developing gestational diabetes mellitus (GDM).

New potential therapeutic targets have been identified for diabetic kidney disease (DKD) – the leading cause of kidney failure in the world – that could see patients treated with new gene and drug therapies preventing the disease’s progression into end stage kidney failure. The study is published in Nature Communications.

The University of Bristol-led breakthrough, involving scientists from the UK, Europe and USA, discovered specific cell changes in the kidney caused by insulin resistance – a major driver of diabetic kidney disease.

Despite its prevalence, the molecular mechanisms underlying DKD development remain poorly understood. Researchers sought to understand the cellular and molecular changes occurring in the kidney (specifically the glomerulus and proximal tubule) which is key to understanding the mechanisms underlying the disease, identifying therapeutic targets and biomarker candidates.

Building on the team’s previous work in this area, the team examined the changes caused by insulin-resistance in four types of kidney cells, and then compared these changes with kidney biopsies from patients with early and late diabetic kidney disease.

The study revealed multiple ‘common’ and ‘cell specific’ changes caused by insulin-resistance representing new targets for pharmacological or targeted gene therapy approaches.

Richard Coward, Professor of Renal Medicine at the University of Bristol and Consultant Paediatric Nephrologist at Bristol Royal Hospital for Children, and one of the study’s lead authors said: “Diabetic kidney disease is the leading cause of end-stage kidney failure in the world, occurring in up to 50 per cent of individuals with diabetes. Patients with end stage kidney disease require daily dialysis or a kidney transplant to survive. If we can find a way to prevent this, it would save and improve countless lives.

“Our aim now is to take several of these therapeutic targets forward in a pre-clinical setting, and hopefully through clinical trials.”

Dr Aisling McMahon, Executive Director of Research at Kidney Research UK, added: “We are determined to find ways to tackle diabetic kidney disease. By providing detailed information on genes and pathways involved in diabetic kidney disease, Professor Coward’s work takes us one step closer to a more complete understanding of this condition, but also towards discovering new targeted agents to prevent it.” 

Reference:

Abigail C. Lay et al, Profiling of insulin-resistant kidney models and human biopsies reveals common and cell-type-specific mechanisms underpinning Diabetic Kidney Disease, Nature Communications (2024). DOI: 10.1038/s41467-024-54089-1